2013 Article Abstracts
2013 Article Abstracts
2013 Article Abstracts
DOI 10.1007/s12031-012-9923-1
Abstracts
The 21st Annual Meeting of the Israel Society
for Neuroscience &
The First Binational Australian-Israeli
Meeting in Neuroscience
Hilton Queen of Sheba
Eilat, December 15–18, 2012
All abstracts appear in alphabetic order based on the last name of the presenting author (underlined name)
S2 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
Rony Azouz
Ben-Gurion University
Hagit Eldar-Finkelman
Tel Aviv University
Ilan Lampl
Weizmann Institute of Science
Orly Weinreb
Technion Haifa
Rami Yaka
The Hebrew University of Jerusalem
Raz Yirmiya
The Hebrew University of Jerusalem
Abstracts
Journal of Molecular Neuroscience 2012
The 21st Annual Meeting of the Israel Society for Neuroscience
& The First Binational Australian-Israeli Meeting in Neuroscience
Hilton Queen of Sheba
Eilat, December 15–18, 2012
The Israel Society for Neuroscience gratefully acknowledges the generous support of
The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem
The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar Ilan University
The Nella & Leon Benoziyo Center for Neurological Diseases, Weizmann Institute of Science
The Nella & Leon Benoziyo Center for Neurosciences, Weizmann Institute of Science
Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva
Cannabinoids ameliorate impairments induced by chronic the visceral consequence for such long delay. We hypothesized
stress to synaptic plasticity and short-term memory that kinase activity or kinases activity loops underlie this form
Abush H, Akirav I* of lingering memory. In order to test our hypothesis we first
Dept. of Psychology, University of Haifa examined carefully the temporal limitation of the association.
Our behavioral results in rats show that CTA can be established
Background: Repeated stress is one of the environmental with the CS-US intervals of up to 8 hours. In addition, there is a
factors that precipitates and exacerbates mental illnesses like negative correlation of aversive taste memory with the CS-US
depression and anxiety. We have previously shown that canna- interval: the greater the CS-US interval, the weaker the CTA
binoids prevent the impairment of learning and memory induced conditioning. Immunoblotting analysis following novel taste
by acute stress. Here we aimed to find whether chronic canna- learning in gustatory cortex and basolateral amygdala reveals
binoid treatment would alleviate the long-term effects of expo- clear and transient phosphorylation of ERK I/II, GluA1-
sure to chronic restraint stress on synaptic plasticity and short- AMPARs and GluN2B-NMDARs. However, the activity of
term memory. Since glucocorticoids have potent modulatory other receptors and kinases are correlated with delayed time of
effects on emotional memory, we also measured glucocorticoid association. We now try to identify causality between these
receptors (GRs) expression levels in the amygdala, hippocam- molecular pathways and remote associative time.
pus, prefrontal cortex (PFC) and nucleus accumbens (NAc).
Results: Late adolescence rats were exposed to 1 hr chronic Functional imaging of local networks in the mouse
restraint stress for two weeks followed by i.p. treatment with olfactory bulb
vehicle or with the CB1/CB2 receptor agonist WIN55,212-2 Adam Y 1,2, Mizrahi A* 1,2
1
(WIN; 1.2 mg/kg). Thirty days after the last exposure to stress, Dept. of Neurobiology, Inst. for Life Sciences
2
rats demonstrated impaired long-term potentiation (LTP) in The Edmond and Lily Safra Center for Brain Sciences, The
the ventral subiculum (vSub)- NAc pathway, impaired perfor- Hebrew University of Jerusalem, Edmond J. Safra Campus,
mance in the PFC-dependent object recognition task and the Givat Ram, Jerusalem, 91904, Israel.
hippocampal-dependent spatial version of this task. Stressed
rats also demonstrated significantly reduced expression of Sensory inputs to the mammalian olfactory bulb (OB) are
GRs in the amygdala, hippocampus, PFC and NAc one month organized in spatially segregated and functionally discrete
after stress terminated. Chronic WIN administration has pre- units called glomeruli. These inputs are then processed by
vented the stress-induced impairment in synaptic plasticity in local neurons that shape odor representations in the OB.
the vSub-NAc pathway and in recognition and spatial mem- Local networks in the OB include different types of neurons
ory tasks with no effect on GRs levels. like inhibitory periglomerular neurons (PGNs) and excitato-
Conclusion: Our findings suggest that cannabinoid activa- ry external tufted cells (ETs). Here, we used in-vivo two-
tion could represent a novel approach to the treatment of photon calcium imaging to characterize the odor response
cognitive deficits that accompany a variety of anxiety- profiles of these local populations in the mouse OB.
related neuropsychiatric disorders. We expressed the genetically encoded calcium indicator
GCaMP3.0 in ETs and PGNs using lentivirus and AAV1,
How a taste memory is waiting hours for visceral respectively. Mice were implanted with a chronic window
information to form conditioned taste aversion? which allowed us to densely map odor responses from
Adaikkan C 1, Rosenblum K* 2 dozens of neurons per animal (n0~1100 PGNs, n0~500
1
Dept. of Neurobiology, University of Haifa, Haifa ETs, n09 mice). The two populations showed distinct re-
2
Dept. of Neurobiology, University of Haifa, Haifa sponse profiles. PGN maps were sparse, whereas single
neurons responded to only few odors. In contrast, ETs maps
The innate reluctance to eat novel taste, gustatory neopho- were dense, whereas single neurons responded to a variety
bia, is one of the most important behaviors that prevent of odors. The differences between the populations were also
animals from ingesting large quantity of a new and possibly manifested by high pairwise signal correlations between
toxic food. The consumption of a novel taste that is not ETs, even for pairs located hundreds of microns away. In
associated with negative visceral consequences leads to the contrast, PGNs responses were usually uncorrelated. These
formation of a non-associative form of sensory memory, results imply that PGNs are involved in local processing
known as incidental taste memory. Conditioned taste aver- while ETs process inputs from larger regions.
sion (CTA) is an associative learning in which animals learn We then compared how PGNs and ET's code 1 sec vs 15 sec
to avoid a novel taste (CS) associated with delayed poison- odor stimuli. Long stimuli invoked dense responses in both
ing (US). In contrast to other forms of associative learning, populations, suggesting that most PGNs are recruited only
CTA can be established with CS-US intervals measured in during persistent odor stimuli. Interestingly, the temporal
hours. It is unknown how a memory of given taste is waiting dynamics of ETs and PGNs were very different. ETs showed
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S5
fast adaptation while PGNs showed continuous or increased is mediated through an effect on inositol metabolism. In agree-
responses as long as the odor was present. These results suggest ment, both IMPA1 (encoding for IMPase1) and SMIT1 homo-
that ETs contribute to adaptive processing across odors. This zygote knockout mice exhibit Li-like behaviors. Since inositol
adaptation may be regulated by persistent inhibition conveyed signaling is cyclic, requiring continuous incorporation of ino-
by PGNs. Our work provides a first comprehensive functional sitol into the phosphatidylinositol pool to produce its second
dissection of local networks in the mammalian OB. messengers, better understanding of brain inositol's turnover
and how Li affects it is crucial for understanding the conse-
The role of the ventromedial prefrontal cortex in first quences of inositol depletion. We hypothesized that Li and bi-
and second order embarrassment allelic IMPA1 knockout dampen brain inositol turnover.
Adler N 1,2, Aharon-Peretz J 2, Shamay-Tsoory SG 1 Methods We used intracerebroventricular (icv) injection of
1
University of Haifa 2Rambam Medical Center 3H-inositol to determine inositol turnover into phosphoino-
sitols (cytosolic) and phosphoinositides (membranal).
Embarrassment is a complex and self-conscious emotion Results Frontal cortex: acute Li treatment of wildtype mice
which requires the presence of a real or imagined person in did not affect radiolabeled phosphoinositols levels while a
order to achieve (Miller, 1996). It has been suggested that significant two and 3.5 fold increase was obtained following
embarrassment is caused by a person's feeling that they're chronic Li treatment and in IMPA1 HO KO mice, respec-
committing an overt disruption of social performance, indi- tively. Hippocampus: acute and chronic Li treatment
cating that it requires intact social abilities and emotion regu- resulted in a trend of 3.5 fold increase in radiolabeled
lation.In order to examine the neural basis of embarrassment phosphoinositols; a significant seven fold increase was
we designed a task that assesses the feeling of embarrassment found in HO KO of IMPA1. No differences were found in
while performing a potentially embarrassing assignment (e.g. the radiolabeled phosphoinositides levels. We then studied
sing or dance) while being videotaped ("first order embarrass- the effect of IP3 (vs. aCSF) trapped in liposomes adminis-
ment") and the ability to feel embarrassment after viewing tered 45 min prior the analysis. IP3 administration resulted
one's performance on film ("second order embarrassment"). in decreased immobility time in the forced-swim test and in
Given the role of the ventromedial prefrontal cortex (VM) in an attenuated response to amphetamine, similarly to the
social behavior and emotion regulation, it was hypothesized effect of chronic Li treatment.
that it would have a key role in first order embarrassment. Conclusions The results corroborate the inositol depletion
A group of seven patients with localized VM lesions was hypothesis.
compared to a group of non- VM lesions (n04) and matched
healthy controls (n011). Mechanisms of neurotoxicity in prion diseases
The results indicate that, as compared to the two control Aguzzi A
groups, VM patients report lower embarrassment while Institute of Neuropathology, University Hospital of Zürich
being videotaped while showing normal levels of embar- Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland
rassment when watching themselves on film.
These results suggest that the VM is important for the online Prion diseases are a group of neurodegenerative diseases
feeling of embarrassment (first order embarrassment) which involving the conversion of the cellular prion protein, PrPC,
requires emotion regulation but not for the second order into a disease-associated form termed PrPSc. We have estab-
embarrassment. lished a model of prion infection in organotypic cerebellar
This study was conducted with the support of the Israel slice cultures that allows us to study prion replication in a
Foundation Trustees (PhD grant 59/29). complex cellular model. Prion replication within the tissue
induces an innate immune response and causes a subtotal
The effect of lithium on brain inositol turnover loss of cerebellar interneurons within 5-7 weeks.
Agam G*, Belmaker RH, Sade Y Progressive accumulation of PrPSc can only occur when
Ben-Gurion University of the Negev and Mental Health conversion of PrPC into PrPSc is faster than PrPSc clear-
Center, Beer-Sheva, Israel ance. Microglial cells are the brain’s phagocytes and were
therefore a plausible candidate for effecting PrPSc clear-
Background The mechanism of lithium (Li)'s action is not ance. We studied this question in slice cultures from
yet resolved. Among numerous findings Li inhibits inositol- CD11b-HSVTK transgenic mice, from which microglia
monophosphatase (IMPase) and reduces brain intracellular can be rapidly and completely ablated through exposure to
inositol. Li also down-regulates the expression of the sodi- ganciclovir. Depletion of microglia from non-infected cul-
um myo-inositol co-transporter (SMIT)1 responsible for tures had no effect on the viability of non-microglial cells in
inositol uptake from the extracellular fluid. The inositol brain slices. In infected tissue, however, microglia depletion
depletion hypothesis suggests that Li's mood-stabilizing action led to a 15-fold increase in prion titers and the deposition of
S6 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
PrPSc. These results suggest that microglia functions as a alpha is not trivial. This endeavor is further complicated
scavenger of prions. by the evident sensitivity of alpha to the level of visual
We then asked which factors may control the priolytic activity attention allocated to processing. This factor might be
of microglia. Engulfment of apoptotic bodies by phagocytes is easily confounded with the perceptual aspects of motor
mediated by milk fat globule EGF factor 8 (Mfge8) which, in manipulation. Indeed, although mu suppression is
the brain, is primarily produced by astrocytes. We found that expected primarily at fronto central sites, similar (and
Mfge8 ablation produced accelerated disease and reduced sometime even larger) EEG modulation can be recorded
clearance of apoptotic bodies in vivo, as well as excessive from traditional alpha-dominated locations at parieto-
PrPSc accumulation and increased prion titers in prion- occipital sites while observing motor acts. In order to
infected C57BL/6x129Sv mice and organotypic cerebellar sli- separate mu from alpha EEG manifestations, I applied
ces derived therefrom. Notably, these phenotypes correlated three analytic algorithms. Parallel Analysis of Factors
with the presence of 129Sv genomic markers in hybrid mice (PARAFAC) and the Tucker model where used on a 3
and were not observed in inbred C57BL/6 Mfge8-/- mice, and 4 dimensional representation of the data, and Prin-
suggesting that additional, hitherto unidentified genetic modi- cipal Component Analysis (PCA) was used on a 2
fiers may exist. Because Mfge8 receptors are expressed by dimensional representation of the data as a simple control
microglia, and microglial ablation increases PrPSc accumula- model. The success of these methods at separating mu from
tion in organotypic cerebellar slices, we conclude that engulf- alpha EEG manifestations was compared. The algorithms
ment of apoptotic bodies by microglia is an important pathway were applied to data recorded while 18 observers either grasp
of prion clearance and is controlled by astrocyte-borne Mfge8. an object repeatedly or watch a video of a hand grasping the
Surprisingly, antibodies - and also F(ab)1 fragments thereof - same objects. A video of a rolling ball was used as baseline.
binding to certain PrP epitopes induced a complete loss of All three methods had low to moderate success in separating
NeuN-positive neurons within 14 days of treatment in a PrP- the different suppressions, although the 3 and 4-dimensional
dependent manner. These results seriously question the safety implementation of the Tucker model yielded a slightly better
of experimental therapies based on anti-PrP antibodies. As result. Future investigation of the optimal parameters required
prion-mediated toxicity depends on the expression and con- to use these methods efficiently is still required.
version/aggregation of membrane bound PrPC it is appealing
to speculate that antibody treatment induces converging neu- Improving the attention system: the benefits of practicing
rotoxic signaling events as prion infections. Indeed, we have automatic inhibition
found a number of compounds that uncouple prion replication Alali K*, Goldfarb L
in slices from prion neurotoxicity; most of these compounds Edmond J. Safra Brain Research Center for the Study of
also suppress the toxicity of anti-PrP antibodies. Learning Disabilities, University of Haifa
Comparing N-way decomposition methods, PARAFAC Background: People often encounter situations in which
and Tucker, for the purpose of differentiating alpha mental processes contradict each other. In the current case,
and mu suppression during observation of motor acts one mental process must be controlled and restricted so that
using PARAFAC and Tucker methods one'sbehavior will fit one's intentions - this involves cognitive
Aharoni M* 1, Perry A 2, Bentin S 3 inhibition. Performing mental inhibition is a mental resource
1
Cognitive Science Dept., Hebrew University of Jerusalem consuming task and it is thought to involve several brain
2
Dept. of Psychology, Hebrew University of Jerusalem 3The mechanisms, such as the Anterior Cingulate Cortex (ACC)
Interdisciplinary Center of Neural Computation, Hebrew and the Pre Fontal Cortex (PFC). The current study examines
University of Jerusalem techniques aimed at improving cognitive inhibition. Here we
examine the notion that one is sometimes able to perform a
EEG oscillations between 8-12 Hz are desynchronized task to perfection when it is done automatically but an attempt
and their amplitude reduced in humans while observing to do it intentionally end in failure. Using this notion we
biological movement. This EEG modulation, commonly examine whether cognitive inhibition gains indirect improve-
labeled mu-suppression, is recorded primarily over the ment by exercising one's well-functioning automatic inhibi-
sensory-motor cortex and reflects motor activity. The tion ability.Recently, we (Goldfarb et al., 2010) have shown
specific sensitivity to motor activity and a presumed that social priming may trigger automatic inhibition. For ex-
source in the sensory-motor cortex distinguish mu ample, social priming of "dyslexia" can help inhibit the read-
rhythms from the parieto-occipital alpha waves. Never- ing process in the Stroop task. Here we investigate this notion
theless, since both rhythms share the same frequency further and examine whether extended training of automatic
range and, at rest, this frequency dominates the EEG inhibition affects the non automatic inhibition channel, and to
across most scalp sites, disentangling mu rhythms from what extent it can aid general mental inhibition abilities.
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S7
Results: We compared between three experiments, with three Supported by the German Israeli Project Cooperation and
phases: baseline, inhibition practice, and test. The three experi- German Research Foundation (DIP, SFB779).
ments differed in their inhibition practice phase. In Exp.1 this
practice phase involved automatic inhibition (social priming of Seeking causative genes for human congenital general
"dyslexia"), in Exp.2 it involved non-automatic inhibition, and anosmia in multiply-affected Israeli families
in Exp.3 it involved a control-non inhibition task.The results Alkelai A* 1, Olender T 1, Oz-Levi D 1, Keydar I 1, Milgrom
revealed that practicing automatic inhibition leads to the most R 1, Feldmesser E 1, Ben-Asher E 1, Ruzzo EK2, Goldstein
improvement in the mental inhibition mechanism. DB 2, Pras E 3,4, Lancet D 1
1
Conclusions: The results suggest that automatic and non Dept. of Molecular Genetics, Weizmann Institute of Science,
automatic inhibition are based on common brain mechanisms Rehovot, Israel 2Center for Human Genome Variation, Duke
and that automatic operation of the inhibition mechanism has University School of Medicine, Durham, North Carolina
a better behavioral outcome than intentional operation. 27708, USA 3The Danek Gertner Institute of Human Genetics,
Sheba Medical Center, Ramat Gan, Israel 4Sackler School of
Long-lasting increase of corticosterone after fear memory Medicine, Tel Aviv University, Tel Aviv, Israel
reactivation: anxiolytic effects and network activity
modulation in the ventral hippocampus Background: General anosmia has negative effects on
Albrecht A* 1, Caliskan G 2, Oitzl MS 3, Heinemann U 2, life quality, including impaired food and beverage en-
Stork O 1,4 joyment, social interactions and avoidance of poison and
1
Institute of Biology, Otto-von-Guericke-University Magde- fire. An estimated 2.5-5 % of the general population
burg, Germany 2Institute for Neurophysiology, Charité- suffers from acquired general anosmia or hyposmia. In
Universitätsmedizin Berlin, Germany 3SILS-Center for contrast, congenital general anosmia (CGA) affects
Neuroscience, University of Amsterdam, The Netherlands merely <0.1 %, and appears in isolated or syndromic
4
Center for behavioral brain sciences, Magdeburg, Germany forms. In specific cases, family members of patients
with syndromic anosmia have been found to suffer from
Pathological fear and anxiety can be studied, in rodents, with the isolated form of CGA. While for an appreciable
fear conditioning and exposure to reminder cues. These para- number of syndromic CGA types a causative gene has
digms are thought to critically involve the ventral hippocam- been identified, none of the isolated CGA instances
pus, which also serves as key site of glucocorticoid action in have been genetically deciphered. Most of the reported
the brain. Here we demonstrate a long-lasting reduction of isolated CGA cases are sporadic, and family-based stud-
kainate-induced gamma oscillations in slice preparations of ies are relatively rare, primarily because samples are
the ventral hippocampal area CA3, 30d after a single fear difficult to ascertain. In our previous report we have
conditioning training. Reduction of gamma power was sensi- recruited 66 families of Jewish origin and performed
tive to corticosterone application and associated with a de- whole-genome linkage analysis for selected families
crease of glucocorticoid and mineralocorticoid receptor with multiple affected individuals with suspected found-
mRNA expression across strata of the ventral hippocampal er variation. This study did not reveal significant link-
CA3. A fear reactivation session 24 h after the initial condi- age, probably due to small family size.
tioning normalized receptor expression levels and attenuated Results: We now report whole-exome next-generation se-
the corticosterone-mediated recovery of gamma oscillations. quencing in selected individuals from four of these families.
It moreover increased both baseline and stimulus-induced Each family was separately analyzed under the appropriate
corticosterone plasma levels and evoked a generalization of mode of inheritance. We focused on family-shared variants
fear memory to the background context. Reduced ventral present at minor allele frequency <0.05 in the 1000
hippocampal gamma oscillation in both fear reactivated and Genomes Project, in 5000 exomes of the NHLBI database
non-reactivated mice were associated with a decrease of and in our own 50 exomes of Jewish individuals. These
anxiety-like behavior in an elevated plus maze. Taking advan- variants involved functionally reasonable genes, including
tage of the circadian fluctuation in corticosterone, we demon- such appearing in our recently constructed database of CGA
strated the association of high endogenous basal candidate genes.
corticosterone plasma concentrations during morning hours Conclusions: All implicated variants are now being fur-
with reduced anxiety-like behavior in fear reactivated mice. ther validated, examined for co-segregation in additional
The anxiolytic effect of the hormone was verified with local family members, and screened for low frequency in
applications to the ventral hippocampus. Our data suggest that ethnically matched healthy controls. The identification
corticosterone acting on ventral hippocampal network activity of specific pathogenic functional CGA variants will
has anxiolytic-like effects following fear exposure, highlight- help elucidate the molecular basis of general olfactory
ing its potential therapeutic value for anxiety disorders. sensitivity.
S8 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
Substrates coated with silver nanoparticles promote unlike other vertebrates that harbor both GSK-3 genes, the
neuronal growth GSK-3alpha gene is missing in birds. In addition, whereas in
Alon N 1,2, Miroshnikov Y 3,2, Perkas N 3,2, Gedanken A 3,2, mammalian adult brain neurogenesis is restricted to few
Shefi O* 1,2 regions, it is robust in the avian brain. We use nasal procedure
1
Faculty of Engineering, Bar Ilan University, Ramat Gan, with a specific GSK-3 competitive inhibitor, L803-mts, to treat
Israel 2Bar Ilan Institute of Nanotechnology and Advanced adult male zebra finches, and to examine its effects on behavior
Materials, Bar Ilan University, Ramat Gan, Israel 3Dept. of and neurogenesis. First we examined the effect of the inhibitor
Chemistry, Bar Ilan University, Ramat Gan, Israel on downstream targets of GSK-3 in the brain. Indeed, treatment
with L803-mts, increased levels of beta-catenin, cyclin-D and
Manipulation of neuronal growth has important applications phosphorylated eukaryotic elongation factor-2 (eEF2) in the
in regenerative biomedicine and bioengineering. Neurons bird's brain, and provided proof of concept for the in vivo
grow and function while sensing and responding to a wide GSK-3 inhibition. These results could also hint for changes in
range of chemical and physical environmental cues through neurogenesis as these targets are involved in cell proliferation.
the tips of their developing neurites. It has been recognized Then we investigated whether the inhibitor affects birds' singing
that cells are highly influenced by the physical properties of behavior and motor activity. We measured a five-fold decrease
substrates, including topography at the micro- and nano- in undirected songs which are used for communication be-
scale. We examine the combination of physical and chemical tween flock members, in treated birds. However, no changes
stimulations by using active materials as the nanotopographic occurred in motor activity, indicating that decrease in singing
platform to promote neuronal regenerative response. was not a result of nonspecific inhibitor effects. We currently
In this study we investigate the effect of silver nanoparticles, study whether L803-mts affects cell proliferation in the ven-
which are known for their excellent antibacterial activity, on tricular zone of treated birds' brain. Our study suggests that
neuronal growth. We grow neuroblastoma cells on surfaces GSK-3beta regulates singing behavior in birds and introduces
coated with silver nanoparticles. The substrates are fabricated birds as a natural alpha knockout model to study the distinct
by using the sonochemical method, a simple, effective and non- functions of GSK-3 isozymes.
toxic technique. We study and quantify the effect of the nano-
particles on the development and morphology of the neurites. We Anterior cingulate dysfunction in OCD measured
find that the silver nanoparticles function as favorable anchoring by EEG response to erroneous content
sites and the growth on silver nanoparticles coated substrates Alyagon U*1, Carmi L * 2, Zohar J 2, Zangen A 1 2
1
leads to a significantly enhanced neurites outgrowth. A compar- Dept. of Life Science and the Zlotowski Center for
ison with other materials demonstrates a clear silver material- Neuroscience , Ben Gurion University in the Negev, Israel.
2
driven promoting role in addition to the nanotopographic effect. Division of Psychiatry, Chaim-Sheba Medical Center,
Our results, combined with the antibacterial effect of silver Tel-Hashomer, Ramat Gan, Israel
nanoparticles, propose silver nanoparticles as an attractive *Both authors contributed equally to this work
nanomaterial with a dual activity for the design of therapeu-
tic platforms for neuronal repair. OCD patients, compared to healthy participants, are known to
demonstrate an enhanced Error Related Negativity after mak-
Zebra finch - a novel natural GSK-3alpha knockout ing mistakes (Gehring, Himle, & Nisenson, 2000). Neverthe-
model to study the role of GSK-3beta in neural plasticity less, it is not clear whether this hyperactive ERN reflects the
Aloni E* 1, Eldar-Finkelman H 1, Bernea A 2 activity of an action monitoring system that is over sensitive to
1
Dept. of Human Molecular Genetics and Biochemistry, punishment cues (Olvet & Hajcak, 2008) or a dysfunction of
Sackler School of Medicine Tel Aviv University 2Dept. of more general and less affective monitoring system that contin-
Natural and Life Sciences, The Open University of Israel, uously seeks for erroneous information in the inner or outer
Raanana environment. The latter option do not obligate the execution of
an actual mistake but merely the identification of erroneous
Neuron death and replacement are considered fundamental content (Tzur & Berger, 2007). We investigated this issue using
components of adult brain plasticity and critical factors in an arithmetic task (Tzur & Berger, 2007) that was delivered to 9
neurodegenerative diseases. However, we still do not fully OCD patients and 9 healthy controls. Participants were
understand all the mechanisms that regulate neurogenesis. Gly- requested to indicate whether a solution of a simple equation
cogen synthase kinase-3 (GSK-3) is a highly conserved kinase is either correct or wrong. A non phase locked wavelet analysis
which serves as a critical regulator in cellular signaling, surviv- revealed that OCD patients demonstrated enhancement of pow-
al, differentiation and proliferation. GSK-3 has two known er compared to healthy participants in low frequency bands
isozymes, alpha and beta. However, their distinct biological (delta, theta and alpha) after merely identifying wrong solu-
functions are not fully understood. We previously showed that tions. In contrast, no differences were found when correct
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S9
1
solutions were presented. Activity had a midline frontal locus, Dept. of Neurobiology, The George S. Wise Faculty of Life
similar to previous findings, suggesting ACC as a possible Sciences, Tel Aviv University, Israel.2Goldschleger Eye Research
source. These findings contribute to our understanding of the Institute, Chaim Sheba Medical Center, Tel Hashomer, Israe
etiology of OCD, and perhaps to a more specific model regard- l3Dept. of Ophthalmology, Rabin Medical Center, Beilinson
ing the cognitive deficits in OCD patients. Campus, Petach Tikva, Israel 4Koret School of Veterinary Med-
icine, Faculty of Agriculture, Hebrew University, Rehovot, Israel
New reactive amall molecule scavengers of nerve agents
Amitai G*, Bar-Ner N, Gez R, Chapman S, Kamus- Background: ApoE4 is the most prevalent genetic risk
Elimelech D, Ashkenazi N factor of Alzheimer's disease. Synaptic pathology which is
Division of Medicinal Chemistry, IIBR, PO Box 19, Ness the leading pathological hallmarks of the disease is accen-
Ziona 74100 tuated by ApoE4. The extent, to which the synaptic effects
are neuronal specific, remains to be determined. The retina,
The development of medical scavengers toward toxic organ- which is well organized in specific layers of cell types and
ophosphorus (OP) nerve agents have primarily been based on synapses, provides a unique model system to study the
stoichiometric or catalytic enzymes e.g. acetylcholinesterase neuronal and synaptic specificity of the effects of ApoE4.
(AChE) or paraoxonase 1 (PON1). However, enzyme scav- We examined these questions by investigating the retinas of
engers may cause immunogenic response, have limited stabil- young naïve ApoE3 and ApoE4 targeted replacement
ity and create excessive payload due to large molecular size mouse, utilizing immunohistochemistry, western blots and
(MW 40-80KD). Therefore, we have embarked on designing electroretinography (ERG).
new small molecules scavengers (SMS) that will rapidly de- Results: ApoE4 had no effect on the either the width of the
toxify OP nerve agents in vivo. The SMS are expected to be different retinal layers, nor the levels of the different cell
non-toxic, stable, highly soluble and non-discriminative to- types. In contrast, ApoE4 had isoform specific effect on
ward optical isomers of OP nerve agents. Their multiple retinal synapses. Accordingly the levels of total synapses
administration routes and pharmacokinetics could be con- (monitored by synaptophysin) were lower in both the inner
trolled by adaptable formulations. The molecular design of and outer plaexiform layers in ApoE4 retinas. Examination
novel SMS was based on combining two functions in one of synaptic specificity of this effect revealed decreased
molecule: direct degradation of OPs and in parallel reactiva- excitatory marker Vglut with parallel increase in the level
tion of OP-inhibited AChE. The direct attack on OPs was of the inhibitory marker Vgat in ApoE4 retinas. Examination
achieved by substituted benzohydroxamic (BHA) and pyridi- of the ratio of excitatory / inhibitory synapses, revealed a
nehydroxmic acid (PHA) derivatives. Some BHAs and PHAs decreased ratio levels in the retinas of ApoE4 mice. This
were then coupled via spacers to pyridine oximes providing findings show that apoE4 has a synapse specific effect. ERG
hybrid compounds with both detoxification and reactivation measurement revealed decreased amplitudes of the a- and b-
potencies. Thus, 24 new compounds were synthesized of waves ApoE4 compared to ApoE3, while no effect was ob-
which 3 compounds were bifunctional hybrids. The new served in the response time. This suggests that the synaptic
compounds were tested for detoxification rate towards sarin, effect of ApoE4 has functional implications. Measurements of
cylsosarin and soman under physiological conditions (pH0 the ApoE levels showed lower levels in ApoE4 retinas com-
7.4, 37 °C). The fastest SMS toward OP agents were methoxy, pared to ApoE3, correlative with the observation in the brain.
dimethoxy and trimehtoxy BHA with t 1/2 01-2 min (1 mM It is still to be determined whether these effects in the ApoE4
SMS and 1 μM OP). The hybrid compounds 2-PAM-(CH2)3- mice are due to loss of function or gain of toxic function.
4PHA and 2-PAM-Benz-4PHA displayed rapid detoxification Conclusions: These findings show that ApoE4 has specific
as well as reactivation potency toward OP-AChE. 2-PAM- synaptic effects in the retina, and that these affect lead to
(CH2)3 4PHA also displayed 30-fold faster kinetics than 2- retinal dysfunction.
PAM toward cyclosarin-inhibited AChE. The latter hybrid
compound exhibited high decontamination activity (>98 %) 'Juvenile stress' exacerbates the impact of an exposure
toward cyclosarin on pig-ear skin in vitro using Franz diffu- to an odor reminder of a stressful experience in adulthood
sion cells. Our results indicate that the new hybrid compounds Ardi Z* 1,2,3, Richter-Levin A 2,3, Richter-Levin G 1,2,3,4
1
are promising scavengers of OP nerve agents. Dept. of Neurobiology and Ethology , University of Haifa,
Supported by DTRA DTRAH1-12-C-0008 Israel 2The Brain and Behavior Research Center, Israel
3
The Institute for the Study of Affective Neuroscience
ApoE4 impairs synaptic activity and function in young (ISAN) 4 Dept. of Psychology , University of Haifa, Israel
naïve mice retinas
Antes R 1 , Solomon A 2 , Weinberger D 3 , Ofri R 4, While most individuals are able to cope with trauma, a
Michaelson D* 1 minority fail to recover and exhibit prolonged and
S10 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
maladaptive behavioral and physiological responses to Does the olfactory epithelium sleep?
the traumatic experience. Many times, these are mani- Arzi A* 1, Shushan S 1,2, Shoffel-Havakuk H 3, Cohen-
fested as symptoms of PTSD. Among the many pro- Atsmoni S 2, Plotkin A 1, Roth Y 2, Sobel N 1
1
posed risk factors, early-life stress is predominantly Dept. of Neurobiology, Weizmann Institute of Science,
associated with higher prevalence of both mood and Rehovot 76100, Israel 2Dept. of OtoRhinoLaryngology
anxiety disorders, particularly depression and PTSD and Head and Neck Surgery, Edith Wolfson Medical Center,
(Heim & Nemeroff, 2001). Dealing with PTSD, a core Holon 58100, Israel 3Dept. of otolaryngology Head and
symptom is the intrusive recollections of the traumatic expe- Neck surgery, Kaplan Medical Center, Rehovot, Israel
rience. These episodes of re-experiencing are often triggered
by reminders (e.g. places, sights, sounds and other sensations) Sleep is a rapidly reversible state characterized by loss of
of the traumatic event (Kardiner, 1941; Marx and Soler-Baillo, consciousness and reduced responsiveness to external stim-
2005). Therefore, the study was aimed to examine the long uli. There is compelling evidence, however, that the sleep-
term ability of an odor reminder to act as an effective reminder ing brain is by no means incapable of processing sensory
of a stressful experience in adulthood. In addition, we evalu- information. For example, odor pleasantness is processed
ated the impact of an exposure to 'juvenile stress' as a predis- during sleep. The sniff-response, an odorant-specific change
posing factor that will exacerbate the impact of an exposure to in nasal airflow whereby pleasant odors drive stronger sniffs
odor reminder in adulthood. and unpleasant odors drive weaker sniffs, is evident in sleep.
The results suggest that an exposure to stress in juvenility Nonetheless, the brain mechanisms underlying sensory pro-
and to an exposure to an odor reminder exacerbates the cessing during sleep remain unclear. The olfactory system
behavioral effects even one month following the exposure provides an unusual framework to elucidate the brain sub-
to stressful experience in adulthood. strates of sleep processing by presenting a unique opportu-
nity to directly record neural activity in humans. Olfactory
Generation of spatial codes relies on the intact function receptor neurons, a form of PNS-CNS transition neurons
of the oculomotor system: a study of Duane retraction outside the skull, located in the olfactory epithelium, enable
syndrome in vivo recording of olfactory responses (EolfG's) from
Arend I 1, Henik A 1, Gradstein L 2 behaving humans. Using this technique we set out to ask
1
Dept. of Psychology and Zlotowski Center for Neuroscience, whether the EolfG's are influenced by the wake-sleep cycle.
Ben-Gurion University of the Negev, Beer-Sheva, Israel EEG, EOG, EMG, EKG and EolfG's were recorded at
2
Dept. of Ophthalmology, Soroka Medical Center, Beer-Sheva, 1 kHz from 8 healthy subjects. EolfG's were recorded
Israel using Ag/AgCl electrode coated with Teflon tubing (0.8 mm
OD) filled with Ringer-agar. Using a computer-controlled
The Simon effect (SE) shows that response times (RTs) are olfactometer we delivered odorants (Vanillin and Dimethyl
faster when stimulus location corresponds with response loca- Sulfide, duration03 s, 15 repetition each, ISI ~25 s) into the
tion, even when stimulus location is task-irrelevant—spatial recorded nostril via Teflon tubing, maintaining steady me-
codes even though irrelevant, affect response choices. It is still chanical and thermal conditions (5.5 SLPM, 37 °C, 80 %
under debate how spatial codes are formed and why they cannot RH) during both wake and sleep. EolfG responses were
be ignored. Attentional accounts for the SE follow the premotor evident in 5 out of 8 subjects, and EolfG amplitude and
theory of attention, suggesting spatial attention is tied with the EEG spectral power were calculated for each trial in each
intention to perform a goal-directed spatial movement. That is, subject. Preliminary results show a significant correlation
spatial attention and motor programming occur together and between EolfG amplitude and delta (0.5-4 Hz)/alpha (8-
operate on the basis of the same spatial maps. We tested the 12 Hz) power (r0-0.41, p00.048) in one subject. This corre-
attentional account for the SE by studying a visual Simon task lation reflected higher EolfG amplitudes as sleep deepened,
in a patient (AR) who suffers from Duane syndrome (DS). DS which suggests that the olfactory epithelium wakes up when
is a congenital eye movement disorder characterized by inabil- we go to sleep.
ity of the patient to perform horizontal eye movements. AR's
RTs were analysed as a function of visual field and contrasted Exposure to stress differentially affects behavior
with RTs from control participants. Results showed no SE and expression of Kappa Opioid Receptor and GABA-A
(stimulus-response interference) when the targets appeared in receptor in male rats
the visual field to which AR could not perform eye movements. Ashkenazi-Karni S 1,2, Horovitz O 1, Metzger N 3,1, Vered R
1,3
These results show that generation of spatial codes relies on , Anunu R 1,2, Richter-Levin G* 1,2,3
1
intact function of the oculomotor system, supporting the role of The Institute for the Study of Affective Neuroscience (ISAN)
2
spatial attention in stimulus-response interference. Dept. of Neurobiology and Etiology , University of Haifa,
German-Israeli Foundation awarded to AH Israel 3Dept. of Psychology. University of Haifa, Israel
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S11
Childhood trauma may predispose to the development of followed by exposure to environmental insults, which better
stress-related affective disorders. Acute exposure of rats to reflects real life.
adult stress following previous exposure to juvenile stress Methods: Early interference with gene transcription was
resulted in altered behaviors reminiscent of affective performed by treatment of 7 days old Wistar male rats for
disorders-like symptoms. These, were linked to activation 4 days with the Sp1/DNA binding inhibitor, mithramycin.
of positive and negative affect brain areas. We compared Environmental insult was mimicked by exposing these rats
expression of GABA-ARα1/α2 subunits, and of Kappa during adulthood (34 days) to sub-chronic (12 days, n030)
Opioid Receptor (KOR), as mediators of positive or nega- or chronic stress (28 days, n048). The effects of mithramy-
tive affect, respectively, in correlation to behavior tests that cin and stress treatment on behavioral response and serum
were taken before and after the adult stress. corticosterone levels were assessed.
Results revealed that juvenile stressed rats spent more time Results: Exposure of mithramycin treated rats to sub-chronic
and had more distance covered in open field center compared stress led to anxious behavior in the open field test, high startle
to control. In plus maze, juvenile stress group spent less time response, low sucrose preference, indifference to novel objects
but had more distance in open arms. Surprisingly, in social and high serum corticosterone levels. However, exposure to
interaction test, juvenile stress resulted in less time exploring chronic stress resulted in normal sucrose preference, startle
familiar object than control group. After adult stress, juvenile response and serum corticosterone, novelty seeking behavior
+adult animals spent more time and had more distance in the and reduced anxiety. In saline treated rats the extension of stress
center of an octagon field than control group. In zero maze, duration led to behavioral and hormonal adaptation to stress.
both juvenile and juvenile+adult groups spent less time and Conclusion: Our study suggests that postnatal temporal
had less distance in open quadrants than control group and interference with multiple gene expression can lead to
adult group. These behaviors were followed by changes in hyper-responsiveness to environmental stimuli, the features
GABA-ARα1 and KOR. Adult and juvenile+adult stresses of which affects the phenotypic outcomes. Such a paradigm
resulted in elevation of GABA-ARα1 level, in ventral PAG. may be used to model gene -environmental interaction in the
In the same area, adult stress increased KOR level only in etiology of behavioral disorders.
juvenile+adult group. Adult stress also elevated GABA-
ARα1 level in dorsal PAG. In juvenile+adult the receptor Involvement of cAMP signaling pathway in inhibition
protein level was much lower. KOR in dorsal PAG was higher of brain NO synthesis by BK
in all groups compare to control. An additive erasing on KOR Asraf K, Ben-Shmuel S, Fleisher-Berkovich S*
effect in juvenile+adult group was evident in BLA. An oppo- Dept. of Clinical Biochemistry and Pharmacology, Ben-
site effect on KOR was found in central amygdala. Gurion University of the Negev, Faculty of Health Sciences,
Results indicate that while it is tempting to view the juvenile Beer-Sheva, Israel
+adult group as an added result of both stressors, each stress
group is in fact a unique condition, with characteristic Background: Bradykinin (BK) is a potent inflammatory me-
profile of effects. diator in the periphery. In Alzheimer's disease, where brain
inflammation occurs, BK release is upregulated relatively early
Transient interference with the ubiquitous transcription during the course of the pathology. Hence, BK was believed to
factor Sp1 leads to disparate behavioral response promote neuroinflammation in several ways, including activa-
to sub-chronic and chronic stress tion of microglial cells, that is responsible for the over-
Asor E 1, Belhanes H 2, Kavushansky A 1, Zubedat S 3,2, production of pro-inflammatory mediators, such as nitric oxide
Klein E 1, Avital A 3,2, Ben-Shachar D* 1 (NO) which in turn lead to neuronal injury. However, BK was
1
Laboratory of Psychobiology, Dept. of Psychiatry, Rambam recently reported to have anti-inflammatory role. We found
Medical Center 2Rappaport Faculty of Medicine, Technion, that BK reduce NO synthesis in microglia cells, but the mech-
Haifa Israel. 2The Yezreel Valley College 3Rappaport Faculty anism is still unknown. As already known, cyclic adenosine
of Medicine, Behavioral Neuroscience Lab, Technion – IIT, monophosphate (cAMP) is an important regulator of inflam-
The Emek Medical Center and matory reactions. Increased cAMP levels results in activation
of protein kinase A (PKA) and subsequently in the phosphor-
Background: It is currently accepted that complex behavior ylation of cAMP response element binding protein (CREB)
and mental disorder results from a combination of biological and increased transcription of inflammation-related genes. In
susceptibility and exposure to environmental stimuli. How- this study we examined the involvement of cAMP pathway in
ever, most of the gene-environment interaction models focus inhibition of microglial NO synthesis by BK.
on the interaction between environmental stimuli and a Results: Exposure of BV2 microglial cells to BK resulted in
single candidate gene. We suggest that an alternative ap- a significant decrease in basal NO production which was
proach is interference with the expression of multiple genes measured by the griess assay, while adding db cAMP
S12 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
(cAMP analog) resulted in a significant increase in NO Amyloid-Beta burdens and re-activation of mTOR. This
production. Similar results were obtained for lipopolysac- work further highlights the therapeutic potential of
charide (LPS)-stimulated BV2 cells. In addition, H-89 (PKA GSK-3 inhibition in treating AD.
inhibitor) mimics BK in reducing NO production in resting
and LPS-stimulated cells. Also, Western blot analysis was The role of nucleus accumbens MAPK signaling pathway
performed using protein of nuclear extracts and antibodies in the expression of cocaine psychomotor sensitization
directed against CREB, phosphorylated at Ser133 (p- Azriel M, Ozeri N, Yaka R*
CREB), revealed that BK inhibits CREB phosphorylation The Institute for Drug Research (IDR), School of Pharmacy,
in resting and LPS-stimulated BV2 cells. Faculty of Medicine, The Hebrew University of Jerusalem
Conclusion: These results suggest that cAMP signaling
pathway is involved in BK's anti-inflamatory effect in Repeated administration of psychostimulant drugs such as
microglial cells, and may play an important role in neuro- cocaine induces psychomotor sensitization, which is
protection during brain inflammation. thought to contribute to the development of drug craving
This research was supported by the Israel Science Founda- by enhancing the incentive motivational value of these
tion (grant 101/11). drugs. Among the enduring neuronal changes responsible
for the expression of cocaine psychomotor sensitization,
Mechanisms underlying the contribution of GSK-3 alterations in glutamate induced signaling and plasticity
to amyloid-beta pathogenesis within the VTA and NAc play a critical role.
Avrahami L #* 1, Farfara D # 2, Shaham-Kol M 1, Vassar R 3, Previously we have shown that repeated cocaine injections
Frenkel D 2, Eldar-Finkelman H 1 increased NAc NMDA receptor subunits expression and
1
Dept. of Human Molecular Genetics and Biochemistry, distribution 21 days but not 1 day after withdrawal from
Sackler School of Medicine, Tel Aviv University 2Dept. of cocaine. These changes were associated with an increase in
Neurobiology, George S. Wise Faculty of Life Sciences, Tel the GluR1 subunit. We also found a time-dependent increase
Aviv University 3Dept. of Cell and Molecular Biology, in ERK activity which was responsible for the increase in
Northwestern University Feinberg School of Medicine, synaptic GluR1 levels in the NAc. In the same line, other
Chicago studies have shown that following withdrawal from repeated
# These authors contributed equally to this work. cocaine injections the ratio of AMPAR/NMDAR evoked
currents, an indicator of LTP in vivo or an increase in
Inhibition of Glycogen Synthase Kinase-3 (GSK-3) is a synaptic strength, is increased in the NAc.Together these
therapeutic strategy for neurodegenerative disorders, such results raised the hypothesis that MAPK signaling pathway
as Alzheimer’s disease (AD). However, the contribution of is critically involved in the increase in synaptic strength in
GSK-3 to amyloid pathogenesis has been under debate. To the NAc which ultimately leads the expression of psycho-
study this, we used ‘5XFAD’ mice co-expressing mutated motor sensitization. We found that inhibiting the activity of
amyloid precursor protein (APP) and presenilin-1 (PS1) that ERK by the MEK inhibitor U0126, 1 day but not 7 days
develop massive cerebral Amyloid-Beta loads. Nasal treat- after sensitization in the NAc (core or shell), decreased the
ment with a substrate-competitive GSK-3 inhibitor, L803- locomotor activity of rats that were challenged with cocaine
mts, reduced Amyloid-Beta deposits and ameliorated cog- to the levels seen in rats that were exposed to cocaine for the
nitive deficits in the 5XFAD mice. Analysis of hemi-brain first time. Further, we found that AMPAR/NMDAR currents
samples indicated that L803-mts restored the activity of mam- ratio that was recorded in the NAc (core and shell) slices
malian target of rapamycin (mTOR) and inhibited autophagy. following microinjection of U0126 10 days after withdraw-
Lysosomal acidification was impaired in the 5XFAD brains as al, was reduced to the level of the saline group. We therefore
indicated by reduced cathepsin D (CatD) activity and de- conclude that MAPK signaling plays a central role in the
creased N-glycoyslation of the v-ATPase subunit V0a1, a expression of cocaine psychomotor sensitization by increas-
modification required for lysosomal acidification. Treatment ing the synaptic strength at this region thereby leads to
with L803-mts enhanced lysosomal acidification in 5XFAD hyperactivity when re-expose to the drug.
brains. Studies in SHSY-5Y cells and presenilin-deficient Israel Science Foundation (ISF); David R. Bloom and Brettler
mouse embryonic fibroblasts further demonstrated that Centers; School of Pharmacy
both GSK-3 isozymes, GSK-3 alpha and GSK-3 beta,
impair lysosomal acidification and treatment with GSK- Mitotic motor proteins co-regulate microtubule
3 inhibitor restores this deficit. Taken together, our data organization in axons and dendrites
implicate GSK-3/mTOR/lysosome axis in AD pathogen- Baas PW*
esis. We suggest that Inhibition of GSK-3 restores lyso- Neurobiology and Anatomy, Drexel University, Philadelphia,
somal acidification that in turn, enables clearance of PA
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S13
In the axon, the microtubules (MTs) are nearly uniformly Inhibition of TGF-beta signaling as a new anti-epileptogenic
oriented with their plus ends distal to the cell body, while in strategy in the blood-brain barrier dysfunction model
the dendrite, MTs are non-uniformly oriented. We have for epilepsy
proposed that these patterns are established and maintained Bar-Klein G 1,2 , Cacheaux L P 3,4 , Rozowsky J 1,2 ,
by molecular motor proteins that transport MTs into these Kaminsky L 1,2, Weissberg I 1,2, Kaufer D 3,4, Friedman A 1,2
1
neurites with either the plus or the minus end of the MT Dept. of Physiology & Cell Biology and Biomedical Engi-
leading. Our general hypothesis has been that cytoplasmic neering, 2the Zlotowski Center for Neuroscience, Ben-
dynein is the principal workhorse for transporting MTs with Gurion University of the Negev, Beer-Sheva, Israel. 3Helen
their plus ends leading, and that the remainder of the work is Wills Neuroscience Institute and 4Dept. of Integrative Biol-
performed by a small number of kinesins usually considered ogy, University of California, Berkeley, California, USA.
to be mitotic kinesins, namely kinesins 5, 6, and 12. The
results of our recent studies on these motors indicate that, in Epilepsy is one of the most common brain disorders and is
fact, they do not fuel microtubule transport in the axon, but often preceded by traumatic or ischemic insult and associated
rather they somehow suppress it. We now think of these with blood-brain barrier (BBB) dysfunction. We have previ-
motors as "brakes" on axonal microtubule transport. We will ously demonstrated that BBB dysfunction underlies the induc-
discuss the evidence for this conclusion, as well as potential tion of a transcriptional program mediated by serum albumin-
mechanisms by which these motors might behave as brakes. induced transforming growth factor β (TGF-β) signaling. We
A potentially exciting hypothesis is that these motors act, at thus tested losartan, an angiotensin II type 1 receptor blocker,
least in part, at the level of the cell body to restrain the which has been shown to block TGF-β signaling, as a potential
transport of MTs into the axon while simultaneously pro- anti-epileptogenic treatment. Epileptogenesis was induced by
moting the transport of MTs of the opposite orientation into BBB opening using a focal application of the bile salt sodium
the dendrites. We posit that it is by this mechanism that the deoxycholate (DOC, 2 mM) or bovine serum albumin (BSA,
neuron co-regulates the polarity orientation of MTs in the 0.2 mM). Rats were then treated with losartan; either locally
axon and the dendritic arbor. (10 μM) in albumin-treated, or systemically (single dose of
This work was funded by the National Institutes of Health, 100 mg/kgi.p. followed by 2gr/L in the drinking water for
USA. 21 days) in DOC-treated rats. Sham operated animals served as
control. Epileptogenesis was monitored using telemetric elec-
A cognitive neuroscience hypothesis of mood trocorticographic (ECoG) and analyzed with "in house" sei-
and depression zure detection algorithm. Brains were collected for molecular
Bar M analysis. We show that losartan prevents albumin-induced
Bar-Ilan University smad2 phosphorylation (p00.03) and upregulation of the as-
trocytic marker GFAP (p00.035). Spontaneous seizure-like
The hypothesis presented here links cognitive processing events (SLEs) were detected in 82 % of albumin- and 100 %
with mood. Specifically, I propose that there is a direct of DOC-treated rats, compared to 29 % of controls (p00.013),
and reciprocal relation between the cortical activation of 25 % of albumin/losartan- and 40 % of DOC/losartan-treated.
associations and mood regulation, whereby positive Importantly, in rats developing epilepsy, losartan significantly
mood promotes associative processing, and associative decreased the number of recorded seizures; 5.02 vs. 0.29
processing promotes positive mood. Previous research seizures/week in albumin and albumin/losartan-treated rats,
has identified a network of brain regions that mediate respectively (p00.002) and 8 vs. 0.9 in the DOC and DOC/
cognitive-associative processing in healthy humans. A losartan groups, respectively (p00.042). We highlight the
critical insight that links those findings to studies of potential of a commonly used, well tolerated anti-
mood and depression is that depression is associated hypertensive drug in the prevention of injury-related epilepsy,
with both structural and functional abnormalities in probably through a TGF-β-dependant signaling blockade.
these same brain regions. The proposed framework has
many implications, most notably for diagnosing and An examination of the effect of type of script read
treating mood disorders such as depression, for contex- on brain activity in regular and dyslexic
tualizing adult hippocampal neurogenesis, for elucidat- readers – an ERP study
ing the role of cortical inhibition and foresight in the Bar-Kochva I , Breznitz Z*
regulation of mood, and for a general non-invasive Edmond J. Safra Brain Research Center for the Study of
improvement of well being. Several key predictions are Learning Disabilities, University of Haifa
derived from this theory, and testing them has already
provided supportive evidence. Background: Brain-imaging studies indicate that reading
NIH and NSF orthographies varying in phonological transparency elicit
S14 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
distinct brain activity in regular readers. Behavioral studies interactions between its protein compounds. Interactomic
have also suggested that regular readers adjust reading-routine data for example, are obtained from small-scale experi-
to the orthography read. Dyslexia is a neurobiological disor- ments, which are highly trustworthy but suffer from low
der, manifested in difficulties in word recognition. The pur- coverage, or from high throughput experiments, which pro-
pose of this study was to examine whether dyslexics would duce more false interactions.
also exhibit distinct brain activity when reading different Results: In this study we propose a computational frame-
orthographies. ERP's of dyslexic and regular readers were work to improve the reconstruction of the PSD network. The
compared while performing a word recognition task in the approach is based on learning the characteristics of PSD
two forms of Hebrew script (the phonologically transparent protein interactions from a set of high confidence interac-
pointed script and the phonologically opaque unpointed tions, and predicting new interactions between candidate
script). A visual non-orthographic task controlled for the vi- proteins. For this we created a "seed" network of trusted
sual difference between the scripts. proteins and interactions by merging data from papers
Results: Behavior. A main effect of form of script on reporting interactions between proteins localized to the
response-times was obtained (F(1,46) 015.26, p < .001, PSD, and expand it with data collected from large scale
ηp20.25), and it was larger in dyslexics than in regular repositories. We then predicted how proteins that are
reader. Electrophysiology. The form of script affected ampli- suspected to reside in the PSD interact with proteins
tudes associated with early visual-orthographic processing in the network. This method yielded a set of predicted
in both groups (regular readers: F(1,23)034.03, p<.001, interactions, half of which had supporting evidence in
ηp2 0.60; dyslexics: F(1,23) 06.37, p < .05, ηp2 0.22) at the literature. We found connections of particular inter-
occipital-temporal sites. The results suggested that this ef- est between proteins of the LRRTM family and PSD-95,
fect was not visual per-se. At later orthographic-linguistic possibly connecting disease related regulators with in-
stages of processing, an effect of form of script on central- tracellular signaling pathways.
parietal amplitudes appeared earlier in regular readers
(350 ms: F(1,23)010.25, p<.01, ηp20.31) than in dyslexics Embracing disorder: making sense of complex
(450 ms: F(1,23)04.77, p<.05, ηp20.17). Both early and population codes
late effects of form of script were larger in regular readers Barak O* 1,2, Sussillo DC 3, Romo RR 4, Tsodyks MV 5,
than in dyslexics. Abbott LF 2,6
Conclusion: The effect of form of script on behavioral 1
Rappaport Faculty of Medicine, Technion – Israeli Institute
measures was larger in dyslexics than in regular readers. In of Technology, Haifa, Israel 2Center for Theoretical Neuro-
contrast, the same effect on brain activity was larger in science, Columbia University. New York, NY 10032, USA
3
regular readers than in dyslexics. This suggests that dys- Dept. of Electrical Engineering, Neurosciences Program,
lexics lack cognitive flexibility of adjusting processing to Stanford University. Stanford, CA 94305 4Instituto de Fisio-
the constraints imposed by different orthographies. logía Celular-Neurociencias, Universidad Nacional Autón-
This study was supported by the Edmond J. Safra Philan- oma de México, 04510 México, D.F., México5Dept. of
thropic Foundation. Neurobiology, Weizmann Institute of Science, Rehovot
76100, Israel 6Dept. of Neuroscience and Dept. of Physiol-
Computational prediction of novel protein–protein ogy and Cellular Biophysics, Columbia University. New
interactions in the post synaptic density York, NY 10032, USA
Bar-Shira O, Chechik G
The Gonda Brain Research Center, Bar-Ilan University, Background: Cognitive tasks require the joint activity of a
Ramat Gan, Israel 52900 large population of neurons. Hence there is no a priori
reason to find single neurons with easily interpretable activ-
Background: The post synaptic density (PSD) is a special- ity profiles. Yet when we record from single neurons, we
ization of the cytoskeleton at the synaptic junction, contain- look for and bias our models by precisely these neurons.
ing hundreds of different proteins. Its function is to detect Here, we use data from the delayed vibrotactile discrimina-
and respond to neurotransmitter that is released from pre- tion task from the Romo laboratory to highlight the "not
synaptic terminals. It is widely believed that characterizing easily interpretable" neurons[1,2].
the protein components of the PSD and their interactions Results: We compare three different models to data
can help elucidate the mechanism of long-term changes in recorded from the prefrontal cortex of monkeys performing
synaptic plasticity, which underlie learning and memory. this task. The first model is a highly organized linear attrac-
Unfortunately, proteomic and interactomic measurements tor model, where the internal connectivity is dictated by the
provide an incomplete (false negatives) and noisy (false neurons' tuning curves. The second model is a randomly
positives) picture of the PSD composition and the connected network with chaotic activity, where the only
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S15
training is done on the readout. The third model is an prefrontal cortex and amygdala, indicating activation of this
intermediate obtained by training the internal and external pathway. To test whether mTORC1 inhibition during mem-
connectivity of an initially random network. We show that ory reconsolidation interferes with subsequent alcohol seek-
the data most resemble neurons from the intermediate mod- ing, we administered the mTORC1 inhibitor rapamycin
el, but that some "orderly" features of the data are present in (20 mg/kg, i.p., or 50 μg/side, intra-amygdala) immedi-
the chaotic model as well. ately after memory reactivation, and observed reduced
Conclusions: Initially random networks are able to perform a alcohol seeking and intake 24 hrs and even 2 weeks
working memory and decision making task after training. Our later. Importantly, alcohol seeking was not affected by
results suggest that prefrontal networks may begin in a random rapamycin when the memory reactivation session was
state relative to the task, and initially rely on modified readout omitted, or when rapamycin was administered 5 hrs
for task performance. As training proceeds, more tuned neurons after memory reactivation, suggesting that the memory
with less time-varying responses should emerge as the net- retrieval initiates a time-limited vulnerability window,
works become more structured. Furthermore, our results pro- during which memories are destabilized and can be
vide a cautionary note about interpretation of seemingly disrupted.
ordered features of the data as hinting on specific network Conclusions: Our findings suggest that reactivation of
structures. alcohol-associated memories activates the mTORC1 path-
References: [1] Barak O, Tsodyks M, Romo R. Neuronal way in specific brain regions, and that inhibition of this
population coding of parametric working memory. Journal pathway can be used to disrupt the memories and reduce
of Neuroscience 2010;30(28):9424. [2] Brody CD, Hernan- relapse.
dez A, Zainos A, Romo R. Timing and neural encoding of Supported by NIH/NIAAA Grant P50 AA017072 and funds
somatosensory parametric working memory in macaque from the State of California (DR, PHJ)
prefrontal cortex. Cerebral cortex 2003;13(11):1196-1207
Research supported by the Swartz, Gatsby, Mathers and Inactivation properties of Na+ channels in the axonal
Kavli Foundations. spike trigger zone of cortical pyramidal neurons
Baranauskas G, Fleidervish I*
mTORC1 inhibition disrupts reconsolidation Dept. of Physiology and Cell Biology, Faculty of Health
of alcohol-associated memories and prevents relapse Sciences and Zlotowski Center for Neuroscience, Ben-
Barak S* 1,2,3, Liu F 3, Ben Hamida S 3, Yowell Q 3, Neasta Gurion University, Beer-Sheva, 84015, Israel
J. 3, Kharazia V 3, Janak PH 3,4, Ron D 3,4
1
School of Psychological Sciences, Tel Aviv University 2The Background: In cortical pyramidal cells, as in many CNS
Sagol School of Neuroscience, Tel Aviv University 3Gallo neurons, spikes generally initiate in the axon initial segment
Research Center, University of California, San Francisco (AIS) - the proximal part of the axon where the neuronal
4
Departmenet of Neurology, University of California, San membrane is not covered with a myelin sheath and which
Francisco possesses a distinctive, specialized assembly of voltage
gated channels and associated proteins. Preferable AIS
Background: Relapse to alcohol abuse is caused by retriev- spike initiation is explained, at least partially, by lower
al of alcohol-associated memories. Memory reconsolidation activation voltage of local Na+ channels. To what extent
is a process in which memories are temporarily destabilized the inactivation properties of these channels differ from
upon their retrieval (reactivation), and then undergo re- those in soma and dendrites? Molecular studies suggest
stabilization in order to persist. During this process, the that Na+ channel inactivation is voltage independent
reactivated memory becomes labile to manipulations, offer- process that derives all of its apparent voltage-dependence
ing an opportunity to interfere with unwanted memories. from activation. If inactivation rate indeed depends only
Activation of the kinase mammalian target of rapamycin on the rate of activation, low-threshold axonal channels
complex 1 (mTORC1) is required for synaptic proteins are expected to be more prone to inactivation and there-
translation, and is implicated in synaptic plasticity, learning fore less available at functionally critical subthreshold
and memory. Here, we tested whether reconsolidation of voltages.
alcohol-related memories upon their retrieval activates the Results: We probed the voltage dependence of the axo-
mTORC1 signaling pathway, and whether these memories nal Na+ channel inactivation by measuring changes in
can be disrupted by inhibiting this pathway, with the goal of fluorescence of Na+ -sensitive indicator, SBFI, elicited
preventing relapse to alcohol seeking and intake. by single action potentials in layer 5 pyramidal neurons
Results: Reactivation of alcohol-related memories in- in neocortical slices. As with conventional Na+ current
creased the phosphorylation of the mTORC1 substrates recordings, we assumed that the amplitude of Na+ flux
4E-BP and S6 kinase, and the S6K substrate S6, in the could provide us with an estimate of Na+ channel
S16 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
BAs). The ability to image the cortical sub-structures in- levels. Both kinins had no effect on COX-1 protein levels.
vivo, in 3D and for the whole brain is one of the holy-grails COX-2 mRNA levels were also affected in an opposite
of neuroscience. In this work we utilized inversion-recovery manner by BK and B1 receptor agonist treatments. Several
magnetic resonance imaging (IR-MRI) to detect and char- lines of evidence have demonstrated that MAPK may be
acterize cortical sub-structures via T1 contrast. involved in regulation of expression of PGE2 by kinins in
Results: We show that T1 distribution along the cortex has a various cell types. Specific MAPK inhibitors (U0126 for,
Gaussian mixture that may allow its segmentation into 5-6 ERK1/2 SB203580 and SB220025 for p38- MAPK and
clusters. Clustering analysis of high contrast IR images of SP600125 for JNK) completely abrogated BK and B1R
the cortex appeared to have laminar arrangement (i.e., IR agonist effects on PGE2 synthesis in basal and LPS stimu-
layers). Previous work (Barazany, 2009) showed that there lated astrocytes. Western blot analysis revealed a significant
is a correlation between the IR layers and its histological increase in phosphorylation of ERK1/2 but not of JNK and
cytoarchitectonic characteristics. The purpose of this work p38, after treatment with BK. No change in kinases' phos-
was to examine the IR layers characteristics at different phorylation was observed upon B1 agonist treatment.
cortical BAs, focusing on BAs of the frontal lobe. We show Conclusion: Our results imply, for the first time a dual and
that the width of the IR layers changes significantly between long-term regulatory role of kinins in astrocyte inflammation.
different cortical regions. This observation indicates that the Supported by the Israel Science Foundation (grant No. 101/11)
IR layers has a morphological meaning and can be used for
regional cortical architecture studies both in healthy and The morphology of microglia is altered in aging
diseased human brains. The cellular interpretation of the and in a mouse model of Alzheimer’s disease
IR layers still needs to be investigated. Baron R, Namirovsky A, Monsonego A*
Conclusions: The results of this work indicate that IR could The Shraga Segal Dept. of Microbiology and Immunology,
become a powerful tool for in vivo assessment of cortical Faculty of Health Sciences, and The National Institute of
layers. The proposed methodology can advance our under- Biotechnology in the Negev, Ben-Gurion University of the
standing of the relationship between regional variability in Negev, Beer-Sheva 84105, Israel.
the cortical lamination and function in developing and adult
healthy brains as well as in various neurological and psy- Objective: Microglia are derived from monocyte lineages
chiatric diseases. which reside within the central nervous system (CNS) al-
ready during development once the vasculature is formed.
Astrocyte inflammation: possible role for kinins The cells integrate within the neural tissue exhibiting a
Barinfeld S, Filipovich-Rimon T, Fleisher-Berkovich S* unique ramified morphology which allow them to constant-
Dept. of Clinical Biochemistry and Pharmacology, Faculty ly scan their territory and contribute to neuronal network
of Health Sciences, Ben Gurion university of the Negev, function and repair. Since microglia cells are long-lived they
P.O.B.653 , Beer-Sheva 84105, Israel are subjected to senescence processes. Although studies
have shown that microglia senescence can be reflected by
Background: The nine amino-acid kinin, Bradykinin (BK) morphological changes, detailed quantification of such
is a powerful mediator of peripheral inflammation. Howev- changes are not suficiently established.
er, the role of bradykinin in the regulation of brain inflam- Methods: We developed a digitized tool that allowed us to
mation is not clear. Elevated levels of bradykinin were quantitatively characterize the fine microglia structure in the
found under pathophysiological conditions such as brain brain's cortex of adult mice and the morphological changes the
inflammation. Brain inflammation includes activation of cells undergo with aging and the progression of Alzheimer's-
glial cells, elevated expression of pro inflammatory like disease. In addition we established quantitative methods to
enzymes such as cyclooxygenase and release of inflamma- evaluate the coverage of the neural tissue by resident microglia.
tory mediators such as prostaglandins. The aim of this study Results: We found that compared with microglia in young
was to investigate long term effects of BK and Lys-Des- mice, microglia in mice aged 21 months labeled either by
Arg10-BK (B1 receptor agonist) on prostaglandin E2 GFP expression under the CX3CR1 promoter or immunos-
(PGE2) synthesis in primary astrocytes. Protein and mRNA tained with anti-Iba-1, are less ramified, have decreased
levels of cyclooxygenase species (COX-1 and COX-2), key amount of branches and lower amount of fine processes.
enzymes in PGE2 synthesis, were also measured following Notably, the morphological aberrations of microglia
treatment with BK and B1 receptor agonist. appeared in a mouse model of AD already at 9 months of
Results: In basal and lipopolysaccharide (LPS) - stimulated age associated with the deposition of amyloid plaques.
cells BK increased PGE2 release as well as COX-2 protein Overall, we demonstrate a significant reduction of the vol-
levels by 30 %-40 %. By contrast, B1 receptor agonist ume coverage by individual microglia with age, a process
decreased PGE2 release and COX-2 protein levels to control that is expedited in a mouse model of AD.
S18 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
Conclusions: Our results indicate that microglia are sub- kinematic study with emphasis on the linear / rotational
jected to age- and disease-related changes that may indicate components of the examined movements. Experiments were
their state of activation along with a compromised ability to conducted on two freely viewing perching barn owls in a
support neuronal function and repair. motion-capture system providing kinematic recordings with
very high precision.
A two-signal model for non-pathological activation Results: Peering motions were compared to other motions
of the choroid plexus epithelium for trafficking with regard to the screw parameters describing the motion.
to the central nervous system For both owls, the screw parameters were almost constant
Baruch K, Kunis G, Rosenzweig N, Kertser A, Schwartz M* along peering motions when compared to the reference
Dept. of Neurobiology, Weizmann Institute of Science, Rehovot motions (p<1e-5). Furthermore, the screw intensity (denot-
76100, Israel ing the similarity of the motion with a screw motion) was
found to be smaller in peering motions for both owls (p0
The healthy brain is an immune privileged site, shielded by 0.04 and p00.002, respectively).
barriers from circulating immune cells. Nevertheless, nu- Conclusions: Screw analysis of the peering head motions of
merous studies have suggested that a continuing dialogue barn owl provided a characterization of those peculiar peer-
between the brain and circulating immune cells is needed to ing movements, supposedly used to improve depth estima-
maintain life-long brain plasticity, including neurogenesis, tion. The insights provided by this study will be
cognitive ability, and resilience to stress. Since the blood- implemented on a robotic agent in order to to build a Micro-
cerebrospinal fluid barrier (BCSFB), at the brain's borders, soft's Kinect–mounted mobile robotic platform that would
is constantly exposed to circulating immune cells, we hy- replicate head movements of barn owls to improve robotic
pothesized that at this junction, the choroid plexus (CP) visual acquisition and scene reconstruction.
epithelium can sense signals coming from the central ner-
vous system (CNS) parenchyma via the cerebrospinal fluid T-type calcium channel CaV3.2 upregulation
(CSF) and through dialogue with circulating immune cells, in epileptogenesis: underlying mechanisms
translate them into a reparative or protective mechanism. and functional consequences
Here we found that different T cell populations, with distinct Becker AJ* 1, Schaub C 2,3, Pernhorst K 4, Opitz T 2, Pitsch
cytokine polarities, accumulate at the CP of healthy animals J 4, Beck H. 2, Yaari Y 5, Schoch S 4, Van Loo KM 4
1
and affect the immunomodulatory properties of the CP Dept. of Neuropathology, University of Bonn Medical Center
2
epithelium and its ability to facilitate trafficking of leuko- Laboratory for Experimental Epileptology and Cognition
cytes. We further show that activation of the CP for expres- Research, Dept. of Epileptology, University of Bonn Medical
sion of trafficking molecules is tightly regulated by two Center 3Dept. of Neurology, University of Bonn Medical
signals; with the first signal coming from the CNS paren- Center 4Dept. of Neuropathology, University of Bonn Medical
chyma, and the second from outside the CNS. Taken togeth- Center 5Dept. of Medical Neurobiology, IMRIC, Hebrew Uni-
er, our findings demonstrate that the CP epithelium is versity–Hadassah School of Medicine, Jerusalem
endowed with immunological plasticity allowing it to serve
not only as a filter for CSF nutrients, but also as an active Background: Temporal lobe epilepsy (TLE) is one of the
interface for selection of circulating immune cells, regulat- most common seizure disorders in adults. However, the
ing immune cells trafficking into the CNS. underlying mechanisms during its pathogenesis, collectively
The first two authors contributed equally to this study. referred to as epileptogenesis, are poorly understood. Using
the pilocarpine model of TLE, we have recently found that
Active vision of barn owls: a kinematic analysis the pore-forming T-type calcium channel subunit CaV3.2 is
Barzilay O 1, Gutfreund Y 2, Wolf A* 1 upregulated early in epileptogenesis. Moreover, deleting
1
Biorobotics and Biomechanics Laboratory, Dept. of Me- CaV3.2impeded the development of TLE in this model.
chanical Engineering, Technion I.I.T.2Audiovisual Systems Therefore, we attempted to identify the molecular signaling
Laboratory, Dept. of Medical Studies, Technion I.I.T. cascades involved in CaV3.2 transcriptional regulation.
Results: First, we determined the promoter region in silico
Background: Most animals use their vision as an active and observed stimulatory and inhibitory clusters. Further-
process. The combination of vision with the motion of more, we found binding sites for the transcription factor
sensory organs generally enhances the quality and quantity early growth response 1 (Egr1/Zif268/Krox-24) and the zinc
of the acquired visual information. In this study, we have sensor metal-regulatory transcription factor-1 (MTF1) to be
investigated head movements of barn owls (tyto alba) with highly overrepresented within the CaV3.2 promoter region.
advanced kinematic tools from screw theory, with focus on mRNA expression analyses and dual-luciferase promoter
side-to-side peering head motions. Screw theory allows a assays revealed that the CaV3.2 promoter was strongly
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S19
activated by the two transcription factors. Congruently, plasticity, consistent with Tomosyn's acting role as a nega-
whole-cell T-type calcium currents were significantly larger tive controller of the vesicle release mechanism. Our find-
after Egr1 and MTF1 overexpression. Furthermore, rAAV- ings also highlight both the feasibility and the potential
mediated overexpression of these factors in mice hippocam- power of combining optogenetics and gene targeting
pi in vivo also caused CaV3.2 upregulation. approaches in order to investigate molecular mechanisms
Conclusions: The transcription factors Egr1 and MTF1 reg- of presynaptic release at central synapses.
ulate CaV3.2 promoter activity and mRNA expression and
hence, the size of T-type calcium currents. These findings Evaluation of the CerS2 null mice brain pathology
may provide new possibilities for pharmacological interven- Ben-David O, Klein A, Futerman AH*
tion aimed at preventing the process of epileptogenesis. Dept. of Biological Chemistry, Weizmann Institute of Science,
Supported by GIF, DFG (KFO 177), BMBF (NGFNplus), Rehovot 76100, Israel
ESF & BONFOR.
Sphingolipids (SLs) are highly enriched in the CNS, espe-
Optogenetic in-vitro activation of hippocampal mossy cially in myelin where they account for more than half of the
fiber synapses reveals major role for tomosyn total lipid content. The lipid composition of different brain
in short-term plasticity areas and brain components was studied in detail in the
Ben Simon Y* 1,2, Castillo PE 3, Ashery U 1,2 1960s and it has been documented that different lipids are
1
Dept. of Neurobiology, Life Sciences Institute, Tel Aviv found in specific cells and regions of the CNS. There are
University, Tel Aviv, Israel 2Sagol School of Neuroscience, exciting clues that levels of ceramides and SLs with defined
Tel Aviv University, Tel Aviv, Israel 3Dominick P. Purpura acyl chains lengths change in a number of neurological
Dept. of Neuroscience, Albert Einstein College of Medicine, conditions. The discovery of the six ceramide synthases
Bronx, NY, USA (CerS) conveyed new information implying that the acyl
chain length is of great importance in both physiology and
Background: Tomosyn is an evolutionary conserved, in pathophysiology. Recently, our laboratory has generated a
syntaxin-binding protein that inhibits vesicle release in sev- CerS2 null mouse. CerS2 is the most ubiquitously expressed
eral invertebrate models, as well as in mammalian chromaf- CerS and has the broadest tissue distribution. This mouse
fin cells. The role of Tomosyn in regulating neurotransmitter showed abnormal bilateral and symmetrical vacuolization
release in the mammalian CNS, however, remains poorly and gliosis in specific brain areas. Myelin degeneration and
understood. Interestingly, Tomosyn is highly expressed at detachment was also observed, probably due to reduced
hippocampal mossy fibers (MFs), the axons of dentate gran- levels of galactosylceramide, a major component of myelin.
ule cells that synapse onto CA3 pyramidal neurons. In this Additional abnormalities included convulsions originating
study, we sought to determine the role of tomosyn in setting from a sub-cortical region and striking alterations in their
the characteristically low initial release probability (Pr) ob- circadian rhythms, in the middle of the night their activity
served at the MF synapse. To this end, we injected into the drops down dramatically. Moreover, young CerS2 null mice
dentate gyrus lentiviral particles containing both a tomosyn present higher levels of anxiety measured in a bright open
RNAi sequence and ChIEF - a channelrhodopsin2 variant field arena and showed longer reaction times in acoustic startle
with improved activation kinetics. Acute hippocampal slices response measurements. In the Pre Pulse Inhibitory (PPI)
were prepared 1-2 weeks following injection and extracel- paradigm CerS2 null mice do not respond in reducing their
lular MF responses in the CA3 area were elicited both reaction time, as expected. These results show that ceramides
optically, enabling activation of RNAi-expressing cells only, play a critical key role in brain function and they might be
and electrically by bulk stimulation of MFs. Tomosyn involved in the pathogenesis of psychiatric disorders. Through
knock-down effects on short-term plasticity were assessed the analysis of the CerS2 null mouse brain and the distribution
by measuring the change in response to various stimulation of the different CerS in different cell types of the CNS we will
paradigms. try to shed some light on the relation between known neuronal
Results: When stimulated optically, tomosyn RNAi- conditions and psychiatric disorders, and SLs composition.
expressing synapses exhibited a significant reduction in various
forms of activity-dependent facilitation, compared to a control Time limited functional properties of transplanted neural
group, consistent with an increase in basal Pr. However, this stem cells
effect was hardly observed when the same slices were stimu- Fainstein N, Einstein O, Cohen M, Ben-Hur T*
lated electrically and uninfected neurons were inevitably Dept. of Neurology, Hadassah University Hospital
recruited along with the infected ones.
Conclusions: These data strongly suggest that Tomosyn Neural stem cells (NSC) possess powerful immunomodula-
levels at MF terminals regulate short-term synaptic tory and neurotrophic properties. NSCs effectively attenuate
S20 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
neuroinflammation, protect the brain from immune- dimorphic neuronal circuit with direct relevance for
mediated injury and facilitate its self repair capacity. How- reproductive behavior.
ever, the therapeutic value of NSC therapy in chronic dis-
eases is critically dependent on their long term functions. Conditioned sexual aversion
We therefore examined whether transplanted NSCs maintain Beny Y*, Kimchi T
their immunomodulatory and trophic properties over time. Dept. of Neurobiology, Weizmann Institute of Science, Rehovot
Transplanted NSCs could not support their own long term 76100, Israel
survival, becoming highly dependent on environmental
cues. Damaging versus induction of a local neurogenic To ensure survival and reproduction, animals recognize their
environment significantly compromised or improved graft conspecifics via detection of pheromones, and engage in
survival, respectively. In accordance, long term cultured innate, gender-specific social behaviors. Sexual preference is
NSC spheres exhibited dramatic decline in proliferative defined as the attraction male mice have for female conspe-
activity, increased apoptosis and reduced neurotrophic fac- cific odors, versus male odors. This preference is innate, and
tor secretion. thought to be 'hard-wired' and genetically programmed in the
Then, in two experimental paradigms, intracerebroventricu- nervous system. This study was set to test the influence of
lar transplanted syngeneic NSCs attenuated an early relapse negative environmental stimuli on pheromone-mediated in-
of experimental autoimmune encephalomyelitis, but failed nate responses, such as sexual olfactory preference, sexual
to inhibit delayed relapses, albeit good survival of trans- behavior and aggressive behavior.
plant. Moreover, following allogeneic transplantation, NSC We applied the conditioned olfactory aversion (COA) para-
grafts failed to inhibit the allogeneic immune reaction and digm on adult wild-type (wt) male mice. Mice learned to
were rejected from the host brain. In correlation, long term associate soiled bedding embedded with female odors with
cultured NSCs lost their capacity to inhibit immune cell delayed lithium-chloride (LiCl) toxicosis, and were tested
proliferation in vitro. In conclusion, long-term functional for their olfactory preference and sexual behavior towards a
changes in transplanted NSCs lead to loss of their therapeu- female intruder. In addition, in order to examine the lasting
tic immunomodulatory and neurotrophic properties. period of this unique association we applied an extinction
Supported by The Taubman Foundation protocol at the end of the experiment.
Results show that following LiCl injections, wt male mice
Sexually dimorphic processing of social cues in the medial learned the aversion to female odors and as a consequence
amygdala: functional and developmental aspects their initial sexual olfactory preference disappeared. Fur-
Ben-Shaul Y* 1, Bergan J 2,3, Dulac C 2,3 thermore, the olfactory conditioned male mice were tested
1
Dept. of Medical Neurobiology, Hebrew University Medical for their behavioral responses toward intruder female mouse.
School 2Dept. of Cellular and Molecular Biology, Harvard Surprisingly, the manipulated males presented avoidance be-
University 3Howard Hughes Medical Institute havior from the female and engaged in significantly less sexual
behavior (mounting and pelvic thrusts) in compared to the
Different individuals display varied responses to given stimuli. control male mice. In the extinction assay, we found that the
A consistent and dramatic example involves the distinct be- preference to female over male odors was regained after two
havioral and physiological responses of males and females to weeks, however the behavioral course persisted. These results
socially relevant cues. The reproducibility of these sex specific indicate that negative past experience can alter male innate
behaviors implies the existence of sex-specific differences in sexual preference and affect its evolutionary reserved behavioral
the neuronal circuits that process such information. However, sequence towards a female conspecific. The neuronal circuits
how differences in neuronal function lead to such behavioral and processes which are involved in this behavioral change
differences remains poorly understood, particularly in mam- remain to be elucidated.
mals. To understand the mechanisms that account for these
differential behaviors, we measured neuronal responses to Decreased "Default-Mode" activity in trained meditators
social stimuli in male and female mice in the first two brain Berkovich-Ohana A*, Arieli A, Malach R
relays along the vomeronasal pathway. Our recordings The Weizmann Institute
revealed that striking changes in neuronal response properties
emerge at the level of the vomeronasal (medial) amygdala, but Background: A growing body of brain imaging research
not in the previous processing stage (the accessory olfactory has focused on "task-negative" brain responses - in which
bulb). Experiments with juveniles and with hormonally chal- performing an extrinsically oriented task leads to reduced
lenged mice indicate that this dimorphism is not present at brain activation compared to baseline, "resting-state" condi-
birth, but rather appears around the time of puberty. Our tion. The source of this task-negative response is still debat-
results thus provide a striking example of a sexually ed; however we have proposed that it reflects a spontaneous
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S21
tendency to shift attentional resoruces intrinsically during cerebral artery occlusion in the rat, results either in over-
rest (Preminger et al., 2010). An interesting question con- expression of TRAIL in the corresponding ischemic areas,
cerns the manifestation of such default responses in individ- and in attenuated expression of its neutralizing decoy recep-
uals that were trained over extended periods in meditation tors. Preconditioning, a mild, transient subocclusion of the
methods. Here, we investigated this issue by comparing the middle cerebral artery, is a neuroprotective modality that
magnitude of default responses in untrained individuals and prevents extensive ischemic damage and is associated with
individuals trained for 16.5 y years (avg.) in Mindfulness significantly attenuated expression of TRAIL and its death
meditation (MM). receptors in the neurons of the ischemic area.
Methods: fMRI data was collected from 15 proficient MM Conclusions: The bulk of these data clearly shows that
and 23 control participants during a DMN visual localizer, TRAIL is a potent mediator of cell death associated with
and a "thoughtless" instructed condition. neuroinflammatory processes, and that neutralization of its
Results: Comparing the controls with the MM revealed a detrimental effects results in restraint of neural damage. It is
significantly higher "Default" activation in the controls thus plausible to hypothesize that the TRAIL system repre-
compared to the meditators. Similarly, the "thoughtless" sents a relevant target for innovative treatment of central
condition showed a weaker level of inhibition in the medi- nervous system disorders.
tators compared to the controls.
Conclusion: Our results show a reduced level of "rebound" The effect of grouping on neural competition
signals during rest in long term meditators. A likely source in object-category selective cortex
of this effect may be a better ability of the meditators to Bernstein M 1,2, Yovel G* 1,2, Oron J 1,2, Sadeh B 1
1
prevent a spontaneous lapse into intrinsic processing and School of Psychological Sciences, Tel Aviv University
2
"mind wandering" during rest. Sagol School of Neuroscience, Tel Aviv University
Preminger, S., Harmelech, T., & Malach, R. (2010).
Stimulus-free thoughts induce differential activation in the Background: Single-cell electrophysiology studies have
human default network. NeuroImage, 54, 1692–1702. shown that multiple stimuli presented simultaneously in
the cell's receptive field compete for representation by mu-
Proinflammatory cytokines a potential targets tually suppressing neural responses. Suppressive interac-
for therapeutic intervention in central nervous system tions among multiple stimuli have been also reported in
disorders fMRI studies that showed lower fMRI signal to simulta-
Bernardini R*, Di Benedetto G, Cantarella G neously presented stimuli than to the same stimuli presented
Dept. of Clinical & Molecular Biomedicine, Univ. of Catania sequentially. These fMRI studies have so far examined such
Medical School, 95125 Catania, Italy competition effect only for low-level stimuli (e.g. gabor
patches). In the present study we aimed in examining wheth-
Background: Cytokines of the TNF superfamily sustain er such effect of neural competition also exists for preferred
inflammation and eventually cell death, by activation of and non-preferred stimuli in object category selective brain
downstream apoptosis pathways set into motion after bind- areas. In addition, we asked whether grouping of two simul-
ing with specific death receptors. The expression of proin- taneously presented stimuli would reduce this competition
flammatory/proapoptotic cytokines is inducible by noxae, effect. We presented pairs of faces and headless bodies
such as proteins, trauma, and ischemia. Tumor necrosis above and below fixation simultaneously or sequentially.
factor related apoptosis inducing ligand (TRAIL) is a mem- Results: Our results show significant competition effect
ber of the TNF family which induces death of both tumor between two faces presented simultaneously in the face-
and normal cells. selective areas, and between two bodies presented simulta-
Results: Human neurons exposed to the Alzheimer's neously in the body-selective areas. Competition was also
disease-related neurotoxic protein amyloid-beta (AB), dis- found when a body was presented above a face, but was
play increased expression of TRAIL and its death receptors. reduced when a face was presented above a body, generating
On the other hand, a TRAIL neutralizing antiserum rescues the perception of a person.
numerous AB-challenged neurons from apoptotic death. Conclusions: Our findings show neural competition be-
Similarly, the exceeding apoptotic rate associated with me- tween multiple object stimuli in object category selective
chanical spinal cord injury is also sustained by TRAIL, cortex. They also show that competition in object-selective
which, in addition, recruits other cytokines, such as FasL areas occurs between objects, and not between features
and IL-1, that sinergistically contribute to enlargement of within an object, therefore, once stimuli are grouped togeth-
damage. Either spinal neuron apoptosis rate and consequent er by perceptual organization processes, they are perceived
functional deficit are significantly attenuated by administra- as a unit rather than two competing stimuli, and neural
tion of anti-TRAIL serum in the mouse. Moreover, middle competition is reduced.
S22 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
Implementing novel methods for evaluating consciousness and ages are capable to read faster than their routine
in chronic vegetative subjects reading rate, and thereby enhance their reading decod-
Bick AS*, Levin N ing and comprehension (Breznitz, 2006). Based on the
fMRI unit, Dept. of Neurology, Hadassah Hebrew- idea of the brain's plasticity and ability to change, these
University Hospital, Jerusalem, Israel two theories were combined and had been the bases for
the creation of the Reading Acceleration Training Pro-
Background: The clinical evaluation of consciousness in gram (RAP) for reading skills enhancement of dys-
coma patients based on their exhibited behavior is difficult lexics. The current study was design to investigate the
and remains erroneous in many cases. Coleman et al (2009) RAP effect on immediate and long post retention on
demonstrated different levels of hierarchical auditory pro- brain activity and reading skills improvement in 20
cessing in patients suffering from disorders of conscious- experimental and 20 waitlist dyslexic readers (-1.s.d in
ness. Moreover a few patients were able to perform willful reading test). ERP's and behavioral measures were
modulation of their brain activity (Monti, 2010) and this obtained.
method was used to communicate with one of the patients. Results: Evidence indicated a significant effect of RAP
These promising results were used to implement a clinical on decoding and fluency skills of the research groups.
service for consciousness evaluation done by the fMRI unit Furthermore an effect of higher amplitudes of N170
in Hadassah. ERP component in the FFA post training was also
Results: 10 subjects were scanned so far. Patients (ages 11- found. However the retention of these effects after
67) were all diagnosed as vegetative state or minimal con- 4 months was moderate.
scious. Patients suffered from traumatic brain injury (6) or Conclusions: An immediate effect of the RAP training
anoxic brain damage (4). The main challenges in translating on the improvement of reading skill and brain activity
this test to clinical diagnosis are the uncontrolled motion of of dyslexic reader was found. However for long post
many patients and the severe brain damage that creates ex- retention of these effects a booster regime of the RAP
treme difficulties in recognition of brain structures. In some training was suggested. Furthermore our results also
patients accuracy of results is questionable due to the signif- raised the question of whether remediation induced per-
icant artifacts. Functional tests included a hierarchical auditory formance gains, reflect an enhancement of previously
test (patients heard noises, language like non words, words (in established processing routines or rather the establish-
familiar and non-familiar voices), their name), an imagery ment of new, alternative, processing routines. This issue
task, and a visual task. While in 8 patients auditory related is directly related to the acceleration paradigm, since it
activation was found, only in 4 differential activation was is conceivable that above a certain stimulus presentation
found for language. 5 of the patients showed differential speed the brain cannot handle the information by rely-
response to their own name. In three patients a response to ing on pre-existing routes and is forced to resort to new
visual stimuli was identified. In one patient the auditory and solutions.
linguistic systems were clearly activated in a hierarchical This study was supported by the Edmond J. Safra
pattern, and moreover willful modulation of brain activity Philanthropic Foundation.
was identified in the imagery test.
Conclusion: FMRI can reveal the existence of awareness The effects of discrimination type and setting
without open channels of communication. Our results show on the electrophysiology of speech processing in humans
the possibility of using fMRI as a clinical tool to assess Pratt H1, Horev N1, Starr A2, Bleich N1, MittelmanN1
1
consciousness and thus improve diagnosis and supply a Evoked Potentials Laboratory, Technion - Israel Institute of
good marker of prognosis. Technology, Haifa, Israel, 2Neurology Research Laboratory,
University of California, Irvine, USA
Can we train the dyslexic's brain to read better?
Binur N, Breznitz Z* Background: Speech discrimination is based on both spectral
The Edmond J. Safra Brain Research Center for the Study of and temporal acoustic cues. In non-speech auditory stimuli
Learning Disabilities, University of Haifa these cues are processed differently in the brain but they have
not yet been studied in relation to speech perception.
Background: The Asynchrony theory suggests that the The electrophysiology and spatiotemporal distribution of
brain systems of dyslexic readers activated during read- speech processing in humans were used to compare processing
ing process information on a different time scale. A of consonants discriminated by spectral and temporal cues.
wider speed of processing gap impairs the between Results: Subjects were presented with series of vowel-
system integration resulting in dyslexic readers. The consonant-vowel (VCV) stimuli comprised of different stimuli
Acceleration theory maintains that readers at all levels along a temporal continuum between clearly distinguished /
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S23
ubu/ and /upu/, with 3 ambiguously distinguished VCV stimuli revealed weakly defined vascular domains with no spa-
with intermediate closure durations to determine processing of tial correlation to cortical columns. Further, point-to-
temporal cues. A series of stimuli along a spectral continuum point resistance analysis revealed that the microvascula-
between clear /ubu/ and /udu/, with 3 intermediate ambiguous ture behaves as a regular lattice.
VCVs were presented to study processing of spectral cues. Conclusions: Overall, our findings support the alternative
Brain potentials include an onset P1, N1, P2 complex and hypothesis where cortical columns are embedded in a homo-
sustained negativity lasting hundreds of msec. While responses geneous vascular network. We conclude that experimentally
to the onset vowel were the same across settings, the consonant- observed micro-stroke vascular dynamics results from the dis-
evoked latencies were sensitive to voice-onset time. The sus- crepancy between the resistance of penetrating arteries and
tained negativity was larger in spectral than temporal discrim- veins vs. the microvasculature. In turn, the combined blood
ination and largest in the mixed setting. rheology and the vascular structure allows for control of vas-
Spatiotemporal distributions of brain activity associated with cular dynamics with minimal changes in capillary diameters.
processing consonants vary between spectral and temporal
discrimination, and depend on the context in which discrimi- ApoE4 induces Aβ42, tau, and neural pathology
nation is performed, i.e., in temporal, spectral or mixed settings. in the hippocampus of young targeted replacement
Conclusions: Brain activity to speech VCV discriminations is apoE4 mice
sensitive to spectral and temporal acoustic cues, is associated Boehm A, Liraz O, Michaelson DM*
with different distribution in the brain and is modulated by Dept. of neurobiology, Tel Aviv University, Tel Aviv
listening circumstances.
Background: Recent findings suggest that the pathological
Highly interconnected microvasculature supports effects of apoE4, the most prevalent genetic risk factor for
restricted blood flow independent of columnar Alzheimer's disease (AD), start many years before the onset
boundaries of the disease and are already detectable at a young age. In
Blinder P1,Tsai PS2, Kaufhold JP3, Knudsen PM2, Suhl P2 the present study we investigated the extent to which such
and Kleinfeld D2,4 pathological and cognitive impairments also occur in young
1
Department of Neuroscience, Tel-Aviv University, Tel-Aviv, apoE4 mice.
Israel 2Department of Physics, UCSD, La Jolla, CA, USA Results: Our work revealed that the levels of the presynaptic
3
SAIC Intelligent Systems Division, Arlington, VA 4Section glutamatergic vesicular transporter, VGlut, in the CA3,
of Neurobiology, UCSD, La Jolla, CA, USA CA1, and DG hippocampal subfields, were lower in hippo-
campal neurons of young (4-month-old) apoE4-targeted
Background: Proper brain function depends on the contin- replacement mice than in those of the corresponding apoE3
uous blood flow supply. Increase in neuronal activity results mice. In contrast, the corresponding inhibitory GABAergic
in a localized vascular response with amplitude and sign nerve terminal and perikarya were not affected by apoE4.
dependent on a plethora of factors. Past methodologies used This synaptic effect was associated with hyperphosphoryla-
to understand the organization of this interface at the cortical tion of tau in these neurons. In addition, apoE4 increased the
column level lacked the ability to jointly resolve the vascu- accumulation of neuronal Aβ42 and induced mitochondrial
lar network structure while directly measuring the location changes, both of which were specifically pronounced in
of cortical columns. Here, we obtained complete vascular CA3 neurons. Spatial navigation behavioral studies revealed
networks concomitant with the location of all neurons and that these hippocampal pathological effects of apoE4 are
non-neurons across several cubic millimeters of mouse so- associated with corresponding behavioral impairments.
matosensory cortex at μm3/voxel spatial resolution. We set Time-course studies revealed that the effects of apoE4 on
to clarify whether the vasculature is organized as units tau hyperphosphorylation and the mitochondria were al-
around cortical columns or –alternatively– embedded in a ready apparent at the age of 1 month and that the apoE4-
continuum of vasculature. This bears on the interpretations driven accumulation of neuronal Aβ and reduced VGlut
of BOLD-based imaging methods and on the overall control levels evolve later and are apparent at the age of 2-4 months.
of functional hyperemia. Conclusions: These findings show that apoE4 stimulates
Results: Three major topologies can be identified in the the accumulation of Aβ42 and hyperphosphorylated tau
cortical vasculature: a robust surface network, penetrat- and reduces the levels of VGlut in hippocampal neurons of
ing vessels and a mesh-like microvasculature. Penetrat- young apoE4-targeted replacement mice. These neurochem-
ing arteries and veins show a weak tendency to plunge ical effects are associated with cognitive impairments. This
outside the perimeter of cortical columns. Interestingly, model is not associated with hypothesis-driven manipula-
we find less penetrating arteries than cortical columns. tions and is thus most suitable for unbiased studies of the
Topological analysis and blood flow simulations mechanisms underlying the pathological effects of apoE4.
S24 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
Functional connectivity and mechanisms unable to perceive multiple objects simultaneously, a fact
of synchronization in finite size neuronal networks preventing them from understanding the visual scene de-
Bonifazi P* 1, Goldin M 1, Kanner S 2, Galron R 2, Herzog spite correct identification of individual visual objects
N 3, Hanein Y 3, Barzilai A 2, Ben-Jacob E 1,4 (simultanagnosia). Here we report a series of observations
1
School of Physics and Astronomy, Tel Aviv University with DP, a patient with rare stroke-related pattern of damage
2
Dept. of Neurobiology, Tel Aviv University 3School of Elec- affecting the right and left posterior parietal cortex (PPC)
trical Engineering, Tel Aviv University 4Center for Theoret- that appear to shed some new light on the syndrome and on
ical Biological Physics, Rice University Houston, USA the role of PPC in conscious perception.
Results: (1) Visual disappearance or fading of salient
Background: One of the main challenges of modern neu- objects or object parts such as face parts or even a single
roscience is to understand how network dynamics are relat- patch on a blank screen whose alternating onsets and offsets
ed to anatomical connectivity. Recently, it has been every few seconds could be reported, as well as anti-
demonstrated the existence of functional connector "hubs" correlated disappearance of two competing objects such as
in the developing hippocampus where such a function is met orthogonal bars (2) Spatial crowding in which a surprisingly
by a heterogeneous subpopulation of pioneer GABAergic intact ability to identify very small digits or color patches
interneurons that display widespread axonal projections. was dramatically degraded with flanking patterns. (3) A
GABAergic hub cells play a central role in the coordination severe deficit in reporting the relative position of objects
of early network synchronizations combining high function- or point to marked locations on a touch screen; (4) Preserved
al, effective and structural connectivity. Are hub neurons ability for perceptual grouping of dot arrays even when
common components of all growing neuronal networks or partially invisible, in a size averaging task. While some
other mechanisms/topologies emerge? of these findings have been previously reported, the
Results: We try to address this question in finite-size neu- dynamic fading and alternating perception of even an
ronal networks grown in culture which may represent a isolated small patch as well as large fragments of the
general model of self-organized neuronal circuits not visual scene, coupled with these findings, is novel, and
depending on a specific architecture. Given the small size is not consistent with common single-object perception
of these circuits, a complete functional-morphological char- descriptions of this syndrome, and theorizing stressing
acterization can be obtained through calcium imaging and global/focal imbalance.
immunohistochemistry. Similarly to the developing hippo- Conclusions: We propose that the PPC serves as a short-
campus, finite networks display spontaneous network syn- term data holding mechanism for spatially coded informa-
chronizations or bursts. Functional connectivity analysis tion by which internal and external context factors can
revealed that cells early activated during global network modulate perception-action and perception-declaration
synchronizations are additionally involved in synchronous links. Bilateral PPC damage causes simultanagnosia be-
inter-bursts events involving a small subset of neurons. cause of failed maintenance of visual information in
Conclusion: These results suggest that a highly synchronous spatio-temporal working memory.
sub-network might regulate and coordinate global network
synchrony. Targeted stimulation through optogenetics will Holistic representation of bodies in body-selective
be next implemented to map the effective connectivity and occipital-temporal areas
the impact of single cell firing on network dynamics. Brandman T*, Yovel G
Shein-Idelson M. for patterning, Brainis I. for cell culture, School of Psychological Sciences & Sagol School of Neu-
David-Pur M. for silicon processing roscience, Tel Aviv University
Occasional access of some trees to conscious awareness Background: The discovery of specialized processing mech-
with no vision of the forest – insight on PPC contribution anisms for human bodies, including body-selective areas in
to perception from a case study of simultanagnosia occipital-temporal cortex and the body inversion effect, has
Bonneh YS* 1 , Pavlovskaya M 2,3 , Hochstein S 4 , led to the suggestion that like faces, bodies are processed by
Soroker N 2,3 holistic mechanisms. Supporting evidence includes behavior-
1
Dept. of Human Biology, University of Haifa 2Loewenstein al whole-part and composite effects, and a step-like increase in
Rehabilitation Hospital, Raanana3Sackler Faculty of Med- response of the fusiform body area to large relative to
icine, Tel-Aviv University, Tel-Aviv 4Life Sciences Institute, small body parts. Here we used fMRI to examine
Hebrew University, Jerusalem whether body-selective areas prefer a whole body over
the sum of its parts. Subjects were presented with
Background: Patients with Balint syndrome following bi- blocks of faceless bodies with and without heads, in
lateral parietal damage are typically described as being either whole or dispersed sum-of-parts configuration.
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S25
For each subject we located face, body and object- "reprogram" the development of dendrites and synapses in
selective areas with a separate functional localizer scan. order to adapt to a stressful environment.
Results: Body-selective areas showed a higher average re- Suuported by grants from GIF and BMBF
sponse to whole bodies vs. sum-of-parts for both intact and
headless bodies. The fusiform face area (FFA) showed higher Acetylcholine receptors and the immune system
average response to whole vs. sum-of-parts only for intact Brenner T* 1, Sicsic C 1, Nizri E 2
1
bodies, not headless. The occipital face area (OFA) and the Hadassah Medical Center, Jerusalem 2Sourasky Medical
object-general areas showed no preference for whole over sum- Center, Tel Aviv
of-parts. Pattern classification analysis revealed above chance
classification of whole vs. sum-of-parts in body-selective areas Research done in recent years pointed to a novel function of
for both intact and headless bodies. The FFA showed above- cholinergic transmission. It has been shown that cholinergic
chance classification for intact bodies but not for headless, transmission can modulate various aspects of the immune
whereas classification in OFA was below chance for both. function, whether innate or adaptive. Cholinergic transmis-
Conclusions: These findings suggest that holistic represen- sion affects immune cell proliferation, cytokine production,
tation of human bodies uniquely exists in body-selective T helper differentiation and antigen presentation. These
areas, but not in object-general areas. The response of effects are mediated by cholinergic muscarinic and nicotinc
face-selective areas depended on the presence of the head receptors and other cholinergic components present in im-
and may reflect face mechanisms, which are more likely to mune cells, such as acetylcholinesterase (AChE) and chol-
be generated by whole intact bodies than by headless bodies ineacetyltransferase. The α7 nicotinic acetylcholine receptor
or dispersed sum-of-parts. was designated anti-inflammatory activity and has shown
promise in pre-clinical models of inflammatory disorders.
Early life stress induces histone modifications We studied the various components of the immune cholin-
in the prefrontal cortex and hippocampus ergic system, and specifically the immunomodulatory
Xie L* , Braun K , Bock J effects of α7 activation. This activation can be accom-
Dept. of Zoology/Dev. Neurobiology, Institute of Biology, plished either by direct stimulation or indirectly, by inhibi-
Otto von Guericke University Magdeburg, Germany tion of AChE. Thus, the presence of the immune cholinergic
system can pave the way for novel immunomodulatory
Background: Early-life stress programs a life-long risk for agents, or to the broadening of use of known cholinergic
developing behavioral dysfunctions and mental disorders. agents.
We tested the hypothesis that this vulnerability is mediated Israel Ministry of Health
by persistent memory traces on our genes, which result in
altered neuronal and synaptic development of emotionally Automatic bias of temporal expectation following
relevant brain circuits. Using maternal separation as early temporally regular input independently of high-level
life stressor we analyzed two main key players underlying temporal expectation
experience-induced synaptic plasticity, ARC and EGR1. Breska A* 1, Deouell LY 1 2,3
1
Results: Gene expression analysis revealed elevated ARC Dept. of Psychology , The Hebrew University, Jerusalem
2
and EGR1 mRNA in the hippocampus (HIP) of stressed Edmond and Lily Safra Center for Brain Sciences, The
animals compared to unstressed controls, whereas the pre- Hebrew University, Jerusalem 3Interdisciplinary Center for
frontal cortex (PFC) was not affected. Western blot revealed Neural Computation, The Hebrew University, Jerusalem
that the protein levels of acetylated histone H3 (Ac-H3) and
H4 (Ac-H4) were elevated in the HIP of stressed animals. The processing of a target event is facilitated if its timing is
Using chromatin immunoprecipitation-quantitative poly- known, e.g. if it appears in phase with a preceding temporally
merase chain reaction (ChIP-qPCR) to investigate the asso- regular input. This effect has been attributed to automatic
ciation between histone acetylations and the promoter entrainment of internal oscillators to the input frequency and
regions of ARC and EGR1 gene we found that promoter phase (exogenous expectation). However, the timing of an
region expressions of ARC and EGR1 gene, which are event can also be expected based on voluntary shifting of
associated with Ac-H4, were significantly increased in the attention to an explicitly memorized interval, and the involve-
HIP and PFC of stressed mice. Furthermore, increased ment of such endogenous factors in facilitation following
expression of EGR1 promoter region was associated with Ac- rhythmic input was not examined. Here, we presented a visual
H3 in the PFC but not in the HIP of stressed mice. target following regularly flickering stimuli, and examined the
Conclusions: Taken together these results indicate that the facilitative effect of the rhythm (faster responses for target in
stress-induced activation of ARC and EGR1 transcription is phase vs. target out of phase) in three block types: 'exogenous',
presumably regulated by histone acetylations and thereby in which rhythm phase was not predictive of target timing;
S26 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
'endogenous entrainment', in which rhythm phase validly Conclusions: These studies have identified a novel circuit-
predicted target timing; 'endogenous-exogenous conflict', in based control of prolactin that suggests novel therapeutic
which subjects were endogenously cued to attend to a mem- targets for hyperprolactinaemia and related reproductive
orized interval, while rhythm phase was not predictive. We disorders. By changes in the discharge pattern and action
found a facilitative effect for the rhythm in the all conditions, potential waveform of TIDA neurons, pituitary concentra-
with similar magnitude in the exogenous and conflict blocks, tion of dopamine may be tuned to adjust serum prolactin
but larger than both in the entrainment block. Importantly, the levels to reproductive demands.
facilitation effect in the conflict block was independent of the Supported by a European Research Council Starting Grant
interval expected based on the color cue, or its validity effect. to CB.
EEG analysis revealed that the CNV, a potential assumed to
reflect expected interval, was driven by the rhythm, suggest- The anticoagulant Protein S mediates TAM signaling
ing that the behavioral effect reflected directional bias of in the Retina to prevent photoreceptor degeneration
temporal expectation by the rhythm, and not general conflict. Burstyn-Cohen T* 1, Lew EL 2, Través PG 2, Burrola PG 2,
In a second experiment subjects did not perform endogenous Hash JH 2, Lemke G 2
entrainment blocks, thus eliminating the possibility that the 1
The Institute of Dental Sciences, Hebrew University –
exogenous effect in the conflict block results from task con- Hadassah, Jerusalem 91120, Israel 2Molecular Neurobiology
fusion. Yet, the results for the exogenous and the endogenous- Laboratory, The Salk Institute, La Jolla, CA 92037 USA
exogenous conflict blocks were replicated. In conclusion,
regular rhythms bias temporal expectation even in the pres- Background: The daily Phagocytosis of photoreceptor out-
ence of voluntarily high-level expectation. er segments is essential for retinal viability, and is mediated
by the Mer tyrosine kinase receptor. Mutations in Mer are
Modulation of tuberoinfundibular dopamine neurons: implicated in retinal degeneration in mice, rats and humans.
novel mechanisms for prolactin control The two ligands that bind and activate Mer are Gas6 and
Broberger C*, Stagourakis S, Hellysaz A, Lyons DJ Protein S. In-vitro experiments suggested that Gas6 is the
Dept. of Neuroscience, Karolinska Institutet, Stockholm, relevant ligand; however Gas6 KO mice do not exhibit
Sweden retinal degeneration. The hypothesis that the blood antico-
agulant Protein S is a ligand for Mer-mediated photorecep-
Bachground: Pituitary release of the hormone, prolactin, is tor phagocytosis was put to test in-vivo.
controlled by tonic inhibition from hypothalamic neuroendo- Results: We generated a conditional KO mouse for Protein
crine tuberoinfundibular dopamine (TIDA) neurons. We re- S to investigate its role in retinal homeostasis. We generated
cently demonstrated that TIDA neurons discharge in a two mouse lines mediating Protein S deletion in Retinal
synchronized gap junction-dependent oscillation (Lyons DJ et Pigment Epithelium (RPE) cells, and in the neural retina.
al., Neuron, 2010). This finding begs the question: are the These retinas were analyzed for retinal degeneration by
network properties of TIDA neurons a target for neuromodu- histology. We also generated double Protein S and Gas6
lation in prolactin release, and if so, through what mechanisms? KO mice to address potential ligand redundancy. We find
Results: Whole-cell patch clamp recordings were performed that retinal deletion of either Gas6 or Protein S alone does
on slice preparations of the male rat mediobasal hypothala- not affect retinal homeostasis up to the age of 12 weeks.
mus, and ion conductances were identified by pharmacolog- However, concerted deletion of both ligands fully reprodu-
ical manipulation and ion substitution experiments. ces the Mer phenotype, resulting in complete retinal degen-
Thyrotropin-releasing hormone, a stimulator of prolactin re- eration at the age of 12 weeks.
lease, was found to depolarize TIDA cells, shifting phasic to Conclusions: We have generated a conditional KO
tonic firing, by activating a TRP-like conductance. Adminis- mouse model for Protein S. Using this mouse , we
tration of prolactin itself caused a similar TRP-dependent show that Protein S is a biologically functional TAM
depolarization but in addition also spike broadening through ligand with a key role in maintaining retinal homeosta-
inhibition of a Ca2+-dependent K+ conductance. Thus, neg- sis. Our results suggest that Protein S and Gas6 act in
ative prolactin feedback may involve causing TIDA cells to concert to activate Mer, thus allowing for the successful
discharge not only more, but also more efficient action poten- phagocytosis essential to maintain retinal homeostasis.
tials, leading to higher dopamine release. Finally, local appli- This raises the possibility that Protein S may function as
cation of serotonin, another transmitter that stimulates a signaling molecule to activate the TAM pathway in
prolactin release caused TIDA neurons to hyperpolarize, abol- other biological settings where TAM signaling is
ishing the oscillation and all action potential discharge. These activated.
actions were the result of the opening of G-protein coupled Funding for this project was received from the NIH to GL,
inwardly rectifying K+ channels. and by EU-IRG and ISF to T.B-C.
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S27
Metallostasis in Alzheimer’s disease and Parkinson’s aim at unraveling which of the pathologies is upstream in
disease AD - tau or Aβ. For this purpose we use the fruit fly as an
Bush AI AD model. We compared the severity of symptoms of flies
Florey Institute for Neuroscience and Mental Health, co-expressing human tau and Aβ42 to flies expressing
University of Melbourne either one of these proteins (in the brain/retina). Expression
of both proteins in the retina resulted in cell death and
The brain houses high concentrations of transition metals neurodegeneration evident as collapsed eye with disordered
zinc, copper and iron. Zinc and copper are released during ommatidia. These are more severe than the symptoms of
glutamatergic neurotransmission, and their reuptake fatigues flies expressing either protein alone. Co-expression of tau
with age. This increases the average concentration of extra- and Aβ in the brain led to reduced lifespan and motor
cellular zinc and copper (a phenomenon called "metallo- abnormalities (e.g. climbing defect), which appear to be
stasis") leading to Ab aggregation and downstream more severe as well. The severe phenotype when co-
pathologies. Intraneuronal cortical iron metallostasis is a expressing both proteins may suggest a synergistic toxic
feature of aging, and is exaggerated in AD where iron is effect of Aβ and tau. Ongoing analysis on brain extracts
trapped by tangles. We hypothesized that the main proteins from these flies will shed light on the relationship between
implicated in the pathology of AD and PD are in proximity tau and Aβ. Recently, aromatic residues were identified as
to these metals because they function to regulate neuronal key factors in the formation of amyloid assemblies. The
metal homeostasis. stable aromatic interaction between protein monomers ena-
bles their assembly into toxic oligomers and fibrils. There-
1. APP is the neuronal ferroxidase partner of ferroportin fore, small aromatic molecules have been proposed as a
and is needed for iron efflux. It is inhibited by zinc, potential inhibitors of amyloid aggregation. We fed animals
which transfers from amyloid collections in AD tissue. co-expressing tau and Aβ in the retina or the brain with two
2. PBT2, a zinc/copper ionophore that is in clinical testing, small aromatic molecules (NQTrp, Cl-NQTrp) which we
reverses metallostasis. have previously shown to ameliorate AD symptoms in Aβ
3. Tau knockout mice accumulate iron in the cortex and expressing flies and mice. This resulted in marked rectifica-
nigra, causing neuronal loss, parkinsonism and cognitive tion of eye neurodegeneration, and an increase in longevity
loss with advancing age. The neurodegeneration is of flies, respectively. These results suggest that treatment
inhibited by iron-chelator treatment. Soluble (functional) with NQTrp or Cl-NQTrp can inhibit the synergistic toxic
tau levels are decreased in AD and PD. effects of tau and Aβ.
4. Loss of zinc flux in the glutamatergic synapse causes
accelerated age-dependent cognitive decline in ZnT3 ko The antiphospholipid syndrome animal model in mice
mice, a phenocopy of AD. provides clear hypotheses for the study of the human
5. Presenilins 1 and 2 play major roles in the uptake and disease
turnover of zinc and copper. The SOD1 activation path- Chapman J* 1,2, Katzav A 1, Menachem A 3, Pick CG 2
1
way is sensitive to PS loss. Neurology, Sheba Medical Center 2Sackler Faculty of
Metallostasis may be the upstream factor that leads to pro- Medicine, Tel Aviv University 3Tel Aviv University
teostasis in AD and PD and is an upstream target for new
pharmacological approaches. The antiphospholipid syndrome is closely related to
systemic lupus erythematosus and the brain is involved
human patients by vascular, inflammtory and antibody
Facing both foes: phenotypic rescue of a drosophila mediated processes. Mice immunized with β2-
model co-expressing Aβ and Tau by aromatic molecules glycoprotein I (β2GPI) are an experimental model of
Caspi M, Scherzer-Attali R, Fernkel-Pinter M, Gazit E, the antiphospholipid syndrome (eAPS) displaying ele-
Segal D* vated titers of circulating antiphospholipid antibodies
Dept. of Molecular Microbiology and Biotechnology, Tel-Aviv (aPL). We studied whether the behavioral hyperactivity
University, Tel-Aviv, Israel and cognitive dysfunction found in eAPS mice is asso-
ciated with the binding and accumulation of IgG in the
Alzheimer disease (AD) is characterized by two hallmarks: brain. eAPS Balb/c mice were immunized with β2GPI
extracellular amyloid plaques of Aβ42 and intracellular and control mice by adjuvant alone. aPL levels in the
hyperphosphorylated aggregated tau protein. Aβ42 pathol- mouse sera were measured by an enzyme linked immu-
ogy was thought to lie upstream of hyperphosphorylated tau nosorbent assay and behavior was assessed by the
pathology and initiate it, but there is contradictory evidence staircase test. Immunofluorescence and immunohisto-
which shows that Aβ toxicity is actually tau dependent. We chemistry staining was used to evaluate in vivo
S28 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
accumulation of IgG in brain parenchyma and in vitro Results: we found a correlation between the expression of
binding of eAPS serum IgG. We found a significant genes which belong to three pathways (the interferon path-
correlation between serum aPL levels, total IgG accu- way, the IL7 pathway and the CCL2 pathway) and the
mulated in the brain homogenates and behavioral hy- patients 's response to interferon.
peractivity. In vivo staining for IgG was significant in Conclusion: Having such an objective tool to predict ther-
neurons and especially inhibitory interneurons (Basket apy response is valuable for further decisions concerning
cells) in the hippocampus of eAPS mice as well as in therapy in patients with MS and advance our ability towards
white matter tracts. A cell membrane binding pattern in tailoring the treatment in each individual with MS.
similar cells was found for eAPS IgG by in vitro
immunofluorescence staining of normal brain sections. Motherhood alters the balance between excitation
Penetration into the brain and direct interaction of and inhibition in the auditory cortex
eAPS IgG with inhibitory interneurons in the hippo- Cohen L 1,2, Mizrahi A* 1,2
1
campus may explain the hyperactive behavior of the Dept. of Neurobiology, Inst. of Life Sciences, The Hebrew
mice. A direct role of aPL in causing CNS dysfunction University of Jerusalem 2The Edmond and Lily Safra Center
points to aPL as an important therapeutic target. for Brain Sciences, The Hebrew University of Jerusalem
Supported by the ISF.
Local cortical inhibition is central in shaping neuronal response
Predictive markers to IFN β therapy in Multiple profiles in the cortex. Diverse response patterns such as lateral
Sclerosis patients inhibition and approximately balanced excitation and inhibi-
Charbit H, Karussis D, Petrou P, Vaknin-Dembinsky A, tion (co-tuning) have been reported. But the precise way in
Lavon I which the excitatory/inhibitory balance affects response pro-
Dept. of Neurology and Laboratory of Neuroimmunology files remains unclear. Here we studied in detail the response
and the Agnes-Ginges Center for Neurogenetics, Hadassah- properties of one class of inhibitory neurons, the parvalbumin
Hebrew University Hospital, Ein–Kerem, Jerusalem, 91120, (Pv)-expressing cells. These inhibitory neurons target the soma
Israel and perisomatic compartments of pyramidal cells (Pyr) in the
local circuit. We used in vivo multiphoton targeted cell at-
Background: Multiple Sclerosis (MS) is a chronic autoim- tached recording, in layer 2/3 to compare the response proper-
mune demyelinating disease. It is characterized by inflam- ties of Pv and Pyramidal (Pyr) neurons. We show that Pv
mation, demyelination and primary or secondary axonal neurons provide an unexpected and unique form of inhibition
degeneration. No clear etiological factor has been discovered. onto Pyr neurons. Moreover, we find that Pv neurons change
IFN β is the mainstay treatment for MS, but its efficacy varies their inhibitory pattern onto Pyr cells following the transition to
between patients. Clinical experience suggests that there are motherhood and when multisensory inputs are processed.
IFN 'responders' as well as 'non responders', however clear
criteria for such classification are still lacking. Time lapse electrical recordings of single neurons
Objective: Our goal was to establish predictive markers of from the mouse neocortex
response to IFN β therapy in Relapsing Remitting Multiple Cohen L* 1,2, Koffman N 1,2, Meiri H 1,2, Yarom Y 1,2,
Sclerosis patients. Lampl I 3, Mizrahi A 1,2
1
Methods: In order to find an association between a certain Dept. of Neurobiology, Inst. of Life Sciences, The Hebrew
genetic profile and clinical response to IFN β, two patients University of Jerusalem 2The Edmond and Lily Safra Center
groups were evaluated: for Brain Sciences, The Hebrew University of Jerusalem
3
The Dept. of Neurobiology, The Weizmann Institute of Science
– patients who are treated with interferon (5 betaferon, 4
avonex, 3 rebif) and responded well to the drug (n012);
The ability of the brain to adapt to environmental demands
– patients who received interferon (4 betaferon, 2 avonex,
implies that neurons can change throughout life. But the
4 rebif) but did not responded to the treatment (n010).
extent to which single neurons actually change remains
The blood was withdrawed just before the next injection. largely unstudied. To evaluate how functional properties of
The expression of 526 genes was analysed by the next single neurons changed over time, we devised a way to
generation nCounter® Analysis System from NanoString perform in-vivo time lapse electrophysiological recordings
on total RNA extracted from peripheral blood mononuclear from the exact same neuron. We monitored the contralateral
cells. This assay provides a method for direct counting of and ipsilateral sesnsory evoked spiking activity of individ-
the exact number of mRNAs molecules with labeled barc- ual L2/3 neurons from the somatosensory cortex of adult
odes called nCounter Reporter Probes without the use of mice. At the end of the first recording session, we electro-
reverse transcription or amplification. porated the neuron with a DNA plasmid to drive GFP
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S29
expression. Two weeks later, a recording electrode was Robotic re-embodiment: controlling a humanoid robot
visually guided in vivo to the GFP expressing neuron for by thought using real-time fMRI
the second time. We found that contralteral and ipsilateral Cohen O 1,2, Mendelsohn A 3, Koppel M 2, Druon S 4,
evoked responses (probability to respond, latency, and pref- Lengagne S 4, Kheddar A 4, Malach R 3, Friedman D* 1
1
erence), and spontaneous activity of individual L2/3 pyra- The Interdisciplinary Center, Herzliya 2Bar Ilan University
3
midal neurons are stable under control conditions. However, Weizmann Inst. of Science 4CNRS, France
this stability could be rapidly disrupted. Contralateral whis-
ker deprivation induced robust changes in single neurons Background: As part of the VERE (Virtual Embodiment
response profiles. Our experiments provide a framework for and Robotic re-Embodiment) project, which aims at
studying the stability and plasticity of single neurons over dissolving the boundary between the human body and
long time scales using electrophysiology. surrogate representations in immersive virtual reality and
physical reality, we are carrying out a number of studies
Stop feeling: executive control attenuates emotional whereby subjects control a virtual character (avatar) or a
effects physical humanoid robot by thought alone, using real-
Cohen N*, Henik A time classification of fMRI signals. We report a robotic
Dept. of Psychology and the Zlotowski Center for Neurosci- embodiment experiment: subjects located in Israel were
ence, Ben-Gurion University of the Negev, Beer-Sheva, Israel preceiving through the cameras of a HOAP3 humanoid
robot in France and were able to control it using motor
Background: The relationship between attention and emo- imagery.
tion has attracted attention of researchers recently. A major Method: We first instruct the subject to imagine left-hand,
question is: are emotions prioritized so that they have right-hand, and feet imagery upon a predefined cue, and
privileged access to our cognitive apparatus or can they be manually (using TurboBrainVoyager, Brain Innovation,
regulated by other systems such as attention? Researchers Holland) define regions of interest (ROIs), which are delin-
have reported that emotional stimuli activate sub-cortical eated by the predictor variables contrast using a general
structures (e.g., amygdala) that cannot be affected by higher linear model (GLM). This is followed by a baseline. In the
functions or cortical processes. Moreover, it has been sug- task part the subjects saw a video feed taken by cameras
gested that emotional stimuli have automatic effects on located at the eyes of the robot in Beziers, France, and
our behavior, even when completely irrelevant to the performed three simple navigation tasks. We use a simple
task at hand. However, it makes sense that we should classification scheme: at each 2-second repetition time (TR)
be able to regulate our emotions when they are com- we calculate the z-score (normalized relative to the baseline
pletely irrelevant to our performance or can interfere values) of each ROI, choose the ROI with highest z-
with achieving our goals. In the current research we score value, and send the corresponding command to
define the specific situations in which the emotional the robot.
system is down-regulated by executive control—an at- Results: Four subjects performed an 8-shape navigation
tentional mechanism that is responsible for monitoring task with a high degree of control on most sessions, despite
and controlling irrelevant information in order to enable the hemodynamic delay (which is expected to be 3-
goal-directed behavior. In several experiments we pre- 8 seconds). One subject used motor imagery only and three
sented a target that activates executive control before or others were allowed to use their fingers and toes.
after the presentation of an emotional picture. Conclusion: Subjects can navigate a robot by using motor
Results: We demonstrate that executive control exerts an imagination in better-than-chance levels with very little
inhibitory influence on emotion. Namely, the influence of training, based on simple classification method. We are
emotional stimuli on performance is attenuated during or now further exploring the control of avatars and robots by
after activation of executive processes. This effect was thought using machine learning and more ambitious tasks.
found using different executive tasks (i.e., Flanker, Simon, This project is supported by EU FP7 VERE grants to A.K.,
stop-signal) and was modulated by the relevance of the R.M, and D.F.
emotional stimuli to the task.
Conclusions: Our findings demonstrate that during or after Early inflammation and NGF deregulation in the amyloid
activation of executive processes, our emotional system is Alzheimer's pathology
down-regulated. This down-regulation occurs when the emo- Cuello AC
tional stimulus is irrelevant to our current goals or when it is Dept. of Pharmacology, McGill University
relevant but can be evaluated as non-threatening. We suggest
that the interplay between emotion and executive control is In Alzheimer's disease (AD) the therapeutic "time-win-
crucial for maintaining adaptive and goal-directed behavior. dow" should be shifted to earlier stages as there is a
S30 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
decades-long "silent", pre-diagnostic phase. We are in- as the placebo itself, studies attempting to identify the placebo
vestigating this early, "silent" phase of the AD amyloid responder are rare and limited. We hypothesize that placebo
pathology in transgenic (Tg) models of the AD pathol- responders share a psychological and cognitive profile.
ogy. Our lab is interested in early pathology. We have Methods: For this aim, we are recruiting patients with
observed that preceding the appearance of amyloid pla- Parkinson’s (PD) and other diseases who have participated
ques there is an abnormal intraneuronal accumulation of in a previous clinical trial where they received placebo in a
oligomeric and prefibrillar forms of Abeta in the cere- double blind manner and their clinical improvement was
bral cortex and hippocampus. This phenotype, in the absence recorded. To date, we have evaluated 15 subjects with PD,
of amyloid plaques, was accompanied by cognitive impair- one placebo responder and 14 non-responders who were
ments and a pro-inflammatory reaction both in the rat and administered the full Minnesota Multiphasic Personality
mouse Tg models. The "pro-inflammatory" process displayed Inventory (MMPI-2) personality questionnaire and 3 short
an intermediate activation of microglial cells with their mobi- cognitive tests: RAVLT word list memory, verbal fluency
lization to Abeta-burdened neurons and elevation of key in- test and trail making test (TMT) A and B.
flammatory markers in the cerebral cortex and hippocampus. Results: We found no differences in cognitive nor in per-
We have reported the existence of an NGF (Nerve Growth sonality traits between men (n 011) and women (n 04).
Factor) metabolic pathway explaining the mechanisms for However we did find a significant sex difference with men
its maturation and degradation in the CNS. Our investiga- expressing stronger belief in medical treatment (p00.006).
tions in the human brain revealed that this metabolic path- Distress was negatively correlated with the patients belief in
way is altered in AD. We have found a compromise in the medical treatment (p 00.029). In addition, hysteria was
proNGF to mature NGF conversion. Likewise, the degrada- found to decrease with age (p00.012) but fears to increase
tion of mature NGF in the extracellular space should be with age (p00.005). Marital distress and cynicism were
enhanced as in both MCI and in AD there is an increment positively correlated with PD severity (p00.004; p00.04),
both in protein levels and enzymatic activity of the metal- respectively, while the need of affection was negatively
loprotease MMP-9. MMP9 being the protease which termi- correlated with PD severity (p00.011).
nates NGF action in the CNS. We hypothesize that these Conclusions: Results show the possibility that men have
consequences of the Abeta oligomer-driven proinflamma- stronger beliefs in medical treatment than women. Our
tory process and deregulation of the NGF metabolic path- results also indicate that disease severity may differ in its
way might be amongst the earliest event in the progression impact on specific characteristics of mood and attitude in
of AD pathology. These alterations are likely to aggravate PD patients.
the pathology and have cognitive consequences. These We thank Mr. Sami Sagol for PhD fellowship
aspects could offer new pharmacological targets as well as
diagnostic opportunities for the prevention or diagnosis of Inosine improves functional recovery after experimental
the disease. traumatic brain injury
Funded by CIHR MOP 218646 -219489 Dachir S* 1,2, Shabashov D 1, Trembovler V 1, Alexandrovich
A 1, Benowitz LI 3, Shohami E 1
1
Profiling of the placebo responder: personality Dept. of Pharmacology, Inst. of Drug Res., School of
and cognitive characteristics in Parkinson’s disease Pharmacy, The Hebrew University of Jerusalem, Jerusalem,
patients Israel 2Dept. of Pharmacology, Israel Institute for Biologi-
Czerniak E.* 1, 2 , Biegon A. 3 , Hassin-Baer S. 2, 4 , cal Research, Ness Ziona, Israel 3Dept. of Neurosurgery,
Schnaider-Beeri M. 2,5 and Weiser M. 6 Children's Hospital, 300 Longwood Avenue, Boston, MA
1
Sackler Faculty of Medicine, Tel Aviv University, 2 J. Sagol 02115, USA
Neuroscience Center, Sheba Medical Center, Tel Hashomer,
3
Brookhaven National Laboratory, New York, USA, Background: In spite decades of research, no specific ther-
4
Parkinson’s Disease and Movement Disorders Clinic, Neu- apy is yet available for traumatic brain injury (TBI), one of
rology, Sheba Medical Center, Tel Hashomer , 5Department the leading causes of mortality and morbidity worldwide.
of Psychiatry, The Mount Sinai Hospital, New York, The most prevalent features in TBI survivors are cognitive
USA, 6Department of Psychiatry, Sheba Medical Center, deficits and motor dysfunction. A potential therapeutic
Tel Hashomer method for improving function of patients following TBI
is to restore, at least in part, plasticity to the CNS. The
Background: The 'placebo response' is defined as a positive present study was aimed at investigating long-term (up to
outcome in patients who have received placebo (an inactive 35d) effects of inosine, a naturally occurring purine nucle-
intervention), over and beyond changes due to the natural oside that has been shown to promote axon sprouting, on
course of disease. Although the placebo response is as ancient cognitive outcome and levels of synaptic proteins which
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S31
promote neurite sprouting and plasticity, in an animal model the fact that many details remain hitherto unknown. Sup-
of TBI. ported by experimental evidence is the possibility that astro-
Results: Experimental closed-head injury (CHI) was cytes perform genuine information processing by means of
induced in mice and rats using a weight-drop device. their calcium signaling and are players in synaptic transmis-
Inosine (100 mg/kg) was administered i.p. at 1, 24 and sion, but the functional implications of this scenario remain
48 hr after CHI. Inosine treatment significantly im- elusive.
proved neurological recovery and performance on a Results: We devised a novel modeling framework for
non-spatial cognitive task (object recognition). Sensori- the study of astrocyte-neuron that can explain several
motor coordination (evaluated using a rotarod) and spa- experimental results and is mathematically tractable with
tial cognition (Y-maze) were not affected. Following potential applications in the study of Artificial Neural
anterograde tracing with biotinylated dextran amine Networks. Moreover, our model yields important predic-
(BDA), the corticospinal tract (CST) in the lumbar spinal cord tions in support of the physiological relevance of
contralateral to the injection site was strongly labeled, with astrocyte-neuron signaling in information processing. In
some axons crossing the midline, and CHI led to a significant particular, facilitating gliotransmission could underlie
increase in sprouting. Inosine did not increase axonal sprout- bistability of synaptic release, namely, the coexistence
ing further, nor did it increase the levels (Western blot) of the of low and high levels of synaptic release for the same
growth-associated protein GAP43 or the presynaptic protein, stimulus. The occurrence of one mode of synaptic re-
synaptophysin, in the cortex or hippocampus of injured mice lease with respect to the other depends on the history of
compared to sham controls. Other possible anatomical synaptic activity and could bring forth long-lasting
changes were not investigated. changes of synaptic strength just by mere long-term
Conclusions: the results suggest that inosine may have potentiation or depression of synaptic release probabili-
beneficial effects on recovery after TBI. Further re- ty. This scenario could ultimately provide a novel mech-
search studying longer treatment regimens and more anism to account for the transient increase of neuronal
severe trauma is required in order to better detect and activity following the brief presentation of a stimulatory
explore the mechanisms by which these benefits are cue, which underlies working memory.
exerted. Conclusions: Our study revealed that astrocyte could
This work was supported by a grant from the Dr. Miriam affect synaptic transmission in a complex fashion,
and Sheldon G. Adelson Medical Research Found depending on the rate and nature of gliotransmission.
Since gliotransmission could occur either for spontane-
Theory and modeling of astrocyte modulation of synaptic ous or evoked neuronal activity, astrocytes could phys-
release iologically set the tone of synaptic transmission with
De Pittà M* 1, Volman V 2,3,4, Berry H 5, Parpura V 6,7, important implications in information processing and
Volterra A 8, Ben-Jacob E 1,9,10 storage by neural networks of the brain.
1
School of Physics and Astronomy, Tel Aviv University, Tauber Family Fnd.; IT-IL Neuroscience Lab; CBTP Rice
69978 Ramat Aviv, Israel 2Center for Theoretical Biological U.; FR-IL Cooperation; NSF; NIH; Swiss NSF
Physics, UCSD, La Jolla, CA 92093-0319, USA 3Computa-
tional Neurobiology Laboratory, The Salk Institute, La CNS-specific immunity at the choroid plexus: a shift
Jolla, CA 92037, USA 4 L-3 Applied Technologies: Simula- towards destructive Th2-inflammation in brain aging
tion, Engineering & Testing, 10770 Wateridge Circle, Suite Baruch K 1, Ron-Harel N 2, Gal H 3, Deczkowska A 1, Shifrut
200, San Diego, CA 92121, USA 5BEAGLE Team, INRIA E 3, Ndifon W 3, Mirlas-Neisberg N 1, Cardon C 1, Mattson
Rhône-Alpes, 69603 Villeurbanne, France 6Dept. of Neuro- MP 4, Gomez-Pinilla F 5, Friedman N 3, Schwartz M* 1
1
biology, University of Alabama, Birmingham, AL 35242, Dept. of Neurobiology, Weizmann Institute of Science,
USA 7Dept. of Biotechnology, University or Rijeka, 51000 Rehovot 76100, Israel 2Dept. of Cell Biology, Harvard
Rijeka, Croatia8Dept. of Cell Biology and Morphology, Medical School, MA 02115, Boston, USA 3Dept. of Immu-
University of Lausanne, Rue du Bugnon 9, CH-1005 nology, Weizmann Institute of Science, Rehovot 76100, Is-
Lausanne, Switzerland 9Center for Theoretical Biological rael 4Laboratory of Neurosciences, National Institute on
Physics, Rice University, Houston, TX 77005-1827, USA Aging Intramural Research Program, National Institutes
10
Research & Development Unit, Assaf Harofeh Medical of Health, Baltimore, Maryland 21224, USA5Dept. of Phys-
Center, 70300 Zerifin, Israel iological Science, UCLA Brain Injury Research Center,
UCLA, Los Angeles, CA 90095, USA
Background: The complexity of astrocyte-synapse interac-
tions may seem discouraging when tackled from a theoret- Aging of the adaptive immune system has been sug-
ical perspective. Computational modeling is challenged by gested as an important factor in brain senescence. Given
S32 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
the fact that interactions of neurons or glial cells with T Difference-in-familiarity was calculated by subtracting the
lymphocytes rarely occur within the healthy central ner- study familiarity score from the test familiarity score. Results
vous system (CNS) parenchyma, the underlying mecha- support a variable addition of familiarity during the study
nism remains elusive. Here we show that the blood- phase. Moreover, the change in familiarity score was positive-
cerebrospinal fluid barrier, the choroid plexus (CP), is ly correlated with correct recognition. This suggests that pos-
constitutively populated by CD4+ effector memory cells itive recognition involves an assessment of the change in
with a T cell receptor (TCR) repertoire specific to CNS familiarity during the study (i.e., delta familiarity), in addition
antigens. With age, CNS-specificity was largely main- to both item's baseline familiarity and to the recollection of
tained, while interleukin-4 (IL-4)/interferon-γ (IFN-γ) episodic details from the study event.
ratio progressively increased, indicating stepwise Th2
bias in the CP compartment. We found this local cyto- New herbal treatment for anxiety in comparison
kine shift to critically affect the CP epithelium, trigger- to SSRI: high efficacy with minimum side-effects
ing it to produce the chemokine CCL11, recently linked Doron R* 1,2,3, Einat N 1, Wiener A 3, Rehavi M 4
1
to cognitive dysfunction. Strikingly, partial restoration of Dept. of Education and Psychology, The Open University
cognitive ability in aged mice, by homeostatic-driven of Israel 2School of Health and Life Sciences, Hadassah
proliferation of memory T cells, correlated with reestab- Academic College, Jerusalem 3School of Behavioral Sciences
lishment of the IL-4 / IFN-γ ratio at the CP, and , Academic College of Tel Aviv-Yafo 4 Dept. of Physiology
modulated the expression of plasticity-related genes at and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv
the hippocampus. Our data indicates that the cytokine University
milieu of the CP epithelium, the interface between the
brain and the blood circulation, is affected by peripheral Anxiety disorders are prevalent and severe diseases with delete-
immunosenescence, with detrimental consequences to rious impact on patients and society. Selective serotonin reuptake
the aged brain. Amenable to immunomodulation, such inhibitors (SSRIs) were shown to be effective in treating a wide
an interface is a novel target for arresting age-related spectrum of anxiety disorders. Despite their therapeutic actions,
cognitive decline. SSRIs are associated with a wide variety of side effects such as
The first three authors contributed equally to this study. weight changes, disturbances and sexual dysfunction. Further-
more, recent studies show that their success rates are not high,
Does study episode contribute a constant or a variable reaching 50 % at most. Therefore, there is a clear need to explore
increase to familiarity? The contribution alternative treatments for anxiety disorders. We have recently
of delta-familiarity to recognition memory produced a novel herbal treatment mixture for the treatment of
Didi-Barnea C*, Goshen-Gottstein Y anxiety disorder. The novel treatment displayed anxiolytic-
Faculty of Social Sciences, Tel Aviv University like effects in treated mice previously exposed to stress. The
aim of the present study was to test whether the novel treat-
According to dual-process theory, recognition memory com- ment induce two common side effects normally induced by
prises two underlying processes: Familiarity and Recollec- the conventional treatment with the SSRI escitalopram, name-
tion. Recollection involves conscious remembering of ly, sexual dysfunction and weight gain. Mice were treated with
contextual details about the prior learning episode. Familiarity, either: (a) herbal treatment (b) one components of the herbal
in contrast, involves a relatively automatic, a-historical assess- treatment mixture (c) escitalopram or (d) control group. Fol-
ment of the item's strength, without having available to con- lowing treatment, sexual behavior and weight gain were eval-
sciousness any further information about the learning episode. uated in the different groups, as well as changes in prefrontal
Most dual-process models concur that familiarity is best de- cortex serotonin transporter levels. We have found that the
scribed using the principles of Signal-Detection Theory (SDT), novel treatment has not altered sexual behavior and did not
with some level of familiarity available for every item. Accord- cause a weight gain, while escitalopram altered these two side
ing to this notion, in the study episode, familiarity increases for effects. Interestingly, serotonin transporter levels in the pre-
the studied items. A highly influential dual-process model frontal cortex of escitalopram treated group were significantly
argues that this increase in familiarity is constant to all studied lower compared to other treatments. These results suggest that
items (Yonelinas, 2001). Other models (e.g., Wixted & Mickes, the novel treatment may have the same behavioral anxiolytic
2010), however, suggest that this increase might be variable. efficacy as SSRIs, while causing fewer side effects, possibly
To examine this question, we asked participants to provide a due to different biological mechanisms. Further studies are
subjective familiarity score for each item at both study and now conducted in order to explore the underlying biological
test phases of a recognition-memory test. Additionally, for mechanisms through which the novel treatment lead to the
each positively recognized item, participants indicated the behavioral anxiolytic effects.
quantity of recollection experienced. ISF 738/11; NIPI-7-2011-12
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S33
Abnormal perceptual functions in attention deficit inspired drug-based trials are also emerging. Nevertheless,
hyperactivity disorder (ADHD) medical management, rehabilitation and exercise are still the
Doron R*, Polat U predominant treatments. However, strong evidence to support
Faculty of Medicine, Tel-Aviv University, Goldschleger Eye the role of exercise in promoting neurological recovery and
Research Institute, Sheba Medical Center. overall health is lacking. In Australia and New Zealand, we
are undertaking 3 randomized controlled trials, Spinal Cord
Background: Visual crowding, collinear facilitation, and Injury and Physical Activity (SCIPA), to test novel
contour integration are visual integration functions (VIF) that interventions that move the paralysed limbs and deter-
are critical for perceptual and cognitive processing. Our recent mine whether they improve neurological recovery and
results support a common early neural basis for the develop- overall health. The trials span acute care, in-patients and
ment of VIF in young healthy children. The results show that the chronic phase after discharge and we are also de-
there is a developmental cascade in which the existence of veloping a community program to overcome barriers
high levels of crowding in young children limits the develop- and promote participation and activity. Another Austra-
mental onset of collinear facilitation until about the age of lian trial in the planning stage aims to prevent massive
6 years when the crowding decreases to nearly an adult's level. secondary loss of tissue spared by the initial injury by
Similarly, the onset of the contour integration skill developed administering immediate hypothermia
after the maturation of collinear facilitation, between 6 and Conclusion: The global search to develop effective thera-
9 years. Since development of some of the cognitive functions pies continues. Rehabilitation is still the main form of ther-
overlaps with this age period, we hypothesized that the devel- apy and better treatments for acute injury to prevent the
opment of VIF in ADHD subjects might be affected. The aim catastrophic loss of tissue, as well as for chronic patients
of this study was to explore whether VIF in ADHD subjects living with SCI, are urgently needed.
during the age of 6-18 years is normal.
Results: We found a high degree of crowding, higher Similarity of activity-dependent structural changes
thresholds for contour integration, and reduced collinear in synapses formed between identical neurons
facilitation in the ADHD group compared with the age- Dvorkin R* 1,2, Ziv NE 1,2
1
matched control group. We also found that their thresholds Lokey Network Biology Research Center 2Rappaport
do not improve with age and remain immature, matching the Faculty of Medicine; Israel Institute of Technology, Haifa,
threshold levels of younger children. Israel
Conclusions: Contrary to the visual processing in young
normal children, which improves with age, the neural mech- Activity-induced modification of synaptic connections (syn-
anisms underlying global perception are immature in aptic plasticity) is widely believed to be a fundamental mech-
ADHD individuals. These results may suggest that abnor- anism for modifying neuronal network function. It is also
mal development contributes to the perceptual processing in commonly (often implicitly) presumed that synapses do not
ADHD, which in turn may limit the development of some change spontaneously or in manners unrelated to their activa-
higher cognitive processing. tion histories. Synapses, however, are not static structures, and
exhibit significant molecular and cellular dynamics with or
Translating science: clinical trials for spinal cord injury without activity on many timescales. An important question
Dunlop S thus arises: What is the relative part of specific activity histories
University of Western Australia in the remodeling synapses undergo?We recorded, for several
days, the remodeling of nearby synapses formed between the
Background: Spinal cord injury (SCI) has devastating and exact same axons and dendrites, synapses that presumably
expensive consequences for patients, carers and society. The experience identical activity histories. We then examined the
incidence varies world-wide (Australia: 4.5/million; USA: degree to which such synapses changed in a similar manner,
25.2-52.5/million) with motor vehicle accidents the major and how this covariance was affected by network activity. We
cause. Extensive and promising basic research has yet to be found that the covariance of synaptic remodeling in synapses
translated into clinical practice. that presumably experienced the same activation histories was
Results: A search of http://clinicaltrials.gov/, China SCI Net only slightly (~12 %) greater that the covariance observed for
http://www.chinascinet.org/ and the Australian and New synapses which did not belong to the same presynaptic neu-
Zealand Spinal Cord Registry www.anzctr.org.au was under- rons. Interestingly this difference disappeared once network
taken to map the current global status of clinical trials. Interna- activity was silenced. Moreover, silencing activity led to a 20-
tionally, there are over 100 registered trials covering a wide 30 % increase in remodeling covariance between all synapses
range of interventions with exercise comprising the majority in the network regardless of their presynaptic identity. These
followed by drug treatments. Cell-based and biologically- findings indicate that the predominance of specific activity
S34 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
histories in determining the remodeling synapses undergo olfactory profile". This is unsurprising considering various
might be more limited that commonly assumed. links between olfaction and autism. Here we investigate two
of these links: First, olfaction depends on precise sensory-
A genome wide association study of human altruism motor acquisition, namely sniffing, and indeed, sensory-
Ebstein RP1, Zhong S2, Khor CC3, Lai PS4, Monakhov M1 motor acquisition is impaired in autism. With this in mind,
and Chew SH*2 we set out to measure sniffing behavior in children under-
1
Department of Psychology, National University of Singapore, going a diagnostic battery for autism. We tested 20 children
Singapore & Department of Psychology, Hebrew University, (ranging in age from 22 months to 10.6 years) with a
Jerusalem, Israel, 2Department of Economics, National computer-controlled air-dilution olfactometer that delivered
University of Singapore, 3Genome Institute of Singapore, either pleasant or unpleasant odors through a nasal cannula.
4
Department of Pediatrics, National University of Singapore; The cannula also served to measure concurrent nasal respi-
Singapore ration. Odorants were delivered once every 30 seconds,
counterbalanced for order. We encountered a major obstacle
As noted by Darwin in the Descent of Man, “The bravest men, of compliance: 8 of 20 children refused to participate, and 6
who were always willing to come to the front in war, and who did not complete a minimum number of trials. In turn, in the
freely risked their lives for others, would on an average perish 6 children with between 6 and 24 trials, there was a striking
in larger numbers than other men” and hence the paradox of correlation between autism severity scores (ADOS) and
altruism. Evolutionists propose a number of concepts such as various sniff parameters (overall r00.96, p<0.03).
kin selection, direct reciprocity, indirect reciprocity, network A second link between olfaction and autism is that
reciprocity, and group selection, to resolve the paradox. Nota- odors serve social communication, and indeed a charac-
bly, the heritability of altruism is comparable to other complex teristic of autism is impaired social communication.
human traits. However, the proximate molecular genetic mech- With this in mind, we set out to measure the response
anisms underlying altruism, remains relatively unexplored. To to chemosignals in young high-functioning adults with
identify loci associated with altruism we conducted the first autism. Human sweat-bound chemosignals modulate
genome-wide association study (GWAS) using incentivized startle response in typically developed adults. Here we
choice experiment in 1805 Han Chinese samples, observing will now measure the influence of sweat-bound chemo-
genome-wide significant evidence of association at ACCN1 signals on startle response in high functioning young
rs3744516 (P06.87×10-10). De-novo replication with was adults with autism. Together, these results from children
observed in a further Han Chinese sample from Singapore and adults will provide an initial characterization of an
(N01052, P00.040). We identified a locus exceeding the olfactory profile in autism.
formal threshold for genome-wide significance contributing
to altruistic giving that maps to a specific gene ACCN1, The microglial sensome
neuronal amiloride-sensitive cation channel 1. To summarize, Hickman S , El Khoury J
by employing the gold standard GWA strategy we have iden- Massachusetts General Hospital & Harvard Medical
tified a proximate mechanism for altruistic giving, ACCN1 School
coding for a neuronal cation channel. In particular, ACCN1 is
associated at GWA significance levels with Rawlsian giving, Microglia, the principal neuroimmune cells and sentinels
the preference for an egalitarian solution to income distribu- of the brain continuously sense changes in their envi-
tion. John Rawls, the moral and political philosopher, envi- ronment and defend against invading pathogens. Similar
sions a society of free citizens holding equal basic rights to circulating blood monocytes, microglia exhibit plas-
cooperating within an egalitarian economic system. It appears ticity, and can assume various priming states that deter-
that evolutionary forces have partially hard-wired Homo sa- mine their responses to danger signals. We used direct
piens towards attaining the Rawlsian just society. RNA sequencing to quantify mRNA without amplifica-
tion or cDNA synthesis, and determined the quantitative
Olfaction in autism transcriptomes of microglia and monocytes of healthy
Eisen A1, Heller I1, Plotkin A1, Weissbrod A1, Zachor D2 adult and aging mice. We validated our findings with
Sobel N1 unbiased proteomic analysis. We report that microglia
1
Dept. of Neurobiology, Weizmann Institute of Science differ significantly from monocytes and express a
Rehovot Israel, 2Autism Center, Asaf Harofeh Medical unique cluster of transcripts encoding proteins for sens-
Center, Zerifin, Israel ing endogenous ligands and microbes, that we term the
“sensome”. In this presentation we will discuss our findings
The few studies that investigated olfaction in autism com- and their implications for the role of microglia in aging and
bine with anecdotal observations to suggest an "autistic neurodegeneration.
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S35
Genetic ablation of hypocretin neurons alters behavioral formation, consolidation and retrieval. In rodents, novel
state transitions in zebrafish taste learning is associated with biochemical changes in
Elbaz I 1,2, Yelin-Bekerman L 1,2, Nicenboim J 3, Vatine G the GC, however, very little is known about the expression
1,2
, Appelbaum L* 1,2 of immediate early genes (IEGs) as network activity
1
The Mina & Everard Goodman Faculty of Life Sciences, markers in correlation with novel taste learning.
Bar-Ilan University, Ramat-Gan 52900, Israel 2The Leslie Here, we used the expression of Activity Regulated Cyto-
and Susan Gonda Multidisciplinary Brain Research Center, skeleton Protein (Arc) as a marker of neural activation in the
Bar-Ilan University, Ramat-Gan 52900, Israel 3Dept. of GC following incidental taste learning. We found that novel
Biological Regulation, The Weizmann Institute of Science, taste did not modulate Arc expression in the GC when
Rehovot 76100, Israel sampling both hemispheres, however novel and familiar
taste groups have different expression pattern when com-
Sleep is an essential biological need of all animals studied to paring left and right GC one hour following learning;
date. The sleep disorder narcolepsy is characterized by whereas the novel taste group exhibit clear lateralized pat-
excessive daytime sleepiness, fragmentation of nighttime tern of Arc expression, the familiar taste group exhibits no
sleep, and cataplexy. Narcolepsy is caused by selective lateralization of Arc expression. Moreover, continuous fa-
degeneration of hypothalamic hypocretin/orexin (HCRT) miliarization with taste reduced the lateralization. For causal
neurons. In mammals, HCRT neurons primarily regulate experiment we injected the protein synthesis inhibitor ani-
the sleep/wake cycle, feeding, reward-seeking and addic- somycin into the left or right GC and found a pattern of
tion. The role of HCRT neurons in zebrafish is implicated bimodal distribution of animals performing the memory
in both sleep and wake regulation. We established a trans- test- one group of animals with clear impaired memory for
genic zebrafish model enabling inducible ablation of HCRT the aversive taste, and one group of animals with no mem-
neurons, and used these animals to understand the function ory deficit, indicating that one hemisphere predominantly
of HCRT neurons and narcolepsy. Loss of HCRT neurons participates in memory consolidation. We found that sepa-
increased the expression of the HCRT receptor (hcrtr). Be- rate networks for processing of novel or familiar taste exists
havioral assays revealed that HCRT neuron-ablated larvae in the GC and manifested by symmetrical IEG activation for
had normal locomotor activity, but demonstrated an increase familiar taste and asymmetrical for novel taste learning.
in sleep time during the day and an increased number of
sleep/wake transitions during both day and night. Mild sleep Altered olfactory perception following tDCS
disturbance reduced sleep and increased c-fos expression Endevelt Y 1, Sela T 2, Lavidor M 2, Sobel N 1
1
in HCRT neuron-ablated larvae. Furthermore, ablation Dept. of Neurobiology, Weizmann Institute of Science,
of HCRT neurons altered the behavioral response to Rehovot, Israel 2Dept. of Neurobiology, Bar Ilan University,
external stimuli. Exposure to light during the night Ramat Gan, Israel
decreased locomotor activity of wild-type siblings, but
induced an opposite response in HCRT neuron-ablated Background: One of the most important characteristics of
larvae. Sound stimulus during the day reduced the lo- odor perception is its hedonic component. Neuroimaging
comotor activity of wild-type sibling larvae, while HCRT results imply that pleasant odors preferentially activate a re-
neuron-ablated larvae demonstrated a hyposensitive re- gion of medial OFC, while unpleasant odors preferentially
sponse. This study establishes zebrafish as a model for activate a lateral portion of left OFC. This has merited the
narcolepsy, and indicating a role of HCRT neurons in hypothesis that activating specific brain regions may change
regulation of sleep/wake transitions during both day and olfactory hedonic perception. To test this, we used transcranial
night. Our results further suggest a key role of HCRT neu- direct current stimulation (tDCS), and measured olfactory
rons in mediating behavioral state transitions in response to perception. The subjects rated the pleasantness and the inten-
external stimuli. sity of 5 different odorants using a visual analog scale (VAS).
Results: To date, 18 subjects (8 F, mean age024) were
Novel and familiar taste learning elicit different network tested. The subjects participated in two conditions: sham
Elkobi A, Inberg S, Rosenblum K* and active. We found that the pleasantness rating of Skatole
Dept. of Neurobiology & Ethology, Faculty of natural (a feces-like odor) was significantly higher after the active
sciences, Center for Gene Manipulation in the Brain, condition compared to baseline (normalized pleasantness
University of Haifa, Haifa, Israel before activation: 0.13±0.02, after: 0.18±0.04, t(15)0-2.6,
p<0.05). When we look only at the 1st day, the pleasantness
Learning of novel taste and its value is rapid, robust and delta (after-before) in the active condition is significantly
ethologically important to survival of the animal. The gus- higher than the Sham delta (Active delta00.11±0.02, Sham
tatory cortex (GC) is critically involved in taste memory delta0-0.02±0.02, t(14)03.5, p<0.004). As for Hexanoic-
S36 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
acid (a goat- like odor), the pleasantness rating was signif- impaired. From a neurophysiological perspective, we
icantly higher only after the active condition compared to have shown a causal link between LFP oscillations,
baseline (before: 0.15±0.04, after: 0.21±0.04, t(15)0-2.1, neural synchrony and behavior, suggesting that oscilla-
p<0.05). In contrast, pleasantness ratings of the pleasant tory synchrony can be used in a behavioral context as a
odors were unaffected by tDCS. The Intensity ratings of substrate for neural computations.
all the odorants were unaffected as well. This work is dedicated to the memory of Dr. Dmitry Davidov
Conclusions: These results suggest that olfactory perception
can be modulated using tDCS. Beyond probing brain repre- Spike shape of human pyramidal cells and the tracking
sentation of olfactory information, the possibility of predict- high input frequencies
ably modulating odorant pleasantness has tantalizing Eyal G 1, Testa-Silva G 2, Giugliano M 3, Mansvelder H 2,
implications and possible applications. Segev I* 4
1
School of Computer Science and Engineering, The Hebrew
Operant conditioning of LFP gamma oscillations University of Jerusalem, Jerusalem, Israel 2 Dept. of
via Brain-Machine Interface: emergence of precise Integrative Neurophysiology, Center for Neurogenomics
spike synchrony and Cognitive Research, VU University, Amsterdam, Neth-
Engelhard B* 1,2, Ozeri N 1, Vaadia E 1,2 erlands 3Theoretical Neurobiology, University of Antwerp,
1
Dept. of Medical Neurobiology, Institute of Medical Re- Belgium 4Dept. of Neurobiology, the Edmond and Lily Safra
search Israel-Canada, The Hebrew University-Hadassah Center for Brain Science and the Interdisciplinary Center
Medical School, Jerusalem 91120, Israel 2Edmond and Lily for Neural Computation (ICNC), the Hebrew University of
Safra Center for Brain Sciences, The interdisciplinary Center Jerusalem, Jerusalem, Israel
for Neural Computation, The Hebrew University, Jerusalem
91904, Israel A spike is a spike is a spike. Indeed, the spike is generally
considered to be a binary signal. Yet, in various neuron
Background: Neuronal oscillations in the low-gamma band types and in different animals, spikes appear in an as-
(30-50 Hz) are thought to reflect synchronized activity in the sortment of shapes and amplitudes. Interestingly, recent
brain and have been associated with numerous cognitive and theoretical studies have demonstrated that the steepness
computational roles. In particular, various clinical disorders of the spike onset is highly correlated with the capability
have been linked with abnormal low-gamma activity such as of the neuron to track high frequency input fluctuations.
ADHD, Autism, Schizophrenia, Epilepsy and others. These This was confirmed in the present modeling study using
abnormalities are thought to reflect in turn abnormalities in detailed conductance-based Hodgkin-Huxley-based model
the degree of neural synchronization in either a local or of 3D reconstructed pyramidal cells of both human and
distributed manner. The precise role of these oscillations, rats. In the H&H model, the steepness of the spike onset
however and the extent of their contribution to single neu- is determined by the steepness of the Na+ activation
rons' synchrony in a behavioral context remains unclear. curve and by its maximal conductance value. Pyramidal
Results: In this study we used a Brain-Machine Interface cells in the rat neocortex can track input frequencies up
(BMI), to train monkeys to specifically increase the power to 200 Hz and time their spiking accordingly (Koendgen
of the 30-43 Hz band in selected sites of motor cortex. Over et al., 2008), whereas human pyramidal cells can track
the course of several sessions the monkeys learned to use input frequencies up to and beyond 1000 Hz (Testa-Silva
the BMI to move a cursor on the screen and obtain a reward. et al., submitted). To explore this surprising result we
The evoked activity was oscillatory in nature, band specific have analyzed the shape of spikes in rat versus the
and clearly apparent on a single-trial basis. The increase in human, using phase plots. We found that the human
the LFP band power was accompanied by a dramatic in- spike is not steeper than that of the rat. Thus, contrary
crease in the amount of neural synchrony, allowing previ- to our initial expectations, the ability of human cells to
ously uncoordinated pairs of neurons to fire together in a track higher frequencies, as compared to the rat, is not
time-precise manner. Furthermore, we found a tight rela- explained by differences in the spike rapidness. We are
tionship between the spatiotemporal patterns of gamma currently further exploring what could be the alternative
oscillations and the patterns of spike synchrony. Finally, explanation for the superiority of human pyramidal cells
the level of gamma oscillations was directly related to the in tracking high input frequencies.
size of the synchronized neuronal ensembles.
Conclusions: Our findings have a two-fold significance: GABAA receptor α2 but not α1 subunit knock down
On the clinical side, they stand as an important step in in dentate gyrus reduces inhibition activity and improves
the development of treatments for a wide variety of learning abilities of rats
conditions in which the level of neural synchrony is Fan M 1,3, Xia L1,3, Kriebel M2, Volkmer H2, Richter-Levin G1,3
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S37
1
Sagol Dept. of Neurobiology, University of Haifa 2NMI rats were subjected to 8 days of sleep restriction (SR) using
Natural and Medical Sciences Institute at the University activity wheels. Immediately following the last day of sleep
of Tübingen 3The Institute for the Study of Affective restriction they went through the underwater trauma (UWT),
Neuroscience an acute stress procedure. Core body temperature was mea-
sured before and during the SR protocol and following the
In the current study, the GABAA receptor α1 or α2 UWT, using radiotelemetry.
subunit was knocked down by injecting a viral vector Results: During SR protocol, sleep restricted rats had higher
into the dentate gyrus (DG) of juvenile rats. A sustain- body temperature throughout the protocol, and juvenile
able expression of infection could be found in DG for stressed rats had higher body temperature only while on
more than 8 weeks after the injection. To examine the wheels. Juvenile stressed rats were also more active during
possible alterations in local circuit activity after DG the dark phase of the SR protocol. Following SR protocol
GABAA receptor α1 or α2 subunit knock down, fre- and the UWT, during the light phase, all rats including
quency dependent inhibition (FDI) and paired pulse controls had lower body temperature, except for the rats that
stimulation protocols were employed. Briefly changing went through the UWT procedure and no SR, which had no
stimulation frequency from 0.1Hz to 1.0Hz, a strong change in body temperature compared to baseline.
inhibition of population spike (PS) could be observed Summary and Conclusion: Sleep restriction had only a
in both control rats and α1 or α2 subunit knock down short-term effect on body temperature that was compensated
rats, but the ratio of inhibition was significantly de- in the days following the protocol. UWT resulted in elevated
creased in α2 subunit knock down rats. Paired pulse body temperature for a few days, an effect that was abol-
stimulation with an interval of 15 ms resulted in the ished by sleep restriction. Juvenile stress, in contrast, had a
inhibition of the second PS and this inhibition was also prolonged effect on thermoregulation and activity, even a
significantly reduced in α2 subunit knock down rats month following the juvenile stress, when the rats were
compared to control rats. To test the potential behavioral either on voluntary activity wheels or motorized ones. The
effects of GABAA receptor subunit knock down, rats results demonstrate yet another aspect of the longevity of the
were tested in the elevated plus maze (EPZ) and on a effects of exposure to stress in juvenility.
novel object recognition task. No differences were
found between the groups in the EPZ. In the novel The importance of P75NTR receptor in mediating
object recognition task the α2 subunit knock down rats microglia activity in Alzheimer’s disease
exhibited significantly longer time compared to both Farfara D, Frenkel D
control and α1 subunit knock down rats of novel object Dept. of Neurobiology, George S. Wise Faculty of Life
exploration. The results suggest that knocking down of Sciences, Tel Aviv University, Tel Aviv, Israel
GABAA receptor α2 but not α1 subunit has significant
effects on learning but not on emotional behavior. The Background: It has been recently postulated that there are
associated induced alteration of DG local circuit activity different microglial cell phenotypes that have the potential
in α2 subunit knock down rats suggests that DG local to be beneficial or harmful in Alzheimer's disease (AD). We
circuit activity is important for hippocampus-dependent have recently shown that gamma-secretase inhibitors impair
learning. microglial activity as measured in gene expression, protein
Grant sponsor: Deutsche Israel Project (DIP) cooperation. levels, and migration ability. (Farfara et al., Ann Neurol
2011). Furthermore, dysfunction in gamma-secretase cata-
The effects of stress in adulthood, following sleep lytic site led to impairment in clearing insoluble amyloid β
restriction or stress in juvenility, on body temperature from brain sections taken from an AD mouse model com-
and activity level pared to microglia from wild-type mice. Gamma-secretase is
Ariel L 1,2, Faraggi M 1,3, Richter-Levin G* 1,2,4 also known by its ability to cleave intra-membrane type-1
1
Dept. of Psychology , University of Haifa, Israel 2The receptors, such as P75NTR. P75NTR is a neurotrophin recep-
Institute for the Study of Affective Neuroscience (ISAN) tor which binds to different neuro-growth factors such as
3
Dept. of Biology , University of Haifa, Israel 4Dept. of NGF and BDNF. It was previously reported that p75NTR is
Neurobiology and Etiology , University of Haifa, Israel highly expressed in microglia cells. Here we aim to inves-
tigate the role of P75NTR in microglia cell activation towards
Background: The effects of stress in adulthood, following Amyloid-β.
sleep restriction or stress in juvenility, on body temperature and Results and conclusions: We discovered that microglia cell
activity level in rats were studied by means of radiotelemetry. line transfected with shRNA P75NTRexpress higher levels of
Methods: Rats were stressed in juvenility using a protocol CD11b, marker for microglia activation, when stimulated
of three-day exposure to different stressors. In adulthood with Alzheimer's disease beta amyloid 1-42 peptide.
S38 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
Furthermore, shRNA P75NTR microglia has an increased pattern of neuroinflammation and neuron loss seen in those
expression of specific pro-inflammatory activation markers brains. The mechanism underlying the specificity of storage
such as CD11b, IL-6, SRA, LRP and TLR4. Interestingly, build-up is, as yet, unknown.
there was significantly reduction in expression and secretion
of important anti-inflammatory factor IL-10 and in expres- Selective lentiviral mediated targeting of glia cells
sion levels of Abeta degrading enzyme such as Insulin in the central nervous system
degrading enzyme (IDE). Our findings suggest the impor- Fassler M* 1,2, Weissberg I 1, Levi N 3, Monsonego A 3,
tance of signaling through P75NTR in microglia cells in Friedman A 1, Taube R 2
1
shaping their activity in neurodegenerative diseases such Dept. of Physiology and Neurobiology, Faculty of Health
as Alzheimer's disease. Sciences and Zlotowski Center for Neuroscience, Ben-
Alzheimer's association, HFSP and ISF Gurion University of the Negev, Israel 2Dept. of Virology
and Developmental Genetics, Faculty of Health Sciences,
Selective glycolipid accumulation correlates with distinct Ben-Gurion University of the Negev, Israel 3Shraga Segal
brain pathology in a mouse model of a lysosomal storage Dept. of Microbiology and Immunology, Faculty of Health
disorder Sciences. Ben-Gurion University of the Negev, Israel
Farfel-Becker T 1, Meshcheriakova A 1, Vitner EB 1, Merrill
AH 2, Futerman AH* 1 Background: In a complex tissue of the central nervous
1
Dept. of Biological Chemistry, Weizmann Institute of Sci- system (CNS), cell cross-talk is essential to preserve normal
ence, Rehovot, Israel 2School of Biology and Petit Institute functions. Current tools for dissecting the molecular mech-
for Bioengineering and Bioscience, Georgia Institute of anisms that mediate cell-cell interactions within the brain
Technology, Atlanta, USA include molecular genetics, imaging and use of transgenic
animals. However, these are technically challenging, time
Background: Gaucher disease (GD), the most common consuming and difficult to control. In this study we report
lysosomal storage disorder, is caused by defective activity the establishment and validation of a lentiviral-mediated
of the lysosomal enzyme glucocerebrosidase (GlcCerase), gene-targeting platform to specific cells in the CNS. It
which results in accumulation of the glycolipids glucosyl- combines unique features of self-inactivated lentiviruses
ceramide (GlcCer) and glucosylsphingosine (GlcSph). The that promote stable gene delivery into non-dividing cells
rare neuronopathic forms of GD are characterized by dev- and efficient display of single-chain variable region
astating neurological disease and neuronal cell death, but human fragments (scFv) or soluble IgG on the surface
little is known about the neuropathological changes that of viral particles.
underlie these events. Results: In vitro, cells that express the receptor-binding
Results: We systematically examined the onset and progres- domain of the SARS CoV spike glycoprotein were targeted
sion of various neuropathological changes in a mouse model by engineered sindbis pseudotyped lentiviruses that incor-
of neuronopathic GD, defined the specific brain areas in- porate specific scFvFc attachment moieties. Additionally, in
volved (some of which were also reported to be involved in vitro targeted gene expression to primary astrocytes was
the human disease) and established that localized microglial also demonstrated, using engineered lentiviruses that
activation and astrogliosis are spatially and temporally cor- incorporate Aquaporin 4 and GLAST (ACSA-1: Astro-
related with selective neuron loss (Farfel-Becker et al., cyte Cell Surface Antigen-1) IgG. In vivo, lentiviral
2011). To understand why only specific brain areas are targeting of astrocytes and oligodentrocyes progenitor
affected, we used periodic acid-schiff (PAS) reaction and cells (OPCs) that express the chondroitin sulfate proteo-
mass spectrometry (ESI-MS/MS) and determined that gly- glycan, NG2 was obtained using viral particles that
cosphingolipid accumulation occurs only in specific neuronal display an anti GLAST and anti NG2 IgG antibodies,
populations in the same brain areas that showed neuron loss respectively.
and neuroinflammation. Remarkably, a two-fold elevation in Conclusions: We conclude that this genetic delivery tool
GlcCer levels in the VPM/VPL of the thalamus did not cause can be used for specific targeting of several genes into
any transcriptional alterations (as determined by a microarray different cell populations. Moreover, it will enable efficient
experiment) in pre-symptomatic mice, suggesting that a cer- fating and imaging studies during CNS development, as
tain threshold of GlcCer or GlcSph levels must be met in order well as enhance the understanding of the molecular mecha-
to elicit the massive neuron loss and inflammation detected in nisms that mediate cell communication in healthy and dis-
this brain area in later stages of the disease. eased brain. This novel approach will be implemented in
Conclusions: Glycolipids accumulate to a different extent in model of epilepsy to study the role of astrocytes in the
different brain areas and in different neurons within the pathogenesis of the disease and challenge its use as a ther-
same area in Gaucher brains, which explains the specific apeutic tool.
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S39
Towards a breath test for early Parkinson’s disease: The neuroscience research capability in Australia is backed by
nanomaterial-based sensors for detecting nigro-striatal a considerable investment in infrastructure, such as can be
dopaminergic lesion in rats found at the Florey Institute in Melbourne, the Queensland
Finberg J 1, Tisch U 2, Aluf Y 1, Abud M 2, Haick H* 2 Brain Institute in Brisbane, Neuroscience Research Australia
1
Rappaport Faculty of Medicine, Technion, Haifa 2Dept. of in Sydney, the Hunter Medical Research Institute in Newcastle
Chemical Engineering and Russell Berrie Nanotechnology and the John Curtin School of Medical Research in Canberra.
Institute, Technion, Haifa The advanced imaging equipment at these research centres is
backed up by capabilities at the Australian Synchrotron at
Background: Symptoms of Parkinson's disease (PD) occur Monash University in Melbourne, including a new medical
only after 50-70 % of nigrostriatal dopaminergic neurons beam line, as well as other infrastructure capabilities around
have already been lost. It is therefore a prime effort in PD the country in hospitals and universities, ranging from X-ray
research to identify at-risk subjects as early as possible, with crystallography to automated antibody manufacturing.
the future goal of instigating neuroprotective therapy before But we face challenges. On the plus side, Australian scientific
large scale neurodegeneration takes place. Recently the research is cited at twice the rate of the OECD average. On the
analysis of volatile organic compounds (VOCs) in exhaled negative side, Australia has not been able to convert its re-
breath has attracted much interest as a possible method to search output into commercial outcomes at the same rate as
rapidly detect a variety of medical conditions. The aim of other developed countries. Indeed, the rate of multi-country
this study is to identify the VOC pattern of early-stage patents for Australian inventions is about one third of the
nigrostriatal dopaminergic lesion in rats with a new OECD average. This means that there is enormous opportu-
nanomaterial-based breath test. nity for Australia to achieve more in translating its strong
Results: Exhaled breath was collected from rats that were research base into commercial outcomes. This is true in neuro-
previously administered 6-hydroxydopamine (6-OHDA) sciences as much as it is in IT and mining automation.
intracerebroventricularly (i.c.v.) at different doses (125 to There are numerous existing collaborations between Israeli
325 μg) in order to cause different degrees of dopaminergic and Australian neuroscience researchers, and we hope that
neuronal loss, or with 5,7-dihydroxytryptamine (5,7-DHT) through the visits made by the Australian delegation and our
or saline as specificity and operational control substances participation at the ISFN meeting we will discover new
respectively. The breath samples were analyzed using an opportunities for effective collaborations between outstand-
array of organically functionalized carbon nanotube and ing neuroscience researchers in our two countries. A brief
gold nanoparticle sensors. Discriminant factor analysis overview of the research interests of the delegation will be
detected statistically significant differences between the presented, along with some additional fields of relevant
study groups and a classification accuracy of over 80 % research not directly represented by the delegation.
was achieved using leave-one-out cross-validation. The The Australian delegation is being managed at the Austra-
chemical composition of the breath samples was studied lian end by the Australian Academy of Technological Sci-
using gas chromatography/mass spectrometry. Significant ences and Engineering. ATSE is an independent, non-
concentration differences of 4 VOCs were found among government organization that promotes the development
the sub-populations. and adoption of existing and new technologies to improve
Conclusions: The source of the altered VOC metabolism in Australia’s competitiveness, and Australia’s economic, en-
PD is unknown, but other studies have shown that increased vironmental and social well-being.
oxidative stress can change production of VOCs from cell
membrane lipids. The results indicate the feasibility of fu- 3-D neural-compass: head-direction cells in the bat
ture development of this non-invasive technique for early presubiculum
PD detection. Finkelstein A* 1, Derdikman D 1,2, Foerster J 1, Las L 1,
Ulanovsky N 1
1
Australia: Neuroscience, Research and Innovation Dept. of Neurobiology, Weizmann Institute of Science,
Finkel A. Rehovot 76100, Israel 2Rappaport Faculty of Medicine,
AM FTSE – President-Elect, the Australian Academy of Technion, Haifa 31096, Israel
Technological Sciences and Engineering (ATSE) and
Chancellor, Monash University. 'Head-direction cells' are neurons that become active whenev-
er the animal's head points in a specific direction in space (like
Neuroscience research in Australia is running strong, as will a compass), and they were suggested to be a key component of
be apparent during the presentations by the Australian del- the mammalian navigation system. Directional tuning of ro-
egation at the ISFN meeting. We are grateful for the oppor- dent head-direction cells was previously characterized only
tunity to participate so fully in this meeting. for the head azimuth (yaw), and it is unclear whether they may
S40 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
also encode elevation (pitch). Here we asked whether 3-D (3-(2-aminoethyl)-indolin-4-yl-ethyl(methyl) carbamate
head-direction tuning exists in mammalian brains, by record- dihydrochloride), and AN-819 (3-(3-methoxy-3-oxo-
ing from Egyptian fruit bats, mammals which are well adapted propyl)-4-(((4-methoxyphenyl)(methyl)carbamoyl)oxy)in-
to 3-D behavior. To this end, we developed a custom 3-D dolin-1-ium hydrochloride) with IC50s of 0.4 and 1.2 μM,
tracking apparatus that allowed monitoring the three head- respectively. Almost all the carbamates tested showed anti-
rotation angles: yaw, pitch and roll, in freely moving animals. oxidant activity against ROS at concentrations similar to or
We conducted single-unit tetrode recordings in bat presubic- lower than those inhibiting AChE. Carbamoylation of the
ulum, yielding more than 300 neurons – 32 % of which were AChE enzyme releases the respective 4- or 6-OH indoline
tuned to head direction – from 4 bats, while the animals were analogs. These compounds were found to be as good as or
actively crawling in an open-field arena, or were passively even better than the parent carbamates at scavenging ROS.
moved while being held upside-down. We found that head- Many of the compounds were able to reduce cytotoxicity
direction cells in the bat were tuned to one or more of the three induced by H2O2 in cardiomyocytes at concentrations rang-
Euler rotation angles (yaw, pitch, and roll), with some neurons ing from 1 pm-100 nM, which act by reducing the fall in the
showing clear tuning to all the 3 angles – including pitch and mitochondrial potential. Thus, several of these novel com-
roll. Population analysis showed that while the bat was held pounds possess advantages over existing AChE inhibitors
upside-down, a substantial fraction of neurons retained a clear for the treatment of AD since they interact at relevant con-
directional firing, but surprisingly, the best tuning in azimuth centrations with several important targets to reduce the
was often shifted by 180 degrees compared to the upright pathological changes occurring in this disease.
position, suggesting a torus-like continuous representation of
3-D head-direction. Taken together, our results demonstrate Novel multi-functional drugs for the treatment
for the first time a 3-D head-direction mechanism in mam- of neurodegenerative diseases
mals, which may be part of a broader neuronal network Finkin-Groner E 1, Yanovsky I 2, Nudelman A 2, Weinstock
supporting navigation in 3-D space. M* 1
1
Institute of Drug Research, Faculty of Medicine, The
Carbamate derivatives of indolines as cholinesterase Hebrew University of Jerusalem, Jerusalem, Israel
2
inhibitors and antioxidants for the treatment Dept. of Chemistry Bar Ilan University Ramat Gan,
of Alzheimer’s disease Israel
Yanovsky I 1, Finkin-Groner E 2, Zaikin A 2, Lerman L 1,
Shalom H 1, Zeeli S 1, Billig T 3, Ginsburg I 3, Nudelman Background: In Alzheimer’s disease (AD), oxidative stress,
A* 1, Weinstock M 2 (OS) glial activation and formation of plaques and tangles are
1
Dept. of Chemistry Bar Ilan University Ramat Gan, Israel believed to contribute to progressive neurodegeneration. None
2
Institute of Drug Research Hebrew University Medical of the acetylcholinesterase (AChE) inhibitors currently in the
Center, Israel 3Institute of Dental Research, Hadassah clinic are able to reduce OS and inflammatory processes at
School of Dental Medicine, The Hebrew University of doses used to treat AD. Therefore, there is a need for a drug
Jerusalem, Jerusalem, Israel which inhibits AChE and butyrylcholinesterase (BuChE), has
anti-oxidant and anti-inflammatory activities. Indole pro-
The cascade of events that occur in Alzheimer's disease pionic acid (IPA) prevents oxidative stress and death of pri-
(AD) involving oxidative stress and the reduction in cholin- mary neurons and neuroblastoma cells exposed to H2O2 or
ergic transmission can be better addressed by multifunction- amyloid beta. Derivatives of indoline propionic acid (InPA)
al drugs than by cholinesterase inhibitors alone. For this were found to be more potent anti-oxidants than those of IPA
purpose we prepared a large number of derivatives of in cell culture. Therefore, a series of novel carbamates was
indoline-3-propionic acids and esters that showed antioxi- synthesized based on the structure of InPA and their AChE,
dant activity both in solution and against cytotoxicity in BuChE, anti-oxidant and anti-inflammatory activities were
cardiomyocytes and primary cultures of neuronal cells ex- evaluated.
posed to reactive oxygen species (ROS). Results: Two compounds: 3-(2- (methoxycarbonyl) ethyl)-
Conclusion: Indoline derivatives having a carbamate in indolin-4-ylethylmethylcarbamate (AN-827) and 3-(2-
position 4 were found to be more potent acetycholinesterase (methoxycarbonyl)ethyl)-1-indoline-6-ylethylmethylcarba-
(AChE) and butyrylcholinesterase (BuChE) inhibitors than mate (AN-680) prevented cytotoxicity induced by OS and
those substituted at positions 6 or 7 while the corresponding the release of cytokines from activated microglial cells at
3-propionic acid esters, were more potent than their respec- concentrations at, or lower than those inhibiting AChE.
tive acids. Compounds with an (N-methyl,N-ethyl)-carba- They inhibited AChE in rat brain and reduced lipid peroxida-
mate substituent were more potent inhibitors of BuChE than tion and formation of nitrites in mouse brain after injection of
of AChE. The most potent AChE inhibitors were AN-890 lipopolysaccharide (LPS). When injected together with LPS,
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S41
AN-827 andAN-680 lowered the levels of pro-inflammatory may induce selection bias. These results suggest that opti-
cytokines (IL-6, IL-1β and TNF-α) in the cortex, subcortex mal handling of fcMRI data will need to take into account
and spleen. The mechanism of anti-inflammatory activity was the consequence of motion artifacts to avoid the report of
evaluated in BV2 cells activated with LPS and shown to occur artifactual patterns of correlation.
through reduction in phosphorylation of p38 and activation of Student scholarship provided by CAPES
the transcription factor AP-1.
Conclusions: Two derivatives: AN-827 and AN-680, which New insights into links between glia function
display anti-oxidant, anti-inflammatory and AChE inhibito- and the development of Alzheimer’s disease pathology
ry activities in vitro and in vivo, may have potential use for Frenkel D* 1,2
1
the treatment of AD and other neurodegenerative diseases. Dept. of Neurobiology, George S. Wise Faculty of Life
Sciences, Tel Aviv University, Tel Aviv, ISRAEL 2Sagol
Head motion in children with ADHD: how it affects School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
connectivity results in neuroimaging studies
Kieling RR 1, Kieling C 2, Da Costa JC 3, Franco AR* 3,4 Background: Glial cells maintain brain plasticity, as well as
1
Neuroscience Program, Pontifícia Universidade Católica protect the brain for functional recovery from injuries. Dys-
do Rio Grande do Sul, Porto Alegre, Brazil 2Dept. of Psy- function of glial cells may promote neurodegeneration and,
chiatry, Universidade Federal do Rio Grande do Sul 3Brain eventually, the retraction of neuronal synapses, which leads to
Institute, Pontifícia Universidade Católica do Rio Grande cognitive deficits that are found in neurodegenerative diseases
do Sul, Porto Alegre, Brazil 4Electrical Engineering Dept., such as Alzheimer's disease (AD). AD patient brains demon-
Pontifícia Universidade Católica do Rio Grande do Sul, strate a significantly higher degree of glial cells dystrophy
Porto Alegre, Brazil than non-demented individuals. We aim to investigate the role
of glial cells in the progression of AD.
Background: Recent reports have suggested that spurious Results and conclusions: The majority of the early-onset
but systematic correlations in resting state functional con- familial AD genetic cases (75 %) relate to the presenilin 1
nectivity MRI (fcMRI) may arise from subject motion to the (PS1) and presenilin 2 (PS2) genes that are considered impor-
sensitivity of resting state data, typical preprocessing meth- tant determinants of g-secretase catalytic site. We have dem-
ods such as motion correction, regression of confounding onstrated that g-secretase inhibitors (GSIs) can lead to
signals and bandpass filtering are not sufficient to eliminate impairment of microglial cell activity, which resulted in a
signal corruption caused by head movement. Here we ana- reduction of phagocytosis of Aβ (Farfara et al. 2011). The
lyzed the impact of head motion on seed-based functional accumulation of amyloid deposits on the cerebral blood ves-
connectivity. Data from the ADHD200 Consortium, com- sels, known as cerebral amyloid angiopathy (CAA), is asso-
prising children and adolescents with ADHD and healthy ciated with cognitive decline and is one of the hallmarks of
controls, were used to estimate subject motion based upon AD pathology. We recently demonstrated (Weiss et al.BBI
head realignment using a rigid body six-parameter affine 2012; Lifshitz et al Neurobiology of Aging 2012 ) that TGF-
transform, summing the displacement at each TR. Mean beta affects astrocyte and endothelial cell interaction, which as
displacements were calculated for translation and rotation. measured, resulted in an acceleration of a CAA-like pathology.
FcMRI was calculated between two seeds within the DMN, Furthermore, we have shown that tau hyperphosphorylation in
the medial prefrontal cortex (mPFC) to the posterior cingu- astrocyte leads to acceleration in AD pathology in a new mouse
late cortex (PCC). A linear stepwise regression with rs- model that contains most of the features of AD pathology
fcMRI as the dependent variable and age and translation including CAA and neurodegeneration. Understanding the mo-
as independent variables was calculated. lecular pathway of glial cell activation will not only shed light
Results: A total of 421 children (119 drug-näive and 302 on the pathogenesis of AD but also help to develop novel
controls) were included in this study. No statistical difference therapeutic applications in AD treatment.
in age and IQ were observed groups (p>0.1). Children with Alzheimer's association, HFSP orginization and ISF
ADHD exhibited excessive motion compared to controls with-
in both modalities (p<0.05). Increased functional connectivity Alleviating tauopathy symptoms in a Drosophila model
between the mPFC and PCC was observed within controls using aromatic inhibitors of amyloid aggregation
compared to patients (p00.036). Regression analyses showed Frenkel-Pinter M, Scherzer-Attali R, Tal S, Alyagor I, Gazit
that difference in rs-fcMRI between groups was lost (p00.091) E, Segal D
when age and movement were incorporated in the analysis. Dept. of Molecular Microbiology & Biotechnology, The
Conclusions: Head motion is one of the greatest factors that Sagol Interdisciplanary School of Neurosciences, George
degrade fMRI data quality. Typically data with large dis- S. Wise Faculty of Life Sciences, Tel-Aviv University.
placements are discarded; however, discarding such data Tel-Aviv 69978, Israel
S42 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
In spite of the fact that various amyloid-forming proteins do involve common mechanisms to those mediating typical
not share simple sequence homology, all amyloid assem- object perception. Furthermore, the perceived differences
blies have common ultrastructural and physiochemical between the two classes of objects would only emerge
properties. We and others have identified a central role of later along the processing hierarchy. Experiment 1 utilized the
specific interactions between aromatic residues in the rec- object-based attention paradigm to show that impossible and
ognition and self assembly process leading to the formation possible objects are represented similarly such that for both
of various amyloid aggregates. Therefore, aromatic aggre- object categories processing features belonging to the same
gation inhibitors, which would compete for the aromatic object was enhanced compared to features belonging to two
interactions between amyloidogenic proteins themselves, different objects. Yet, responses for impossible objects were
may serve as general anti-aggregation inhibitors for various overall slower compared to possible objects. The goal of
amyloid proteins. Indeed, our in vitro studies have shown Experiment 2 was to examine whether these differences could
that NQTrp, a small aromatic molecule composed of a be attributed to early versus late processing by manipulating
quinone-tryptophan hybrid, inhibits aggregation of various exposure duration. Importantly, differences in accuracy be-
amyloidogenic proteins including Aβ, alpha-synuclein and tween possible and impossible objects emerged only for long
lysozyme. Based on this, we have shown that NQTrp can stimulus exposures thus verifying our working hypothesis.
cause complete phenotypic recovery of an Aβ-Alzheimer's Overall, these findings suggest that the visual system utilizes
disease (AD) Drosophila and mouse models. To test whether intact shape attributes to create an organized representation of
this generic inhibition potential is effective also in vivo we impossible objects and highlight the importance of these
began to explore NQTrp as potential inhibitor of tau aggre- attributes for perceptual organization.
gation in a Drosophila tauopathy model. The microtubule-
binding protein tau is a component of neurofibrillary tangles Using machine learning to identify patients with syslexia
in AD and related disorders that are collectively referred to disability
as tauopathies. In an available Drosophila model of Frid A 1,2,3, Breznitz Z* 1
1
tauopathies, overexpression of wild-type human tau in Edmond J. Safra Brain Research Center for the Study of
the fly retina resulted in neurodegeneration which is Learning Disabilities, University of Haifa 2Dept. of Software
manifested as a 'rough' eye phenotype with disordered Engineering, Ort Braude Academic College of Engineering,
ommatidia. Utilizing this model we found dramatic re- Carmiel, Israel 3Dept. of Computer Science, Tel-Hai Aca-
duction in the flies' eye neurodegeneration when fed demic College, Upper Galilee, Israel
with 0.75 mg/ml NQTrp in the culture medium through-
out their lifetime. Likewise, NQTrp alleviated the loco- Background: Dyslexia is a learning disability that impairs a
motion defects typical of targeted overexpression of person's ability to decode words accurately and fluently. This
wild-type human tau in the fly CNS. These results deficit can manifest itself in the language-related domain as
support the notion that aromatic aggregation inhibitors difficulties in phonological and orthographic working memo-
can work efficiently on various amyloidogenic proteins ry, brain systems asynchrony, poor executive function skills
in vivo. Testing inhibition of in vitro tau aggregation and/or poor rapid naming processing. However it is not clear
using NQTrp is underway. yet whether the dyslexia phenomenon is only related to lan-
guage or if it can also be seen as a non-language deficit.
Evidence for similar early but not late representation Moreover, if it is also related to non-language activity, it is
of possible and impossible objects important to verify if it is possible to identify dyslexic readers
Freud E* 1,2, Hadad B 1,3, Avidan G 1,2, Ganel T 1,2 at the earliest stage of information processing for better and
1
Dept. of Psychology Ben-Gurion University of the Negev, effective remediation. Based on this, an effective algorithm
Beer Sheva, Israel 2Zlotowski Center for Neuroscience, was developed for analysis and classification of subjects as
Ben-Gurion University of the Negev, Beer Sheva, Israel either Regular Readers or Dyslexic Readers, by using EEG
3
Dept. of Education, University of Haifa, Israel. recorded channels with Event Related Potentials (ERP) meth-
odology during an auditory, short non-linguistic, simple, sub-
Impossible objects are defined as 2D drawings that phonetic choices reaction time task.
represent 3D objects that could not exist in real space. Results: Three results are presented: (i) the ability to success-
Yet, despite being perceived as exceptionally unusual, fully identify readers using the single feature, taking advan-
impossible objects still possess fundamental Gestalt tage of only three out of 64 electrodes, reached 80 % accuracy,
attributes, such as closure, distinguishable surfaces and (ii) using an ensemble of classifiers, lead by a majority voting
volume properties. Based on this notion and on recent mechanism (each classifier trained separately on a different
neuroimaging findings from our lab, we hypothesized feature – electrodes pairings) 85 % accuracy reached, (iii) we
that the initial perception of impossible objects will show that the majority of differences lie in the left hemisphere.
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S43
Conclusions: Successful classification at such an early ADHD subjects fail to suppress microsaccades and eye
auditory processing stage may indicate the origins of the blinks during anticipated stimulus presentation
dyslexia phenomena. Another interesting conclusion was Fried M, Bonneh Y, Sterkin A, Polat U*
that each feature could successfully be separated using Faculty of Medicine, Tel-Aviv University, Goldschleger Eye
different electrode leads, i.e. there exist wide differences Research Institute, Sheba Medical Center
in information processing and different brain areas may
indicate that there are different causes of the same Background: ADHD is the most prevalent psychiatric disorder,
problem, perhaps the existence of different subtypes of estimated to affect about 10 % of the population. Currently, the
dyslexia. diagnosis is based mainly on subjective parameters, though there
This study was supported by the Edmond J. Safra Philan- are several computer-based tools, such as TOVA, to support the
thropic Foundation. diagnosis. However, no objective tool based on physiological
measurements is available for diagnosing ADHD. It was previ-
Chronic inflammatory pain and morphine analgesia: ously shown that several ocular parameters correlate with atten-
Involvement of microglia and interleukin-1 tion. We thus aimed to search for objective markers of ADHD
Fridel K* 1, Wolf G 1, Nasaev E 2, Brenner O 2, Meilin S 2, based on ocular parameters.
Shavit Y 1 Methods: Twenty subjects diagnosed with ADHD and 20
1
Dept. of Psychology, Hebrew University, Mount Scopus, control subjects performed 2 sessions of TOVA, while their
Jerusalem 2MD Biosciences, Ness Ziona, Israel eye movements were tracked. ADHD subjects performed
the first session un-medicated and the second session
Background: Peripheral inflammation induces changes in 1.5 hours after taking medication (Ritalin). Control subjects
the central and peripheral nervous system, which are performed the second session 1.5 hours after the first, both
(mostly) associated with hyperalgesia, and accompanied without medication. We measured the average rates of eye
by activation of spinal glia cells and the release of blinks and microsaccades during the time interval -75 to 150
interleukin-1 (IL-1). In naive mice, IL-1 has been shown milliseconds relative to stimulus onset (peri-stimulus).
to mainly induce hyperalgesia and to counter-regulate mor- Results: We found that un-medicated ADHD subjects have a
phine analgesia. In contrast, accumulating evidence sug- significantly higher average blink rate than control group during
gests that in states of peripheral inflammation IL-1 may the peri-stimulus interval; this average rate is significantly re-
contribute to hypo-algesia, via changes in peripheral opioid duced with medication, but still remains significantly above the
mechanisms. The present study examined the involvement control rate. We also found that the average rate of microsac-
of IL-1 and microglia in pain sensitivity and in opioid cades in ADHD group in the un-medicated session during the
analgesia in a state of chronic peripheral inflammation. peri-stimulus interval is significantly higher than in the control
Methods: Inflammation was induced by sub-dermal injec- group and that is reduced to the level of the control group after
tion of complete Freund's adjuvant (CFA) at two sites medication.
around the left ankle in mice. Animals were assessed for Conclusions: These results suggest that un-medicated ADHD
mechanical allodynia, mobility, swelling, and hind-paw subjects fail to suppress both microsaccades and eye blinks
histology. during anticipating the stimulus presentation. We also show that
Results: (A) Morphine analgesic efficacy was extended medication increases the suppression capacity of ADHD subjects
by peripheral inflammation;(B) Neither genetic nor phar- towards the normal range.
macological blockade of IL-1 signaling impeded the
development of allodynia in the inflamed paw; (C) The romantic OdorSpace
Genetic and pharmacological blockade of IL-1 pre- Frumin I 1, Weissler K 1,2, Snitz K 1, Haviv L 1, Sobel N* 1
1
vented the potentiated morphine analgesia;(D) Pharma- Dept. of Neurobiology, Weizmann Institute of Science
2
cological blockade of microglia prevented the Dept. of Psychology , Tel Aviv University
potentiated morphine analgesia; and (E) Morphine injec-
tion reduced histological markers of inflammation Olfaction and the MHC family of genes influence mate selec-
around the joints by 24 hrs post-injection. tion. MHC is both linked to the individual olfactory genome,
Conclusions: These findings indicate that morphine analge- and also influences body odor. Therefore, exploring the olfac-
sia is potentiated in a state of chronic peripheral inflamma- tory preferences of individuals has the potential of foreseeing
tion and that IL-1 (possibly released by microglia) is their mate selection preferences. To test this hypothesis, we
involved in this potentiation. Furthermore these findings used a web-based platform developed in our lab called Odor-
indicate that morphine plays an anti-inflammatory role in a Space. The basic idea involves dispensing odor kits, and rating
state of chronic peripheral inflammation. a series of psychophysics measures regarding each smell. We
This work was supported by an ISF grant No. 512/08 micro-encapsulated four different odors (cis-3-hexen-ol,
S44 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
isoamyl acetate, methyl anthanilate and isovaleric acid) packed choice trials, by a 'change of intention' scenario rather than
in a kit and asked romantic couples to log in to site (www. confusion or hesitation: the subject prepares the type of action
odorspace.com), where they were asked to fill in a question- indicated by the prime but 'changes his/her mind' and actually
naire. They were asked to enter general demographic data, to acts differently. In this experiment, the 'change of intention' is
rate their overall relationship quality as well as the quality of composed of an initial intention prompted exogenously by a
their sexual relationship, on a 1 to 100 visual analog scale masked prime, which is then overruled either by an exogenous
(VAS). They were then asked to rate 30 descriptors for each instructing arrow in the Instructed case, or by an endogenous
of the odors in the kit (for a total of 120 ratings, on a similar intention in the free-choice case. The results allowed us to
VAS). Typical descriptors were "To which extent is the odor reveal the process of change of intention in a second experi-
edible", "How fresh is the odor", etc. Both partners filled the same ment in which both the initial and the overruling intention are
questionnaire consecutively, albeit with a scrambled order of endogenous.
descriptors. We calculated the correlation between the answers
of both partners, and correlated that number with the rated overall Aversive olfactory memories with different reinforcers
and sexual quality of the relationship, as provided by the subjects. Galili D*
So far we received entries from 18 couples. Rated quality of the Max Planck Institute for Neurobiology, Munich, Germany
relationship positively correlated with the smell match correlation
for the romantic couples (R00.556, p<0.0005). Rated sexual Drosophila melanogaster flies show complex behaviours like
quality also positively correlated with smell match correlation but associative learning. Using the available genetic tools com-
was weaker (R00.47, p<0.005) (Pearson's correlation). There bined with behavioural measures allows us to study the spe-
was no significant correlation between the length of relationship cific neuronal circuit of learning and memory. In olfactory
to neither the smell matching score nor the rated qualities. conditioning, flies are simultaneously presented with odour
and reinforcement, and their associative memory is tested later
Neural signature of change of intentions by the degree of odour avoidance. Using olfactory condition-
Furstenberg A* 1,2, Breska A 3, Deouell LY 3,1, Sompolinsky ing with different aversive reinforcers, we directly compare
H 4,1,2 the neuronal circuit of different aversive memories (i.e. heat
1
Edmond and Lily Safra Center for Brain Sciences, The He- and electric shock). We found that flies avoid the conditioned
brew University, Jerusalem 2Interdisciplinary Center for Neu- odour that has been paired with the heat, while too high
ral Computation, The Hebrew University, Jerusalem 3Dept. of temperature leads to impairment of the performance. Calibra-
Psychology , The Hebrew University, Jerusalem 4Racah In- tion of reinforcement intensities revealed that the memories of
stitute of Physics, The Hebrew University, Jerusalem heat and shock share commonalities. We identified responsi-
ble neurons that are selectively required for the heat, but
Intention is an intermediate concept between will and action not shock memory. Furthermore, we found that condi-
and is defined in this work as conscious or non-conscious tioned odour avoidance with both heat and shock
preparation to act. The goal of this work is to identify a neural requires intact dopamine neurons. These results imply
index of change of intention and characterize the conditions that these two noxious stimuli are perceived using dif-
that lead to it. In order to obtain an electro-physiological ferent receptors but commonly recruit the same neuro-
model for 'change of intention' we used a masked priming transmitter system to signal aversive reinforcement.
paradigm while recording EEG. The task was to press a right
or left button following either a visible arrow cue ('instructed Extracellular pH regulates the ZnR/GPR39-dependent
condition') or a visible 'free-choice' cue. The subjects were Ca++ responses in primary hippocampal neurons
unaware of the presence of the masked prime, nevertheless we Ganay T
observed a behavioral effect of the prime: on Instructed trials Dept. of Morphology, Faculty of Health Sciences, Ben-Gurion
performance was slower and less accurate when the prime and University, Beer-Sheva
instruction cue pointed in different directions (i.e., incongru-
ent trials), than on congruent trials; on free-choice trials per- Background: Zinc ion is the second most important ele-
formance was slower in the incongruent cases, and primes ment in the body and is abundant in the brain, with very
significantly biased freely chosen responses in the direction of high concentration in the hippocampus, among other brain
the prime. We revealed a spatio-temporal electrophysiological regions. Zinc is selectively stored in presynaptic vesicles
signal around 250-350 ms after prime onset which we inter- and has been shown to be released in a calcium- and
pret as an EEG signal induced by the prime, representing activity-dependent manner. Recent studies have demonstrat-
preparation to move right or left according to the prime cue ed that synaptically released zinc can act on a post-synaptic
direction. This signature allowed us to explain the behavior metabotropic zinc receptor/G protein-linked receptor 39
cost of incongruence, both in Instructed as well as in free- (mZnR /GPR39)that is localized in CA3 neurons.
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S45
Activation of GPR39 triggers a Zn-dependent metabotropic Sulcus showed a unique preference for HBR imagery selec-
Ca++ response which then regulates Cl transport in the post tively. Based on our findings, we suggest an integrative frame-
synaptic cells. work for the cortical network which subserves HBR.
Results: We have developed a primary culture of hippocam-
pal neurons in which we are able to monitor ZnR activity. Effects of sensory modality and flight kinematics on 3-D
Cultures obtained from GPR30 KO mice do not exhibit a spatial codes in bat hippocampus
Zn-dependent Ca++ response. . Zn binding is mediated by Geva-Sagiv M 1,2, Las L 1, Ulanovsky N 1
1
histidine and aspartate residues on GPR39, these residues Dept. of Neurobiology, Weizmann Institute of Science,
are often implicated in pH sensing. Localized pH changes Rehovot 76100, Israel 2Interdisciplinary Center for Neural
have been suggested to occur in the brain during normal Computation, The Hebrew University of Jerusalem, Givat-
function or pathologic conditions. Using calcium imaging, Ram campus, Jerusalem 91904, Israel
we show that the neuronal mZnR response is regulated by
pH. Our preliminarily results show that the mZnR/GPR39- Hippocampal neural recordings are an important model system
dependent Ca2+ response is reduced at pH 8 and abolished for understanding spatial cognition: The ensemble activity of
at pH 6.5 on WT cultured neurons. hippocampal 'place cells' encodes the location of an animal
Conclusion: In this study, we will focus on the role of ZnR/ within its environment. However, little is known on how inputs
GPR39 in regulating a major Ca2+ signaling pathway that is from different sensory systems affect hippocampal spatial rep-
sensitive to extracellular pH. resentation. Here we set out to dissociate the effects of using
two long-range sensory systems – vision and echolocation – on
Feed-forward and top-down somatosensory body hippocampal neural activity in a unique animal model, the
processing in the human brain Egyptian fruit bat. We trained bats to orient using vision with-
Geva R 1,2, Tal Z 1,2, Amedi A* 1,2,3,4 out sonar – in a lit environment, and by sonar without vision –
1
Dept. of Medical Neurobiology, the Faculty of Medicine, in the dark. Through simultaneous recordings of multiple cells
The Hebrew University of Jerusalem 2Institute for Medical in the hippocampal CA1 region of flying bats, we are in the
Research Israel-Canada (IMRIC), The Hebrew University process of characterizing the differences in the neural codes for
of Jerusalem 3Edmond and Lily Safra Center for Brain space of individual cells, and in the ensemble activity, based on
Sciences (ELSC), The Hebrew University of Jerusalem the two sensory systems. Preliminary results from hippocampal
4
Cognitive Science Program, Hebrew University of Jerusa- recordings in flying bats showed clear three-dimensional (3-D)
lem, Jerusalem, Israel place fields in the light, and in the dark. Some cells showed
clearly reproducible 3-D place fields between two consecutive
We perceive ourselves as single individuals, each an insepa- flight sessions in light conditions, while exhibiting consistent
rable combination of body and mind. Key to this perception is 'remapping' when switching from light to dark conditions (that
the brain's ability to maintain the Holistic Body Representa- reverted when switching back to the light condition).
tion (HBR), which combines information from a variety of We will also discuss the selectivity of place-cell firing to the
body parts, sensory input modalities and higher cognitive 3-D-directionality of flight, and the possible dependence of
sources. Yet, it is not clear how all these sources of informa- the neural activity on flight curvature. So far, we have found
tion converge and the neural correlates of HBR remain elu- that some cells show clear preferences for left-right flights
sive. Our goal is to reveal the networks underlying HBR. or for right-left flights – similar to previous reports in rats.
This study focuses on the neural correlates of HBR using
fMRI in humans. We combine tactile perception and imag- A novel sarcosinyl-linked Olanzapine antipsychotic
ery paradigms with a visual-based mental body transforma- agent, PGW5, exhibits high efficacy with no metabolic
tion task to examine feed-forward (body parts to brain) and side-effects in rodent models
top-down (higher cognitive function to body part) process- Gil-ad I* 1, Vered I 2, Taler M 1, Portnoy M 3, Zipori M2,
ing contributions to the HBR in humans. Specifically we Shbiro L 2, Tarasenko I 1, Globus R 1, Weizman A1,
focus on the integration of bottom-up and top-down somato- Weller A 2
1
sensory and visual information of the whole body. Biological Psychiatry Lab, Felsenstein Medical Research
The ventral and dorsal premotor (PM) cortex and the anterior Center, Campus Rabin, Tel-Aviv University 2Dept. of Psychol-
intraparietal sulcus (aIPS) were the main areas involved in ogy & Gonda Brain Research Center, Bar Ilan University
3
HBR. We show that information from several body parts con- School of Chemistry, Tel-Aviv
verges in these areas. The aIPS was the major focus of activa-
tion for all aspects of HBR, integrating whole-body processing Background: Schizophrenia is a chronic disease associated
in tactile perception and tactile imagery and showing equal with hypo function of glutamate transmission. Psychotic
feed-forward and top- representation. The Parietao-Occipital symptoms are induced by NMDA antagonists. Atypical
S46 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
neuroleptics induce weight gain and metabolic syndrome Results: KCC2 activity was monitored by measuring the
associated with the development of medical comorbidities rate of NH4+ influx into neurons using fluorescent imaging.
(atherosclerosis, hypertension, dyslipidemia, diabetes) as well Mouse brain slices from mZnR WT animals incubated with
as depression, and eating disorders. We have developed the excitotoxin kainate demonstrated a nearly two-fold in-
a novel antipsychotic drug, PGW5, possessing an olan- crease in KCC2 activity in CA3 hippocampal neurons com-
zapine moeity linked to positive modulators of NMDA pared to controls. This upregulation of KCC2 activity was
sarcosinyl. Objective 1. Evaluate the efficacy of PGW5 abolished in slices treated with the cell impermeable Zn2+
in mice models of schizophrenia. 2. Determine the met- chelators CaEDTA and tricine. Furthermore, kainate treat-
abolic profile of PGW5 compared to Olanzapine in a rat ment did not change KCC2 activity in the presence of Gαq,
model of weight gain. PLC and MEK1/2 inhibitors that eliminate GPR39/mZnR
Results; Efficacy studies were performed in male mice (Balb/ signaling. Importantly, in slices from mZnR KO animals
c or C57bl) exposed to MK801 or PCP. PGW5 (12.5-50.0 mg/ kainate did not significantly change KCC2 activity.
kg) was administered orally. In open field tests, PGW5 effec- Conclusions: GPR39/mZnR activation by Zn2+ during kainate-
tively antagonized MK801-induced hyperactivity up to 6 hr. induced seizure-like activity results in upregulation of KCC2
At effective doses, PGW5 was not sedative, and demonstrated activity in CA3 hippocampal neurons. We suggest that synaptic
significant anxiolytic activity. In a subchronic study, PGW5 Zn2+ released during excitatory activity may initially enhance
but not Olanzapine antagonized PCP-induced impaired social inhibitory tone, providing an intrinsic homeostatic mechanism.
preference. In adult female Wistar rats, PGW5 (25 mg/kg/d)
ingested daily (over 14 of 16 days, dissolved in 10 ml of Resting state patterns reflect functional abnormalities
Ensure Plus Chocolate), as opposed to Olanzapine, did not in human visual cortex
induce weight gain or alteration in lipid profile. This sub- Gilaie-Dotan S 1,*, Hahamy-Dubossarsky A 2,*, Nir Y 3,
chronic administration of PGW5 was accompanied by an Bentin S 4, Malach R 2
increase in the neurotrophic factor BDNF in the cortex and 1Institute of Cognitive Neuroscience, UCL, London, UK
hippocampus, whereas Olanzapine but not PGW5 increased 2Dept. of Neurobiology, WIS, Rehovot, Israel 3Dept. of
the hippocampal expression of the NPY receptor Y5. Psychiatry, University of Wisconsin–Madison, Madison,
Conclusions: PGW5 is a novel neuroleptic, potentially effica- Wisconsin 4Dept. of Psychology, HUJI, Jerusalem, Israel
cious (according to research in mouse models) against positve * Equal contribution
and negative symptoms of schizophrenia. PGW5 administra-
tion, in contrast to Olanzapine was not associated with weight Even in the absence of stimulation or task, the cerebral
gain. The possible mechanisms underlying the differential cortex shows an incessant pattern of ultra slow fluctuations
effects of the drugs involve brain BDNF and NPY regulation. which are coherent across brain regions. In the healthy brain
these coherent patterns (also termed resting state functional
Zn2+ neurotransmission during kainate-induced connectivity) often exhibit spatial similarity to the large
in-vitro seizure-like activity results in upregulation scale organization of task-induced functional networks.
of KCC2 activity via mZnR/GPR39 However, it is not clear to what extent the resting state
Gilad D 1,2, Sekler I 1,2, Hershfinkel M* 1,2 patterns can also reflect task-induced abnormalities in cor-
1
Dept. of Physiology and Cell Biology, Faculty of Health tical activations which are often detected in various brain
Sciences, Ben-Gurion University, Israel 2Zlotowski Center pathologies. Here we examined whether an abnormal visual
for Neuroscience, Ben-Gurion University Israel. activation pattern is recapitulated in the resting state func-
tional connectivity. We examined LG, a sighted young adult
Background: Synaptic Zn2+ is stored in pre-synaptic vesicles with developmental object agnosia and no apparent cortical
and is co-released with glutamate in a sub-population of structural abnormality. We have previously reported that
glutamatergic nerve terminals. A distinct metabotropic Zn2+- upon visual stimulation, LG's intermediate visual areas
sensing receptor (mZnR), was shown by our lab to trigger (V2, V3) are paradoxically deactivated. Here, examining
intracellular Ca2+ rise following synaptic Zn2+ release in CA3 LG's resting state functional connectivity revealed the same
hippocampal neurons. We have shown that exogenous Zn2+ or pattern of functional abnormality- including a strong atypi-
Zn2+ released by physiologic stimulation of hippocampal cal decorrelation between areas V2-V3 and the rest of the
mossy fibers upregulates KCC2 activity via mZnR/GPR39 visual system. Thus, our results suggest that resting-state
by increasing its surface expression. KCC2 is the principal functional connectivity could provide a powerful tool for
Cl--outward transporter in mature neurons and its upregulation detecting task-related abnormalities in cortical activity with-
by mZnR/GPR39 signaling is sufficient to produce a hyper- out resorting to task performance.
polarizing shift in GABA reversal potential (EGABA) and may LG, Michal Harel. Funding: Marie-Curie(SGD); ISF, EU,
thus alter neuronal excitability. Kimmel award(RM); NIMH(SB); HFSP(YN)
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S47
Biological motion perception in individuals occipital activation that resonates to flickering visual
with form perception deficits stimuli. Typical SSVEP-based methods use analog stim-
Gilaie-Dotan S* 1, Behrmann M 2, Lorenzi L 2, Bentin S 3, uli at low frequencies (5-20 Hz), whereas we embed the
Rees G 1, Saygin AP 4 SSVEP cues naturally inside the interactive media at
1
Institute of Cognitive Neuroscience, UCL, London, UK high frequencies close to the fusion flicker threshold
2
Dept. of Psychology, CMU, PA, USA3Dept. of Psychology, using a digital display. This allows for a user-friendly
HUJI, Jerusalem, Israel 4Cognitive Science, UCSD, CA, interactive experience that can be used for classic BCI
USA as well as novel applications.
Method: EEG was recorded using 8 electrodes positioned at
What neural computations underlie the perception of biolog- occipital locations. Amplification, analog and digital filter-
ical motion is a key question in vision science and neurosci- ing, and algorithms were computed using Matlab, Simulink
ence. The classical point-light biological motion stimuli used (MathWorks, USA), and hardware and software from g.tec
in most studies not only incorporate the dynamics of animate (Austria). Stimuli were presented on a back projected large
motion, but also evoke the percept of bodily form. Psycho- screen at 120 FPS, at 30,40 and 60 Hz, generated using
physical and neuroimaging studies have provided support for Unity (Unity Technologies, USA) game engine. A classifier
the involvement of both form and motion-based processing in was first obtained by exposing the subject to simple
perception of these stimuli. Here, we explored whether bio- stimuli using the minimum energy EEG method (Friman
logical motion perception critically relies upon form process- et al., 2007). A rerun verified accuracy of at least 90 %,
ing. We examined individuals with form perception deficits followed by the interactive experience. We explored
(ventral visual brain-damaged patients and a developmental various types of stimuli: simple shapes, images, and an
visual agnosic with no apparent brain damage), and matched interactive scenario that included four star-shaped stim-
controls (healthy individuals and brain damaged patients with- uli. The subjects selected one of the stars and had to
out form perception deficits whose lesions were in the MCA maintain attention to it after it started moving around
territory and did not include ventral temporal cortex). In a the screen.
series of experiments using established noise-masking meth- Results: Ten subjects participated in the pilot, and the sys-
ods, we adaptively measured perceptual thresholds in detect- tem was able to classify their SSVEP responses at 90 %
ing point-light biological motion. Perception of non- accuracy or higher in the interactive experiences.
biological form-from-motion was also assessed. We found Conclusion: SSVEP responses can be classified with cues
that patients and individuals with form perception deficits that are embedded naturally in an interactive media in high
were not obviously impaired in their biological motion per- frequencies. We are now exploring the psychological
ception, but were impaired in non-biological form-from- aspects of this effect in terms of the sensation of agency
motion tasks. Critically, biological motion perception of ven- and the emotional relevance of the stimuli.
tral patients did not differ from those of MCA-territory le- This project is supported by the EU project VERE (grant
sioned patients on average, and was better than patients whose number 257695).
lesions included premotor or superior temporal cortex. Thus,
our data suggest that biological motion processing relies on a Therapeutic potential of combining the multi-target
broad network of brain regions, where ventral visual cortex is neuroprotective compound M30 with a fortified high
not as critical to biological motion perception as frontal or calorie/energy diet in a transgenic mouse model of ALS
superior temporal brain regions. Golko S*, Weinreb O, Amit T, Kupershmidt L, Youdim
Royal Society (SGD,MB), Marie-Curie (SGD,APS), MB, Mandel SA
NSF&NIMH(MB), Wellcome Trust (GR), NIMH (SB) Eve Topf Center for Neurodegenerative Diseases Research,
Faculty of Medicine, Technion
Neuro-responsive media: SSVEP-based interactive
experiences Background: Given the multiplicity of pathological mech-
Giron J* 1,2, Segal M 3, Fried E 4, Jackont G 1,2, Friedman D 1 anisms in Amyotrophic lateral sclerosis (ALS), the manage-
1
The Interdisciplinary Center, Herzliya 2Tel Aviv University ment of the disease nowadays is based on the recognition of
3
independent artist 4independent interaction designer the importance of a multiple target and multidisciplinary
care including the energy intake and expenditure of patients.
Background: There is now wide interest in controlling Recently, we demonstrated that the multi-target, brain per-
external devices using brain-computer interface (BCI); we meable iron chelator M30, carrying the propargyl moiety of
are aiming at extending BCI to interactive media experien- our neuroprotective anti-Parkinsonian drug rasagiline and
ces. Our method uses the steady state visually-evoked po- the iron-chelating moiety of VK28, conferred a significant
tential (SSVEP) paradigm, which is based on detecting improvement in survival time and motor performance of
S48 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
G93A-SOD1 Tg ALS mice. Goal: Our experimental proto- relative to those who only shared the input, marking the
col aims to test the possibility that strengthening the basal physiological effect of co-presence.
energy status of G93A-SOD1 Tg ALS mice would provide a In accordance with our hypothesis, subjects who watched
supportive basis for optimization of the neurorestorative the movie together showed significantly higher levels of
efficacy of M30. For this purpose ALS mice are adminis- physiological coupling then those who watched the movie
tered a combination of M30 and a high calorie/energy sup- alone or those who watched the movie with a different partner,
plementeddiet (M30 + CED), starting at the 56th day of on a different occasion. In addition, we revealed that collective
birth until death. movie watching involves a specific physiological state,
Results: We demonstrated that the M30 + CED cocktail marked by heightened levels of arousal during emotional
significantly delayed the onset of dysfunction compared to scenes.These results support the hypothesis that other people
each individual treatment. Furthermore, the combined for- distinctively affect our biological responses to external stim-
mulation showed superiority in extending the lifespan of the uli, even when there is no direct exchange of verbal informa-
ALS SOD1 mice compared to the effect of each of the tion. Moreover, it suggests thatphysiological coupling is one
individual components, suggesting a synergism between of the biological processes underlying this phenomenon.
M30 and the CED. Lastly, gene expression analysis of genes
related to energy homeostasis and lipid and glucose metab- An integrative metabolic analysis of mesial temporal
olism in the gastrocnemius muscle, liver and brain samples, epilepsy
showed significant tissue-specific changes by the M30 + Gonen N* 1, Ruppin E 2,3
1
CED treatment compared to either M30 or CED alone, Sagol School of Neuroscience, Tel Aviv University, Israel
2
further supporting their protective complementary action. Sackler School of Medicine, Tel Aviv University, Israel 3Bla-
Conclusion: This study supports the current assumption in vatnik School of Computer Science, Tel Aviv University, Israel
the treatment of ALS, stating that combining therapeutic
agents with different mechanisms of action may be superior Background: Mesial temporal lobe epilepsy (MTLE) is a
to monotherapies and provides a novel design for a multiple- chronic disease which is acknowledged as the most preva-
target therapeutic protocol for clinical trials in ALS. lent of all focal epilepsies. While there is a vast amount of
knowledge regarding the anatomical, physiological and cel-
The mere co-presence: studying the physiological effects lular aberrations of the disease, very little progress has been
of the presence of others made in understanding its underlying mechanism and in
Golland Y*, Levit-Binnun N discovering possible pharmaceutical treatments. The main
School of Psychology, Interdisciplinary Center, Herzliya purpose of this project was to study the metabolic aspects of
the disease using a state of the art method - the integrative
An extensive effort is currently invested in revealing the metabolic analysis tool (iMAT).
biological mechanisms involved in social interactions. Results: By integrating raw transcriptomic data from the
Recently it has been proposed that the biological signals CA1 sub-region in the hippocampus, we have portrayed an
of two interacting individuals exhibit joint, temporally integrative metabolic description of the different stages of
aligned response patterns (Hasson et al. 2012), aka MTLE. We have successfully replicated many experimental
physiological coupling. Thus, people not only couple results on known aberrations of the disease in the metabolic
together on the behavioral and emotional levels during level and have shown for the first time that some of them are
interaction, but also enter a state of biologically main- noticeable already in very early stages. We further study
tained interpersonal resonance in which various somatic which metabolic genes and pathways are strongly associated
and neuronal processes show similar dynamical changes. with MTLE and compose an integrative overview of the
A series of recent studies demonstrated that physiolog- disease. In addition, a list of suggested metabolic bio-
ical coupling in the neural and autonomic domains markers and drug targets was prepared.
accompanies different forms of interpersonal information Conclusions: This discovered biomarkers and drug targets
exchange. In the current study we explored whether may be further validated experimentally and by doing so
physiological coupling occurs when individuals are offer significant progress in the treatment of MTLE such as
merely co-present, without directly exchanging informa- early discovery of the disease, novel pharmacological treat-
tion. To that end we recorded continuous autonomic ments and better detection of the severity of MTLE and the
signals of subjects while they watched a movie together state of its progression.
with other people or while they watched a movie alone.
We hypothesized that subjects who shared both the Neurobehavioral dissociation of reinforcement
input (a movie) and the physical presence with each sensitivity and its relation to personality traits
other will show higher levels of physiological coupling Gonen T* 1,2, Eldar E 3, Hendler T 1,4
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S49
1
Functional Brain Center, Wohl Institute for Advanced Im- perception from motor-sensory interactions are not yet
aging, Tel Aviv Sourasky Medical Center, Tel Aviv , Israel known. We studied the closed-loop scheme of motor-
2
School of Psychological Sciences, Tel Aviv University, TA, sensory interactions using a novel experimental paradigm
Israel 3Princeton Neuroscience Institute, Princeton Univer- in which human participants localized objects using artifi-
sity, Princeton, NJ 4School of Psychological Sciences, Sagol cial whiskers. The setup enabled monitoring all relevant
School of Neuroscience, Dept. of Physiology and Pharma- motor variables, such as hand velocity and synchronization
cology, Tel Aviv University, TA, Israel and sensory variables, such as position and contact-induced
force.
Background: Motivation is defined as the drive to facilitate Results: We found that motor variables were dynamically
or inhibit behavior in response to environmental cues. The controlled within each perceptual trial, such that they grad-
"Reinforcement Sensitivity Theory" is a neurobehavioral ually converged to steady values. We constructed a model
model for motivational processes postulating three neural wherein perceptual confidence increased via Bayesian up-
systems mediating the response to reward and punishment, date rules and extracted internal parameters of the subjects,
and implies correspondence of these systems to core per- such as sensory noise and intrinsic confidence thresholds,
sonality traits of Sensitivity to Punishment (SP) and Reward by fitting the model prediction to the subjects' performance.
(SR). However, this relationship has been scarcely exam- A perception-oriented optimal control formalism, with a
ined at the neural level. One obstacle for such investigation novel processing cost term, was then applied and correctly
is that sensitivity to reinforcements carries two behavioral described the behavioral converges of the "whisking
aspects of motivation: 'liking' (i.e. hedonic) and 'wanting' humans". A corollary result of the new framework is that
(i.e. incentive). We aimed to dissociate these elements by the update flow of information is actively maintained
measuring brain activity via fMRI and to further inspect the constant.
relation to SP and SR personality traits. Conclusions: We believe that the novel experimental para-
Methods: 46 subjects were scanned while playing an eco- digm can serve as a fully monitored testing bed for future
logical computer game constructed to manipulate motiva- research of active sensing in humans. Furthermore, we
tional tendencies, with random events of rewards and believe that the developed theoretical active perception
punishments allowing for subtraction of the hedonic framework can be applied to many other modalities and
(uncontrolled) element from the incentive (controlled) pro- behaviors and is a key principle in active perception in
cess. Results: GLM analysis of controlled vs. uncontrolled humans and animals.
events enabled to identify an incentive network, including
regions related to action (e.g. M1, SMA) and arousal (e.g. Activity-dependent neuroprotective protein (ADNP)
hypothalamus, PAG). Importantly, we found differences in and ADNP2: brain and blood regulation
activation between high and low SP/SR traits: higher SR Gozes I* 1 2 3, Malishkevich A 1, Arviv C 1, Dresner E 1
1
was related to less activation of punishment related areas, Sackler Faculty of Medicine, 2Adams Super Center Brain
and vice-versa. Studies; 3Sagol Neuroscience School, Tel Aviv Univ., Israel
Conclusions: Our paradigm enabled to neurally dissociate
the incentive and hedonic elements in the response to rein- Activity-Dependent Neuroprotective Protein (ADNP) and
forcement, thus allowing for inspection of personality traits ADNP2 are members of a protein family, containing zinc-
related to incentive motivation. This approach revealed that finger motifs and a homeodomain profile. ADNP knockout
these traits are mediated by differential activation in several in mouse results in failure of cranial neural tube closure and
motivation systems, and not simply in one system or anoth- embryonic death. Partial knockdown of mouse ADNP
er. Such neurobehavioral distinction can provide new ave- results in age-dependent neuronal cell death as well as
nue for the diagnosis and therapy of psychopathologies, astrocyte tau pathology coupled to cognitive and social
which can be often characterized along the hedonic and deficits. At the cellular level, partial knockdown of ADNP
incentive dimensions. is associated with inhibition of neurite formation as mea-
The Levie-Edersheim-Gitter Institute for functional Brain sured by decreases in microtubule-associated protein 2.
imaging Similarly, silencing of ADNP2 RNA renders the cells more
susceptible to oxidative stress. ADNP was identified as a
An active perception model for whisking humans chromatin accessory protein, interacting with components of
Goren G*, Saig A, Assa E, Arieli A, Ahissar E the SWI/SNF chromatin-remodeling complex, including
Dept. of Neurobiology, Weizmann Institute of Science, Israel Brg1. Our current studies show that ADNP2 is also interact-
ing with the SWI/SNF complex. Previous studies have
Background: Perception involves motor control of sensory demonstrated that 1] the SWI/SNF complex is critical for
organs. However, the dynamics underlying emergence of neuronal differentiation and 2] Brg1 is involved in
S50 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
erythropoiesis regulation, and is recruited to the β-globin face regions compared to ventral regions (fusiform gy-
locus by selective association with zinc-finger containing rus). The latency of visual evoked potentials (VEPs)
transcription factors. Here, chromatin immunoprecipitation coincided with that of Gamma-band responses, but
(ChIP) assays revealed, for the first time, specific recruitment VEPs exhibited lower category and exemplar decoding
of ADNP as well as Brg1 to the mouse β globin promoter in rates. Our results argue against a strict sequential pro-
murine erythroleukemia cells. Furthermore, specific down- cess of face categorization preceding exemplar discrim-
regulation/silencing ADNP or ADNP2 in zebrafish embryos ination. They also shed light on the information flow
or mouse erythroleukemia cells inhibited erythroid matura- within the human face processing network.
tion, which is critical for survival in the externally developing Kimmel Award for Innovative Research to R.M., MH093061
fish larvae (1). Thus, ADNP and ADNP2 play an important to E.Z and MH086385 to C.E.S.
role regulating development, from fish to mammal.
Reference: (1) Efrat Dresner, Anna Malishkevich, Shelly Proinflammatory cytokines activate nociceptors
Leibman Barak, Shahar Alon, Carmit Arviv1, Rivka Ofir1, by 38-MAPK-dependent relief of slow inactivation
Yoav Gothilf and Illana Gozes. Novel Evolutionary- of TTX-resistant sodium channels
Conserved Role for the ADNP Protein Family that is Im- Gudes S, Leibovich H, Binshtok AM*
portant for Erythropoiesis. J. Biol. Chem. EPUB, 2012). Dept. of Medical Neurobiology, The Hebrew University
Gildor Chair, Adams Super Center, AMN, CFTAU, Allon Faculty of Medicine, Jerusalem, Israel
Therapeutics (IG, Director, Founding Scientist).
Proinflammatory cytokines, interleukin-1 β (IL-1β) and
Similar dynamics for categorization and exemplar tumor necrosis factor α (TNFα) not only sensitize nocicep-
discrimination in human face-related cortex tors via gene regulation, but also rapidly and directly acti-
Davidesco I* 1,2, Zion-Golumbic E 3,4, Groppe DM 5, Keller vate them, generating action potentials and inducing acute
CJ 5,6, Bickel S 5, Harel M 7, Schevon CA 8, Goelman G 9, pain hypersensitivity. We have previously demonstrated,
Schroeder CE 3,4, Mehta AD 5, Malach R 7 that IL-1β acts via p38 mitogen-activated protein kinase
1
Interdisciplinary Center for Neural Computation, Hebrew (p38 MAP kinase), to increase the excitability of nocicep-
University of Jerusalem, Jerusalem, Israel 2Edmond and tors by relieving resting slow inactivation of tetrodotoxin-
Lily Safra Center for Brain Sciences, Hebrew University of resistant (TTX-r) voltage-gated sodium channels. In the
Jerusalem, Jerusalem, Israel3Dept. of Psychiatry, Columbia current study we examined whether this p38 MAP kinase-
University College of Physicians and Surgeons, New York, mediated modulation of slow inactivation is a common
NY, USA 4Cognitive Neuroscience and Schizophrenia Pro- mechanism of proinflammatory cytokines to induce acute
gram, Nathan Kline Institute, Orangeburg, NY, USA 5Dept. inflammatory pain.
of Neurosurgery, Hofstra North Shore LIJ School of Medi- We show that a short exposure to TNFα (1 min) pro-
cine and Feinstein Institute for Medical Research, Manhas- duced a significant increase in peak amplitude of TTX-r
set, NY, USA 6Dept. of Neuroscience, Albert Einstein sodium currents. This increase was not accompanied by
College of Medicine, Bronx, NY, USA 7Dept. of Neurobiol- changes in voltage dependence or kinetics of activation
ogy, Weizmann Institute of Science, Rehovot, Israel 8Dept. of and fast inactivation. Similarly to the effect of IL-1β,
Neurology, Columbia University College of Physicians and application of TNFα caused a significant relief of slow
Surgeons, New York, NY, USA 9Medical Biophysics, Hadas- inactivation, thereby increasing the amount of sodium
sah Hebrew University Medical Center, Jerusalem, Israel channels available for activation from subthreshold volt-
age potentials. Both TNFα-mediated increase in TTX-r
Humans are faster in categorization (i.e., differentiation be- sodium current and TNFα-mediated relief of slow inac-
tween faces and houses) compared to identification (i.e., dif- tivation were prevented by application of the p38 MAP
ferentiating between individual faces). However, it is unclear kinase inhibitor (SB-202190), implying the essential role of
whether this behavioral difference is reflected in the neuronal p38 MAPK in this TNFα-sodium channel interaction. Our
dynamics in the visual cortex. Here, we utilized the millisec- results suggest that a relief of slow inactivation is a common
ond temporal resolution of electrocorticographic (ECoG) mechanisms for cytokine-induced nociceptive hyperexcitabil-
recordings obtained from face-related areas in human patients. ity. Furthermore, we demonstrated that modulation of this
The dynamics of differential ECoG responses to categories of mechanism by lacosomide (an anti-epileptic agent) which
objects, including faces, was compared to that of individual enhances slow inactivation of TTX-r sodium channels, reverts
face exemplars. The neural differentiation in the Gamma-band cytokine-mediated changes in neuronal activity. These data
between categories and exemplars emerged rapidly (~100 ms suggests that lacosamide, could be used clinically to attenuate
latency) and simultaneously, despite a substantial difference in inflammatory pain.
amplitude. Differential responses appeared earlier in lateral supported by ERC grant
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S51
Distributed coding in the trigeminal system long- but not short-term SRM acquisition.In order to further
Gugig E 1, Lottem E 2, Azouz R* 1 validate the susceptibility of MeA neurons to long-term plas-
1
Dept. of Physiology and Cell Biology, Ben Gurion Univer- ticity we used theta burst stimulation in the AOB to induced
sity of the Negev 2Champalimaud Ctr. for the Unknown, long-term electrophysiological changes at the AOB-MeA syn-
Lisbon, Portugal aptic pathway in vivo. Surprisingly,we found that MeA neu-
rons underwent LTD following this type of stimulation,widely
Untangling the neural code underlying sensory perception used for LTP induction.Altogether,our results indicate that the
requires the mapping of physical stimulus parameters to neuro- MeA is a place of long-term plasticity,where protein synthesis
nal responses. The speed by which rodents discriminate between is required for the acquisition of long-term SRM.
tactile stimuli, and neuronal response reliability in the whisker
somatosensory system suggest that temporal coding might be GABA-related gene expression alterations in dorsal
used to encode sensory stimuli. The interaction between and ventral hippocampus and the amygdala in response
whiskers and object surfaces induces a complex temporal pat- to stress in juvenility and 'controllable / uncontrollable
tern of whisker vibration which may carry important tactile stress' in adult
information. To determine the temporal kinetic features of whis- Hadad O 1,2,3, Richter-Levin G 1,2,3,4
1
ker motion that are represented by first-order sensory neurons, Dept. of Neurobiology and Etiology , University of Haifa,
we recorded from trigeminal ganglion neurons (TG) during Israel 2The Brain and Behavior Research Center, Israel
3
stimulation with complex pattern of whisker vibration. We find The Institute for the Study of Affective Neuroscience
that each of the different TG mechanoreceptor subtypes trans- (ISAN) 4Dept. of Psychology, University of Haifa, Israel
mits a distinct kinetic feature of the stimulus. Our results suggest
that TG neurons transmit a distributed representation of whisker An exposure of rats to stress during juvenility (i.e. juvenile stress
motion, based on tactile kinetic features. model) was found to impair the ability of animals to cope with
stressful challenges in adulthood. Moreover, these behavioral
Long-term social recognition memory is mediated manifestations were associated with lasting alterations in the
by molecular processes in the medial amygdala limbic system, such as GABAergic system functioning and
Gur R, Wagner S* alterations in levels of circulating CORT (Horovitz et al., in
Dept. of Neurobiology and Ethology, Faculty of Natural press), neuromodulatory pathways and alterations in the expres-
Sciences, University of Haifa, Israel sion of cell adhesion molecules. These findings suggested that
exposure to stress during juvenility may lead to altered limbic
The ability to remember and recognize specific individuals is functioning, possibly by dysregulating maturational processes in
fundamental to vertebrate social behavior,especially for the es- these regions. These alterations may result in mood and anxiety
tablishment of social structures such as family,pack or clan.Most symptoms, particularly in association with additional exposure to
mammals largely rely on olfaction for social recognition, using stressors in adulthood (Avital and Richter-Levin, 2005; Avital et
mainly the main (MOS) and accessory (AOS) olfactory systems, al., 2006; Ilin and Richter-Levin, 2009; Jacobson-Pick et al.,
which project converging inputs to the medial amygdala 2008; Tsoory and Richter-Levin, 2006; Tsoory et al., 2007,
(MeA).Several lines of evidence indicate that the MeA is indeed 2008a,b).
involved in social recognition memory (SRM),but its exact role A previous study demonstrated alterations in GABAergic
is unknown.In the presented study we first established that adult interneurons' related genes in hippocample sub-regions and
male rats do show short-(30 min) as well as long-term (>24 h) in the BLA following learning the water maze task (Hadad et
SRM using the social discrimination task,which is based on al., in preparation). We now investigate potential alterations of
the difference in the time spent by the subject on olfactory expression of these genes following exposure to juvenile
investigation of a familiar and a novel juveniles, simulta- stress. The current study focuses on long-term effects of 'Con-
neously presented to it.We then examined the dependence of trollable vs. Uncontrollable stress' in the TWS on gene expres-
this memory on protein synthesis in the MeA by locally sion alteration in different regions of the hippocampus and the
blocking MeA protein synthesis during SRM acquisition.SD amygdala on the background of exposure to 'Juvenile-stress'.
rats received bilateral saline or anisomycin (50 ug) injections
into the MeA ten minutes before the first exposure to the Increased resting state inter-hemispheric coherence
social stimulus and SRM was tested 30 min or a day later by in high functioning subjects with Autistic Spectrum
the social discrimination task.We found that anisomycin injec- Disorder
tion completely blocked long-term SRM acquisition,while no Hahamy A 1, Dinstein I 2, Bermann M 2, Malach R 1
1
effect was observed when saline was locally injected.Moreover, Dept. of Neurobiology, Weizmann Institute of Science,
anisomycin administration did not affect short-term SRM acqui- Rehovot 76100, Israel. 2Dept. of Psychology, Carnegie
sition at all.Thus,protein synthesis in the MeA is required for Mellon University, Pittsburgh, USA.
S52 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
Analysis of BOLD- resting state patterns is rapidly advanc- Conclusions: These observations suggest that reduced
ing as a potential diagnostic tool for a variety of brain amount of sleep is associated with functional and structural
disorders. In particular, resting state inter-hemispheric (IH) changes in neural substrates involved in affect regulation
functional connectivity has proven to be a sensitive marker and impulse control, supporting the notion that sleep medi-
for neural aberrations. Here, we examined the IH connec- ates the effects of environmental risk factors in the devel-
tivity of adult, high functioning individuals with Autism opment of behavioral problems.
Spectrum Disorder (ASD) in comparison to age- and IQ- Research supported NIAAA R37 AA07065, R37 AA007065-
matched controls participants. We report an IH connectivity S1, NIDA K01 DA2 0088, and R01 DA027261
increase in the ASD group in the Ventral Premotor Cortex, a
region associated with the language related fronto-prietal Differences between adults who do and do not stutter
network. This VPM IH increase was also correlated with in fMRI activation during speech perception
the degree of communication deficit in the ASD partici- Halag-Milo T 1, Kronfeld V 2, Amir O 3, Ezrati R 3,
pants. As communication deficits are an important diagnosis Ben-Shachar M* 2
1
criterion for ASD, we thus suggest that increased IH con- Cognitive Science Dept., Ben-Gurion University of the
nectivity of the VPM may serve as a marker for high Negev, Beer Sheva 2 The Leslie and Susan Gonda
functioning autism in the adult brain. (Goldschmied) Multidisciplinary Brain Research Center,
Bar-Ilan University, Ramat Gan3Communication Disorders
Sleep shapes the brain: a potential mechanistic role Dept., Sackler Faculty of Medicine Tel-Aviv University, Tel
for sleep in mediating risk in children of alcoholics Aviv
Hairstonm IS* 1,2, Cummiford CM 2, Conroy DA 2, Zucker
RA 2, Heitzeg MM 2 Background: Stuttering is a developmental speech impair-
1
Academic College of Tel Aviv Yafo 2University of Michigan ment, manifested as blocks, prolongations, and repetitions
of sounds and syllables in speech production. Several neuro-
Background: Reduced quality or amount of sleep in child- imaging studies have attempted to characterize differences
hood is associated with impaired academic performance, in brain activity between people who stutter (PWS) and
poor impulse control, and impaired social functioning, and fluent speakers while producing speech. Only a few studies
predict the development of emotional and behavioral prob- focused on cortical differences during speech perception,
lems including depression, anxiety, hyperactivity, and sub- reporting mixed results (Loucks et al, 2011; de Nil et al,
stance use problems. Despite such evidence, a mechanistic 2008). The current study used fMRI to investigate neural
link between sleep and developmental risk remains elusive. differences between PWS and fluent speakers while
Here we provide additional evidence linking sleep with performing a speech perception task. We examined brain
psychopathology by associating sleep patterns with environ- activity while subjects (11 PWS and 25 controls, ages 19-
mental and behavioral risk markers on the one hand, and 53) were listening to short Hebrew paragraphs or to auditory
with brain morphology and function in regions involved in baseline epochs (signal-correlated noise). We used an inci-
affect regulation and impulse control, on the other. dental sound detection task to monitor subject's attention
Results: 72 children, 8-12, from the Michigan Longitu- throughout the scan.
dinal Family Study (N 059 children of alcoholics Results: We analyzed BOLD signals in three bilateral brain
(COAs), N 013 non-COAs) participated in the study. regions: inferior frontal gyrus (IFG), posterior superior tem-
COAs slept less compared to non-COAs. Within and poral sulcus (pSTS), and Heschl's gyrus (HG). PWS exhibited
across groups, less sleep correlated with more conflict significantly stronger brain activity within the right IFG and
at home, as reported by the children, and more behav- within the left HG in comparison to fluent speakers. In the
ioral problems at school as reported by the teachers. right IFG, PWS presented a bilateral activation pattern, while
Further, the volume of the right hippocampus positively controls showed significant left lateralized activation.
correlated with amount of sleep, while the thickness of Conclusions: Neural differences between PWS and fluent
the right anterior cingulate correlated positively with speakers are not restricted to speech production but are also
delayed sleep onset, a marker for insomnia. Teacher- evident in a speech perception task that does not involve
rated externalizing negatively correlated with both left speaking. Results suggest that right IFG serves as a general
and right hippocampal volumes, while conflict in the compensatory region in adult PWS, showing increased ac-
home correlated positively with the volume of the right tivation in both production and perception tasks. The over-
nucleus accumbens (NAcc). We then considered whether activated auditory cortex in PWS contrasts with typical
sleep was associated with neural responses to rewarding under-activation of that region in PWS during production.
stimuli in the NAcc, finding that more sleep was asso- Within the "efference copy" model of stuttering, our finding
ciated with greater activation in the presence of reward. suggests that HG enhances its perceptual responsivity to
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S53
overcome the inhibitory effect of the exaggerated efference Studies suggest that children with developmental dyslexia
copy delivered from the motor system during production. (DD) may differ from typical readers in aspects other than
Study supported by the Israel Science Foundation #513/11 reading; the notion of a core deficit in the ability to acquire
and by the European Commission IRG231029. and retain procedural knowledge as procedural memory has
been advanced.
Location specificity in perceptual learning is a result Methods: Forty 10-11 year-olds were assigned into two
of sensory adaptation groups, according to their reading abilities (DD, typical
Harris H*, Sagi D readers), matched in age and IQ and received structured
Dept. of Neurobiology, Brain Research, The Weizmann training in tactile discrimination of Braille letter pairs, while
Institute of Science, Rehovot, Israel blindfolded. In each trial, participants were asked to report
whether the target stimuli were identical or different from
Background: In perceptual learning (PL) practicing visual each other. The initial training session was followed by two
tasks improves sensitivity to the trained stimulus in a highly additional sessions, 24-hours and two weeks later.
specific manner. Conversely, Performance deterioration was Results: Both groups improved robustly. In session 1, dys-
shown following intensive training, comprised of many repeti- lexic children started significantly less accurate and slower
tions. The suppressive effect of excessive training trials has but showed rapid learning and successfully closed the gap.
been attributed to sensory adaptation, a selective sensitivity At 24 hours post-training both groups showed robust,
reduction. Harris et al. (Current Biology, 2012) found, using delayed ("offline") gains in accuracy. In addition, the dys-
the standard texture discrimination task (TDT) that location lexics were able to effectively retain the gains in speed and
specificity, a defining yet limiting feature of perceptual learn- accuracy even after two weeks.
ing, is absent when adaptation is removed. To remove adapta- Conclusions: Children with DD are as effective in the acqui-
tion, we added task-irrelevant ("dummy") trials with the texture sition and retention of tactile discrimination of Braille litters as
oriented ±45° relative to the target's orientation. Here the newly regular readers of the same age. The notion of a general
proposed link between learning specificity and sensory adapta- procedural learning disability in DD is not supported.
tion is challenged using a different training procedure that
enhances adaptation. One group of observers was trained with Head saccades in barn owls: the role of area centralis
the standard TDT training paradigm while another group was in acquiring targets.
trained with reduced adaptation. To maximize adaptation, stim- Hazan Y, Gutfreund Y*
ulus onset asynchrony (SOA) was gradually decreasing from Dept. of Psychology And Biophysics ,Rappaport Medical
high to low, until chance level performance was reached. Faculty,Technion, Haifa
Results: Results show (1) within-day deteriorations are more
dominant in the enhanced adaptation conditions and are mod- In our lab we study active vision in the barn owl. Barn
ulated by the presence of "dummy" trials (2) the effectiveness owls are known for their rich repertoire of active vision
of "dummy" trials in reducing adaptation was evident under behaviors and their very limited eye movements which
the enhanced adaptation training procedure (3) performance are compensated by conspicuous head movements.
level at the transfer location was better for the reduced adap- These properties provide a substantial experimental ad-
tation group comparing the standard training group. vantage since head motions are much easier to track
Conclusions: We suggest that adaptation interferes with than eye movements. However, barn owls like all birds
invariant pattern-discrimination learning by inducing lack an anatomical structure of a fovea in their retina. It
network-dependent changes in local visual representations. is an open question to what extent barn owls foveate
Moreover, applying adaptation based predictions on PL targets and what part of the retina is used. The goal of
specificity holds for several training procedures. this study was to provide evidence that area centralis (a
retinal area with a maximal density of photoreceptors) is
Effective learning and retention of Braille letter tactile used as a functional fovea in barn owls. For this pur-
discrimination skill in dyslexic children pose we attached miniature wireless video cameras on
Hayek, M1 Karni, A1& Dorfberger, S1,2 barn owls' head. Cameras were adjusted to point in the
1
EJ Safra Brain Research Centre for the Study of Learning general direction of the gaze. Owls were positioned on
Disabilities, University of Haifa, Haifa, Israel.2Gordon a high perch and food targets were scattered on the
College of Education, Haifa, Israel floor. Video sequences were taken while the owls spon-
taneously scanned the room. These videos were ana-
Introduction: Perceptual and motor training can dramati- lyzed offline. First, frames of fixation periods were
cally improve performance on a given task, and lead to the isolated, then, by averaging fixation images the position
establishment of long-term procedural (skill) memory. in the frame with the highest probability to contain a
S54 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
food target was extracted. We show, in two owls that explained by energy masking in the peripheral auditory sys-
the area with high probability was invariant across trials tem: once the signal-to-noise ratio within the critical band
indicating the existence of a single functional fovea in centered at the target tone frequency is large enough, the tone
the barn owl's retina. In the second part we used an is detected. However, when additional information is supplied
optalmoscope to map the projections of known retinal to the auditory system, for example by slowly modulating the
landmarks on the video frames. From these we derived masker over a wide frequency range or adding a co-modulated
the expected projection of area centralis. We show that sideband, masked thresholds can be reduced substantially
the position of area centralis matched, to a good ap- below the values expected from pure energy masking. We
proximation, the position of the behaviorally determined have previously demonstrated correlates of the reduction in
functional fovea. The findings that barn owls use head masked thresholds for tones in modulated maskers (comodu-
saccades to accurately and consistently foveate targets lation masking release, CMR) in the neuronal responses of cat
will promote further comparative studies on visual auditory cortex (Las et al. 2005).
search in barn owls. Here we are using intracellular recordings in vivo in rat
auditory cortex in order to study neuronal responses in the
Network probing of emotional dynamics in schizophrenia auditory cortex to tones masked by broadband noise or by
patients and their healthy siblings slowly fluctuating broadband noise maskers. We charac-
Hendler T terized the responses of neurons in auditory cortex to
Tel Aviv Medical Center and Tel Aviv University pure tones, broadband maskers, amplitude-modulated
broadband maskers, and narrowband maskers with and
Dynamic functional integration of distinct neural systems without comodulated side bands, as well as their com-
plays a pivotal role in the formation of emotional experi- binations with tones of varying levels. The main effects
ence. Schizophrenia patients often exhibit flatten and/or of noise on tone responses are consistent with energetic
inappropriate affect, suggesting a dysfunctional processing masking. While we found release from masking when
of emotional cues and their meaning. We propose a new tool using modulated broadband noise maskers compared
to probe changing interactions within and between emotion- with unmodulated noise maskers, we did not observe
al and cognitive related networks using fMRI. The approach in the rat the 'hypersensitive locking suppression' ob-
is based on continuous computation of an index of network served in cat intracellular recordings, possibly because
cohesion, which is sensitive to both strength and vari- the locking of the neuronal responses to the amplitude
ability of signal correlations between pre-defined modulation pattern was weak.
regions. Schizophrenia patients and their siblings were
compared to healthy with regard to passive viewing of fMRI dependent components analysis reveals context
emotional film excerpts. To depict the individual varia- effects on the cortical networks dependency structure
tion in network dynamics during the emotional cinemat- Hertz U* 1,2, Zoran D 2,3, Weiss Y 2,3, Amedi A 1,2
1
ic experience, a comparison between each viewer's time Dept. of Medical Neurobiology, Institute for Medical Re-
courses of rated emotion intensity, parasympathetic and search Israel-Canada (IMRIC), Hadassah Medical School,
neural indices were calculated. Thus, the limbic- Hebrew University of Jerusalem, Jerusalem 91220, Israel
2
cognitive inter-network cohesion indices at specific Interdisciplinary Center for Neural Computation, The
points of difference between the patients and healthy Edmond & Lily Safra Center for Brain Sciences (ELSC),
groups can typify abnormality in the dynamics of cog- Hebrew University of Jerusalem, Jerusalem 91905, Israel
3
nitive driven emotional regulation. School of Computer Science and Engineering, Hebrew
University of Jerusalem, Jerusalem 91905,Israel. 4School
Detection of tone in noise in rat auditory cortex of Computer Science and Engineering, Hebrew University
Hershenhoren I 1,2,3, Nelken I 1,2,3 of Jerusalem, Jerusalem 91905, Israel
1
Dept. of Neurobiology 2Interdisciplinary Center for Neural
Computation 3The Edmond and Lily Safra Center for Brain One of the major benefits of whole brain fMRI is the detection
Sciences Hebrew University, Jerusalem of functional large scale cortical networks. Dependent Com-
ponents Analysis (DCA) is a novel approach to extract both
Sounds in natural settings always appear over a noisy back- cortical networks and their dependency structure. DCA is
ground, and the way the auditory system extracts sounds from fundamentally different from the prevalent data driven
such backgrounds is of extreme importance both theoretically approaches, i.e. spatial ICA, as instead of maximizing the
and practically. The masked threshold (lowest level at which independence of components it optimizes their dependency
the presence of a tone can be detected in the presence of a (in a tree graph structure, tDCA), allowing cortical areas
masker) increases with noise level. Such results can be to be part of multiple cortical networks. tDCA was used
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S55
to examine changes in cortical activity when learning Short term learning induced white matter plasticity
visual to an auditory sensory substitution algorithm in the fornix
originally employed as a rehabilitation tool for the Hofstetter, S 1,2, Tzur Moryosef S 1,2, Tavor I 2, Assaf Y* 1,2
1
blind. A learning effect was manifested primarily in Sagol School of Neuroscience, Tel Aviv University 2Dept of
changes in the dependency structure, in that auditory neurobiology, Tel Aviv University
networks became directly dependent on object recogni-
tion networks. tDCA may prove a useful and robust tool Diffusion tensor imaging (DTI) is a diffusion MRI method
that provides a rich description of task related brain sensitive to the tissues micro-structure. Previous studies in
activity, ,mental states and neural disorders. our lab discovered that short-term spatial learning tasks,
both in humans and rats, can lead to changes in diffusion
The haptic loop: top-down processes control unaware parameters, indicative of structural neuroplasticity. Mean
motor responses to colors with embodied metaphoric diffusivity (MD) decrease was found in the hippocampus
content after 2 hours of training in a car racing game. Rats under-
Hilsenrat M, Reiner M going 1 day of Morris water maze (MWM) training showed
Dept. of Education in Technology and Science Technion- similar MD decrease in the hippocampus and septum. In line
Israel Institute of Technology Haifa, Israel with these results we aimed to investigate structural changes
in the fornix of humans and rats, the main hippocampal
Background: Bodily interactions are regulated by the hap- projection known to be involved in memory. Maps calculat-
tic loop, in which applied forces to objects, changes in ed from DTI were processed with a common method for
response to sensory stimuli that in turn changes the sensory studding white matter: TBSS.
input, and so on, generating a haptic cycle. Humans often Results: Human group: Voxel based statistics revealed a
metaphorically associate visual stimuli, including colors, group (learning (n036) vs. control (n014)) by time (scan
to physical properties, such as temperature, weight, and time) interaction (clusters≥16, p<0.05, uncorrected). MD
softness. We ask whether metaphorical associations of decreased in the learning group by 3.82 %. The hippocampal
stimuli are reflect patterns of motor response, and ex- MD decrease was positively correlated with changes in MD in
amine whether visual exposure to colors that were men- the fornix (r00.61, p<0.05 corrected). Rats groups: Group
tioned in the literature as linguistic metaphors of (learning (n019), control (n07) and naïve (n04)) by time
softness or hardness, are correlated with different pat- interaction was found (p<0.05, corrected). MD decreased in
terns of motor responses, in accordance with their met- the learning group by 3.46 %. Changes in MD in the hippo-
aphorical significance. campus were found to correlate with MD change in the fornix
Results: Using a touch-enabled, immersive virtual environ- (r00.76, p<0.05, corrected), and reduction in the time re-
ment, we found that people that explore haptically virtual quired to reach the platform was found to correlate with MD
surfaces with the identical physical qualities of roughness change in the fornix (r00.76, p<0.05,corrected).
and hardness, but with metaphorically different colors, Discussion: This work provides the first indication of white
namely “hard” colors and “soft” colors, differed significant- matter plasticity in the fornix following a spatial learning
ly in the applied average normal forces, according to the task in both humans and rodents. It appears that structural
color of the surface. The participants were not aware of the changes in the white matter can occur in short time scales
metaphorical significance of the colors. The differences in and can be detected with DTI. Results found in the fornix
forces applied on surfaces with colors of similar metaphor- are complimentary to the hippocampus, the fornix's origin.
ical meaning were not significant. On average, participants Not only that both structures are involved in this task, the
applied weaker forces to surfaces with hard colors. extent of change they undergo is connected.
Conclusions: Results suggest that the metaphorical differ-
ence in colors, have an impact on motor behavior, which Plasticity in auditory perception: exposure to the speech
participants are unaware of. Colors that belong to a meta- nature of sine-wave stimuli modifies brain activity
phorical category are associated also, with similar motor- Horev N*, Pratt H
response patterns, and form a similar action category. This Evoked Potentials Laboratory, Technion - Israel Institute of
provides support for the top-down hypothesis in perception- Technology, Haifa, Israel
action, and points at perceptual embodied metaphors, to be a
factor in action. This study integrates semantics into the Sine-wave speech (SWS), in which speech formants are
haptic loop; it shows that motor components of the cycle, replaced by 3 tones, can be perceived either as speech or
are correlated with the nature of the color of surfaces, and non-speech, depending on listeners' expectations about the
constitute a central component in the haptic cycle of un- nature of the stimuli, providing a tool to study neural activ-
aware perception. ity specific to speech using identical acoustic stimuli.
S56 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
Auditory Evoked Potentials (AEPs) were recorded from 61 1995). In the current study, we examined possible altera-
scalp electrodes of 19 subjects in two sessions, during active tions in GABA-Aα2 protein levels in emotional neural
discrimination of SWS stimulus pairs using spectral (/ubu/ - / circuits following an exposure to stress in adulthood on
udu/) or temporal (/ubu/ - /upu/) cues. In the first, "non- the background of previous exposure to stress in juvenility.
speech" session, subjects discriminated between SWS stimuli, Results indicated that exposure to stress in juvenility exac-
unaware of their speech-like nature. In the second, "speech", erbated the effects of an exposure to stress in adulthood. In
session, the same subjects were first exposed to the natural accordance with our hypothesis, an exposure to stress al-
speech counterparts of the SWS and came to perceive the tered the GABA-Aα2 protein levels in core emotional brain
SWS as speech. Then they performed the same discrimination regions, mainly in the amygdala and PAG. Maps of region-
task. Electrophysiological responses to the first stimulus in the specific alterations of GABA-Aα2 expression differed be-
pairs were analyzed and sLORETA current density source tween control, juvenile stress, adulthood stress or juvenile
estimation was carried out to derive statistical activation dif- +adulthood stress groups, indicating that emotional circuits
ference maps when the very same physical stimuli were in the brain have unique pattern of response under each
perceived as speech or non-speech, and the distribution of condition. The results indicate that classification and segrega-
brain activities were compared. Perceiving the very same tion of behavioral performance together with biochemical
stimuli as speech or non-speech was associated with signifi- markers should be carried out at the system level. Any de-
cant voltage differences around the main scalp recorded AEPs scription at the level of a single specific region is inaccurate.
peaks. sLORETA source estimation revealed higher activation Supported by the HDRF foundation
of auditory cortices to "speech" stimuli at early (around
230 ms) stages of processing, and at the time of a sustained Brain connectivity in prenatal stressed rats: a rest
negativity (340-500 ms), stronger activation to "non-speech" functional connectivity MRI study
stimuli, reflecting later processing stages. Differences were Ilinca R 1, Zohar I 2, Weinstock-Rosin M 2, Goelman G* 1
1
prominent mainly within the right superior temporal cortex Hadassah - Hebrew University School of Medicine
2
and the right prieto-temporal junction. Right hemisphere ac- Hebrew University of Jerusalem
tivity was lower when stimuli were perceived as speech com-
pared to non-speech, while left hemisphere activity did not Background: Chronic stress during pregnancy has been
differ. Our data provide evidence for changes in brain distri- shown to affect offspring development and behavior at adult-
bution of processing non-speech sounds following a single hood. In rats, prenatal stress alters brain morphology and
exposure to their speech nature. induces anxiety and depressive-like behavior in adulthood.
Citalopram given to the pregnant stressed mothers did not
Stress exposure and GABA-aα2 receptor protein significantly affect behavior of prenatally-stressed (PS) male
expression in emotional neural circuits rats and even induced anxiety and depression in offspring of
Horovitz O 1,2 , Ashkenazi-Karni S 1,3 , Richter-Levin unstressed mothers. We tested whether this change in behavior
G* 1,2,3,4 was correlated with neuronal nodal connectivity - a new meth-
1
The Brain and Behavior Research Center, 2The Institute for od to estimate the global effective connectivity of a region, as
the Study of Affective Neuroscience (ISAN) 3Dept. of Neu- measured by a non-invasive resting state MRI (rs-fcMRI).
robiology and Etiology , University of Haifa, 4Dept. of Results: Eleven different brain circuits/structures were in-
Psychology , University of Haifa cluded in the analysis. Significant differences between Con-
trol and PS rats were found in motor, pre-frontal cortex, insula
Human studies suggest that childhood trauma pre-disposes and sensory areas. Offspring of citalopram-treated control
individuals to develop stress-related disorders. In line with mothers showed significantly lower nodal connectivity at
that, an acute exposure of male rats to 'Adult stress' on the multiple systems compared to untreated controls, but were
background of an exposure to post weaning, pre-puberty similar to the pattern seen in untreated PS rats with the
(juvenile) stress resulted in altered behaviors which were exception of the hypothalamus where a higher nodal connec-
reminiscent of trauma-related symptoms in humans (for a tivity was observed. Also, the only significant difference was
review: Horovitz et al., 2012). These altered behaviors were expressed in the reward-circuit. On the other hand, offspring
also linked to activation of core sub-cortical emotional neu- of stressed dams given citalopram showed major differences
ral circuits such as the amygdala and the Periaquaductal in nodal connectivity compared to untreated PS rats.
Gray (PAG). GABA seems to play a crucial role in the Conclusions: Behavioral data and nodal connectivity esti-
pathogenesis of several stress-related disorders (Petty, mates correlated well in the untreated PS group and
1995). Specifically, GABA-A receptor subtypes are associ- citalopram-treated controls but not with PS citalopram-
ated with regulation of neuronal excitability and rapid treated group. This suggests that the relation between be-
changes in anxiety, panic, and acute stress responses (Petty, havior and neuronal connectivity is a complex one and that
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S57
the effect of the drug administered to the mothers can be between perception and action (stimuli and response) can
expressed in alterations of neuronal connectivity that may affect performance even when the spatial information of the
not always correlate directly to behavior. stimulus is irrelevant to the task. In our study subjects
performed two tasks, either separately (in the single task
Connectivity analysis of resting state EEG recordings condition) or simultaneously (in the dual task condition). In
of patients with temporal lobe epilepsy (TLE) the first task (the shape task), two stimuli were presented
Inbar D* 1, Litvak V 2, Ben-Hur T 1, Ekstein D 1 bilaterally - two distinct shapes (circle and triangle) that
1
Dept. of Neurology, Hadassah Hebrew University Hospital, were colored in either red or blue. The subject's task was
Ein-Kerem, Jerusalem, Israel 2The Wellcome Trust Centre for to name one of the shapes according to its color (e.g., to
Neuroimaging, UCL Institute of Neurology, London, UK name the red shape) and ignore the other shape. In the
second task (the tone task) subjects were required to respond
Background: Epilepsy is a common brain disorder with with either a left or right button according to the pitch of a
0.5-1 % prevalence in the population. Temporal lobe epi- tone. The input for both tasks appeared simultaneously, and
lepsy (TLE) is the most common focal type of epilepsy. subjects were instructed to respond to both tasks as fast as
Functional connectivity analysis reveals the extent to which possible, without prioritizing either of them. We found a
brain areas function together and therefore might comprise an sizable dual task cost when the two tasks were performed
emerging neural network. Our objective was to study func- simultaneously. Moreover a significant compatibility effect
tional connectivity in patients with TLE. was found between the side of the relevant shape and the side
Methods: In our study we apply dynamic causal modeling of the correct response in the tone task, for both tasks- a
(DCM) to resting state of routine EEG recordings in 7 TLE between tasks Simon-like effect. These results demonstrate
patients and 3 controls. We explore the intra-hemispheric an obvious overlap between representations of space in per-
connectivity, and compare it with the controls and between ception and action, and lead us to the notion that perhaps both
the two hemispheres: the epileptic focus hemisphere versus perception and action use the same spatial template in the
the non-epileptic focus hemisphere. We then study the find- brain for spatial coding, even when the spatial information
ings in light of the clinical data comes from two distinguished tasks. Spatial information
Results: We present our preliminary results pointing out a seems to be difficult to ignore, and it might be coded auto-
difference in the connectivity strength between the medial matically, as a basic feature of an object.
temporal lobe (MTL) and other intra-hemispheric nodes, in
the epileptic focus hemisphere versus the non-epileptic fo- Sensorimotor synchronization and working memory
cus hemisphere. Moreover, the results show a notably large Jacoby N 1,2, Jakobi H 1, Lieder I* 1, Tishby N 1, Ahissar M 1
1
variability in the connectivity maps between subjects, as Hebrew University 2Bar Ilan University
expected from the variability in the nature of the disorder
and the compensatory mechanisms of the brain between Traditionally, sensory and motor tasks were considered related
subjects. to low-level processing. Reverse Hierarchy Theory, suggested
Conclusions: Dynamic causal modeling of resting state by Ahissar and Hochstein (1997), challenges this view by
EEG activity reveals in subjects with TLE different connec- emphasizing the importance of top-down processes in sensory
tivity patterns in the epileptic focus hemisphere in compar- tasks that were traditionally considered as low level. In this
ison to the non-epileptic focus hemisphere, in a subject study, we give evidences that a motor task, sensorimotor
specific manner. These preliminary results are an initial synchronization (SMS) is also linked with high-level process-
and promising step towards an improved lateralization of es, mainly ones that involve working memory.
the epileptic focus and determination of other individualized SMS, the temporal coordination of a rhythmic movement
characteristics as pathway of spread and generalization. with an external rhythm, is studied experimentally by tap-
ping experiments (Repp 2005) in which subjects are re-
Spatial attention across perception and action quired to finger tap in synchrony with an auditory stimuli.
Israel MM*, Cohen A One type of tapping experiments is the step-changes exper-
Dept. of Psychology, The Hebrew University of Jerusalem iment, where subjects are required to adapt their taps to a
metronome alternating between two tempi. Subjects (N030)
Converging evidence in cognitive neuroscience has gener- performed a battery of cognitive and sensory tasks, and two-
ated the notion that perception and action may share the step tapping experiments. We found high positive inter-
same spatial representation, on the neuronal level as well as subject correlations between successful performance in the
the cognitive level. The Simon effect (Simon, 1969) dem- tapping experiment (decreased tapping variance) and work-
onstrates this complex relationship between perception and ing memory related tasks, the highest correlation to an n-
action. According to this phenomenon, spatial relation back auditory task, in which subjects are required to report
S58 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
whether the current tone matches a tone n-steps earlier (n is A novel genetic animal model for bipolar disorder
changed adaptively). We also found significant correlations Jukic M 1, Avin A 1, Baron T 1, Bar M 1, Zega K 1, Novikov
to other tasks that pound on verbal or tonal memory. How- O 1, Tarasiuk A 1, Kofman O 2, Brodski C* 1
1
ever, the Block Design task, a standard spatial-reasoning Dept. of Physiology and Cell Biology, Ben Gurion University of
visual task, usually considered to measure general cognitive Negev 2Dept. of Psychology, Faculty Ben Gurion University
abilities and not directly related to working memory, did not of Negev
show a significant correlation. We propose that these corre-
lations can reflect the involvement of high-level working Genetic predisposition and dysfunction of monoaminergic
memory mechanisms for the representation of tempo in the neurons are thought to play a critical role in bipolar disorder.
SMS control loop, and therefore in line with the Reverse However, how these factors interact in the pathophysiology
Hierarchy Theory's predictions. and pharmacotherapy of this disease is poorly understood.
Gatsby Charitable Foundation Previously, we demonstrated that the embryonic mid-
hindbrain organizer, which is composed of a transient cell
Auditory ERP marker for automatic structural regularity population in the brainstem, controls the development of
detection predicts word recognition performance dopaminergic and serotonergic neurons. Recently, mid-
Jaffe-Dax S* 1, Ahissar M 1,2 hindbrain organizer
1
Edmond and Lily Safra Center for Brain Sciences, The associated genes have been suggested as susceptibility
Hebrew University of Jerusalem 2Psychology Dept., The genes for bipolar disorder. The aim of the present study
Hebrew University of Jerusalem was to test the face and predictive validity of mid-
hindbrain organizer mouse mutants as a model for bipolar
Detection of repeated stimulation patterns (stimulus regular- disorder. To this
ities) is an important learning mechanism, which is largely end we investigated manic- and depressive-like behaviour in
automatic. In the auditory system it is often tapped by ERP these mutants and studied whether these behaviours can be
components as mismatch negativity peaking ~150 ms from reversed by mood stabilizing drugs. In addition, neuropath-
regularity violation, and early left and right anterior nega- ological changes that have been associated with bipolar
tivities peaking ~200 ms from linguistic and musical struc- disorder were studied in these mice, providing insights into
tural violations, respectively. We now asked whether the molecular basis of the altered behaviour of the mutants.
structural regularities introduced into a simple paradigm of We found that mutants are hyperactive and showed in-
2-tone frequency discrimination can also be detected auto- creased risk taking behavior. Importantly, mutants showed
matically, and whether the ability to automatically detect in contrast to wild-types intra-individual fluctuations in their
such a structural regularity predicts the individual's aptitude locomotor activity, hedonic and risk taking behavior. In
for regularity detection in other contexts. addition, mutants showed an increase in risk taking behaviour.
We administered two protocols of 2-tone frequency discrim- Olanzapine and lithium, which are used for the treatment of
ination. Each protocol had a simple structural regularity – in mania, reversed some of behavioural alterations in mutants.
each trail one of its two tones was fixed across trials (i.e. The establishment of mid-hindbrain
REFERENCE) and the other was higher or lower. In protocol organizer mutants as a model for bipolar disorder will pro-
1 it was the 1st tone whereas in protocol 2 it was the 2nd. Our vide a tool to investigate particular aspects of the patho-
previous behavioral data (Nahum et al., J Neurosci 2010) physiology of this devastating disease and will serve a
indicated that protocol 1 was performed significantly better rationale towards the development of novel and efficient
even though its objective complexity is equal to that of pro- mood stabilizing drugs.
tocol 2. Participants' automatic ERP response at ~200 ms from
the onset of the 1st stimulus (P2) was larger in protocol 1, Vomeronasal responses to vaginal secretions in male
where the 1st tone is the repeated reference than in protocol 2. mice
This difference indicates that participants detected the struc- Kahan A, Ben-Shaul Y*
ture of protocol 1. Our participants were also tested with few Dept. of Medical Neurobiology, Hebrew University Medical
cognitive tasks. Their automatic sensitivity to the auditory School
structure was correlated with their sensitivity to visual regu-
larities in word recognition, i.e. their rate of discriminating Male mice show a preference for the voided urine of estrus
correct versus incorrectly spelled frequent words. These find- females over that of non-estrus females. However, this prefer-
ings reveal that automatic regularity detection can be tapped ence is absent for bladder urine, suggesting that other secre-
even without structural violation. Moreover, automatic sensi- tions along the urogenital tract confer the estrus dependent
tivity predicts behavioral success in a range of tasks, both at preference. Because the mouse vomeronasal system is highly
the group (protocol asymmetry) and at the individual level. sensitive to various socially relevant secretions, we set out to
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S59
study its role in mediating this preference. We stimulated the shapes, we minimized categorical and semantic influences
vomeronasal organ of male mice with vaginal secretions and on fMRI measurement, further providing "pure" evidence
measured responses in the accessory olfactory bulb using for object size representation in visual cortex.
multi-site extracellular electrodes. We found that vaginal secre-
tions indeed activate the mouse vomeronasal organ in a strain The effect of malfunctioning DNA damage response on
specific manner. Furthermore, individual AOB neurons can neuronal-glial circuits: altered neuronal synchronizations
discriminate between estrus and non-estrus secretions from and atrophied astrocytic morphologies in cerebellar
an individual female. Finally, we show evidence that, at least cultures from Atm-deficient mice
in some cases, responses to urine and to vaginal secretions Kanner S 1, Bonifazi P 2, Goldin M 2, Galron R 1, Ben-Jacob
involve distinct chemical substances. These results suggest that E* 2,3, Barzilai A 1,4
1
the vomeronasal system in male mice plays an important role Dept. of Neurobiology, George S, Wise Faculty of life
in detecting the reproductive state of female mice, a crucial Science, Tel Aviv University, 2School of Physics and astrono-
ability for directing efficient reproductive behavior. my, Tel Aviv University, 3Center for Theoretical Biological
Supported by EU7 Marie Curie grant. AK supported by the Physics (CTBP), Rice University Houston, TX 77005-1827,
Lady Davis Fellowship Trust USA 4Sagol School of neuroscience, Tel Aviv University
Representation of conceptual size in the ventral visual Background An aberrant response to DNA lesions is im-
cortex plicated in many human neurodegenerative disorders. In
Kalanthroff E* 1, Gabay S 2,3, Henik A 1, Gronau N 2 healthy cells, the accumulated DNA damage is rapidly
1
Dept. of Psychology and Zlotowski Center for Neurosci- detected, leading to the activation of a web of signaling
ence, Ben-Gurion University of the Negev, Israel 2Dept. of pathways known as the DNA damage response (DDR). In
Psychology, The Open University of Israel 3Dept. of Psy- cells with neurodegenerative dysfunction some components
chology, Carnegie Mellon University, USA of the DDR machinery are impaired and the gene coding for
the ATM protein is mutated in the human genetic disease
Background: It has recently been argued that objects are Ataxia Telangiectasia (A-T).
represented in the ventral temporal cortex according to their Results In order to study the effect of impaired DDR on
real-world size (Konkle & Oliva, 2012). Size representation neuronal circuits, we used calcium imaging and immuno-
was investigated using images of small and big objects of equal histochemistry to compare the morphology and dynamics of
retinal size (e.g., a paperclip and sofa, respectively). A possible primary cerebellar cultures grown from postnatal ATM-
confound in such studies is that small and big stimuli typically deficient and wild-type (WT) mice. Cerebellar network
belong to object categories that differ in shape and function exhibited spontaneous network synchronizations after two
(e.g., small objects are typically graspable and/or manipulable, weeks in-vitro. Compared to WT circuits, ATM-deficient
while big objects often have a more static nature). The present circuits displayed a lower number of global synchroniza-
study aimed to control for these confounding factors by using tions and a larger number of sparse synchronizations, i.e.
abstract, meaningless shapes, which were associated with spe- synchronous events involving less than a dozen of cell-
cific size representations by virtue of extensive training. s.To relate the different circuit synchronization dynamics
Method: Participants implicitly learned a 10-point size scale to altered morphological structures, we tested the hy-
composed of 5 animals, organized along the scale by real- pothesis that A-T is at least partially a glial disease.
world size, and 5 abstract shapes, arbitrarily distributed in- staining of astrocytes revealed a less complex cell arbor-
between the animal points along the scale. All stimuli were isation in ATM-deficient versus WT circuits as mea-
presented in the same retinal size. Following training, a sured by number of branches originating from the cell
functional magnetic resonance imaging scan was conducted bodies.
while participants made a conceptual size discrimination Conclusion We present evidence that malfunctioning
task on the abstract shapes. DDR affects neuronal synchronization and astrocyte
Results: A region-of-interest (ROI) analysis revealed larger morphology. In ATM-deficient circuits, sparse synchro-
responses to "big" than to "small" shapes within the para- nizations that are not capable to propagate through the
hippocampal place area (PPA), but not within the fusiform rest of the circuit might represent network failures. The
area (FFA). In addition, a whole-brain analysis showed reduced astrocytic branching arborization result in an
larger BOLD responses to "big" than to "small" objects in atrophied structural organization of the astrocytic net-
primary visual areas. work functionally coupled with neuronal circuits. These
Conclusions: Our findings support earlier findings of results support the idea that neuronal network failures in
medial-to-lateral organization of big and small object pref- genetic neurodegenerative diseases are correlated to the
erences in the ventral temporal cortex. By using abstract "breakage" and impairment of the astrocytic network.
S60 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
performing whole cell patch recording simultaneously with a that narcolepsy-injected mice were significantly hyper-
direct light illumination from the recording pipette. The holder active in the staircase test and had significant short
spares the use of additional manipulator and thus enables a memory deficits in the Y-maze test compared to con-
much more accurate, stable and reproducible illumination. In trols. The behavioral and cognitive results are similar to
addition, replacement of standard pipettes is easily done as those observed in line narcolepsy patients.
with available commercial holders. Here we used the opto- Conclusion: This is the first report of passive transfer ex-
patch in-vivo to record the membrane potential of neurons perimental narcolepsy induced by autoantibodies and sup-
from different cortical layers of the motor cortex in ports an autoimmune pathogenesis of narcolepsy.
optogenetically-mutated mice. Using the optopatch we dem-
onstrated both direct and indirect disynaptic activation of the Brain tumour biology and development of new therapies
intracellularly recorded cells by the light illumination. Kaye A 1,2
1
We thank Benny Pasmantirer and Oz Diner for designing Dept. of Surgery, The University of Melbourne 2Dept. of
the final version of the Optopatch. Neurosurgery, The Royal Melbourne Hospital
Loss of orexine neurons in the hypothalamus Despite the introduction of the Stupp Protocol utilising
and narcolepsy-like behavior induced by autoantibodies concomitant radiation and temozolamide chemotherapy fol-
in mice lowing surgery for high-grade cerebral glioma, there has
Katzav A* 1,2, Arango MT 2,3, Kivity S 2, Chapman J 1,2, been little substantial improvement in the prognosis for of
Givaty G 1,2, Agmon-Levin N 2, Anaya JM 3, Shoenfeld Y 2 these tumours over the past three decades. The median
1
Dept. of Neurology and Sagol Neuroscience Center, Sheba survival for high-grade glioblastoma multiforme remains
Medical Center, Tel-Hashomer, Israel 2Zabludowicz Center around 12-14 months. However, there has been substantial
for Autoimmune Diseases, Sheba Medical Center, progress in understanding the cell and molecular biology of
Tel-Hashomer, affiliated to Sackler Medical School, Tel Aviv cerebral glioma, and in particular, the critical intracellular
University, Israel 3Center for Autimmune Diseases Research signalling pathways that underpin the major biological pro-
– CREA, Universidad del Rosario, Bogota, Colombia cesses in the development of cancer. These include cellular
proliferation, control of apoptosis, induction of angiogenesis
Background: Narcolepsy is a sleep disorder characterized and cell migration and metastasis. In addition, new technol-
by abrupt attacks of somnolence caused by the loss of ogies have enhanced our understanding of the molecular
orexine neurons in the hypothalamus. Autoimmune mecha- genetics of cerebral glioma. Numerous chromosomal abnor-
nisms are implicated in narcolepsy byincreased frequency of malities have been identified, and in some tumours, it
specific HLA alleles and the presence of specific autoanti- appears that there is a step-wise process of chromosomal
body (anti- Tribbles homolog 2 protein antibodies) in the instability in the genesis of high-grade glioma. Epidermal
sera of narcolepsy patients. The aim of the present study was growth factor receptor amplification is present in nearly
to assess whether experimental narcolepsy can be passively 80 % of high-grade cerebral gliomas. Loss of tumour sup-
transferred to mice. pressors, such as PTEN occur as an initial process in the
Methods: We examined behavior and brain pathology of development of nearly all cerebral glioma. In addition, the
naive C3H mice injected intra-cerebra-ventricularly (ICV) AKT-mTOR pathway is known to be particularly important
with pooled IgG from narcolepsy patients positive for anti- in the control of cellular growth and proliferation, and in the
Trib2. Control mice were injected with pooled matched development of resistance to therapies. A number of critical
healthy control IgG. Mice were filmed and analyzed for targets for biological therapies have been identified and
immobility attacks weekly before and after ICV injection many biological inhibitors are already in clinical trials.
by using Noldus PhenoTyper cage and EthVision software. These therapies potentially offer the possibility of control
Mice were also examined for behavior and cognition in the of these otherwise fatal tumours.
staircase, novel object recognition and Y-maze tests. Brains
were removed and analyzed by immunofluorescence for Neurophysiological investigation of spontaneous correlated
neurodegeneration in the hypothalamus. and anticorrelated fluctuations of the bold signal
Results: We found loss of neuronal marker (NeuN) and Keller C* 1,2, Bickel S 2, Honey C 3, Davidesco I 4, Groppe
synaptic marker (synaptophysin) staining in the lateral D 2, Entz L 5, Kelley C 6, Lado F 7, Mehta A 8
1
hypothalamus area in narcolepsy-injected mice com- Dept. of Neuroscience, Albert Einstein College of Medicine,
pared to controls. A specific loss of orexine-positive Bronx, NY, United States2Neurology and Neurosurgery,
neurons in narcolepsy-IgG was found. We observed Hofstra University School of Medicine, North Shore LIJ
narcolepsy-like immobility attacks in narcolepsy injected Health System and Feinstein Institute for Medical Research,
mice 4 weeks post injection but not before. We found New Hyde Park, NY, United States 3Dept. of Neuroscience,
S62 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
Princeton University, Princeton, NJ 4Interdisciplinary Background: The role of the secondary somatosensory
Center for Neural Computation, Hebrew University of cortex (SII) in somatosensory processing is poorly under-
Jerusalem, Jerusalem, Israel 5Institute for Psychology of stood.We investigated texture coding in SII.
the Hungarian Academy of Sciences, Budapest, Hungary Results: We performed single unit recordings from layers 2-
6
Phyllis Green and Randolph Cowen Institute for Pediatric 5 of SI and SII in anaesthetized rat during artificial whisking
Neuroscience, New York University Child Study Center, against sandpapers with different coarsenesses. For SI
New York, NY,United States 7Dept. of Neurology, Montefiore recordings only the principle whisker was left intact,while
Medical Center, Bronx, NY 8Center for the Developing for SII recordings,a whole row was left intact with 3
Brain, Child Mind Institute, New York, NY whiskers palpating the textures. Selectivity indexes (S.I.);
the Response for texture X divided by the average response
Background: Correlated fluctuations of the BOLD signal of all the textures, were calculated for each texture, and the
measured at rest directly relate to fMRI activation. As the preferred texture was determined. When we calculated the
BOLD signal represents an indirect measure of neural ac- averaged S.I. and the ratio of highly selective cells in each
tivity, the neurophysiological underpinnings of these corre- layer we obtained a texture selectivity hierarchy in the
lations must be elucidated. The origin of antiphase somatosensory SI and SII cortexes: L4(SI)<L2-3(SI),L5
fluctuations in BOLD ('anticorrelations') is an area of (SI) and L4(SII)<L5(SII)<L2-3(SII). To ensure that the
intense debate. While some believe this measure is differences between SI and SII were not due to differences
artificially induced by removal of the global BOLD in the stimulus paradigms we performed control experi-
signal, others argue for its existence and significance ments in which only a single whisker was left for SII experi-
in disease states. Here, by measuring ECoG and BOLD ments and a whisker row was left intact in SI experiments.
signals from the same individuals, we tested the hypoth- In SI no significant changes were observed in layer 4 neu-
esis that BOLD anticorrelations correspond to anticorre- rons, but a significant decrease in selectivity in layers 2-3
lations in high-frequency ECoG power. A better and 5 neurons.In SII the response magnitude decreased,yet
understanding of anticorrelations will aid in our under- the texture selectivity did not change significantly in layer 2-
standing of this signal in disease states. 3,increased in layer 4 and dropped in layer 5. We performed
Methods: Pre-operatively, a resting state fMRI was two-photon imaging from the upper layer2-3 of SII, the
recorded in 5 patients with epilepsy undergoing surgical most selective for textures, in order to investigate the neu-
evaluation of seizure foci. Following implantation of sub- rons' functional mapping.Our results showed that neurons
dural grids and strips, we recorded ECoG during a 3- tend to cluster according to their preferred texture.Moreover,
5 minute period of rest where subjects were instructed to functional cortical columns were observed in which the pre-
lay quietly with their eyes closed. Data was filtered into the ferred texture was significantly similar across layers 2-5.
high gamma band (50-150Hz), enveloped, and smoothed to Conclusions: Texture coarseness coding is sharper in SII
obtain the high gamma power signal. Pair-wise correlations compared to SI.These findings suggest that SII and espe-
of electrodes were performed, and spatial maps of HGP and cially layer 2-3 of SII serve as a higher processing station for
BOLD correlations were compared. texture coding.
Results and conclusions: 1) A strong correspondence was
found between HGP and BOLD correlations regardless of Stimulus-specific adaptation in inferior colliculus
network sampled, supporting and extending previous stud- does not index deviance detection
ies with whole brain intra-individual neuronal and hemody- Khouri L, Hershenhoren I, Antunes FM, Nelken I*
namic measurements. 2) A small but significant subset of Dept. of Neurobiology, Hebrew University of Jerusalem
networks exhibited neuronal anticorrelations; 3) neuronal
anticorrelations exhibited a spatial selectivity to regions of The auditory system differentiates rare from common
anticorrelated BOLD fluctuations. Together, these findings sounds by decreasing responsiveness to common and there-
suggest that BOLD correlations and anticorrelations have by emphasizing responses to rare sounds - a phenomenon
neurophysiological correlates that are reflected in fluctua- that (on the neuronal level) is called Stimulus Specific
tions of neural activity. Adaptation (SSA). SSA has been demontsrated at the level
Page and Otto Marx Jr. Foundation to ADM; NINDS of the auditory midbrain (Inferior Colliculus, IC), the medial
F31NS080357-01 and EFA189045 to CJK geniculate body, and the Auditory Cortex (AC). SSA as
usually tested may result from neural fatigue (e. g. due to
Texture coarseness coding in the secondary somatosensory adaptation of excitation of narrowly-tuned inputs). Such a
cortex (SII) of the rat mechanism, however, is not truely sensitive to the deviance
Khateb M*, Pachter I, Schiller Y, Schiller J of the rare sound with respect to a predictable background.
Rappaport Faculty of Medicine, Technion, Haifa, Israel To differentiate between true deviance sensitivity and
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S63
adaptation due to neural fatigue, we employed a set of glia, an astrocyte, as a main actor in the Purkinje layer of the
control stimuli and compared neural responses recorded mouse cerebellum.
from AC and IC to predictions of a feed-forward model with
adaptation of exciation in narrowly-tuned inputs. In line with Learning of grammatical structure: a biologically
previous results, we found substantial SSA in a subset of inspired learning mechanism and its application
neurons recorded in the IC. Neurons showing substantial to language acquisition
SSA were sensitive to a wide range of tone frequencies, while Kolodny O* 1,, Lotem A 1, Edelman S 2
1
neurons showing little or no SSA showed narrow frequency Dept. of Zoology, Tel Aviv University 2Dept. of Psychology,
tuning. Moreover, SSA in IC was well in line with the pre- Cornell University
dictions of the adaptation of excitation model. In contrast,
cortical responses to deviant sounds were stronger than pre- Background: The brain has evolved mechanisms for learn-
dicted by the model. Our results suggest that (1) SSA in IC ing the organism's environment by finding recurring pat-
results from adaptation of excitation in narrowly tuned inputs, terns, representing them in memory, and acting upon this
(2) SSA in IC does not encode deviance; and (3) true sensi- knowledge to generate adaptive behavior. We used insights
tivity to stimulus statistics only emerges after additional layers from several traditionally disparate fields to construct and
of processing (potentially in the auditory thalamus, but cer- implement a learning mechanism which is biologically re-
tainly in auditory cortex). alistic in that it is incremental, uses limited memory and
computational resources, and is composed of biologically-
Predicting layer-specific genes in the mouse cerebellum inspired building blocks. This implementation may explain
using ISH images a variety of phenomena in tasks ranging from learning of
Kirsch L, Liscovitch N, Chechik G* language in humans, through learning of birdsong, to ani-
Gonda Multidisciplinary Brain Research Center, Bar-Ilan mals' learning of regularities in foraging environments. In
University the work I currently present I focus on results from language
learning.
Background and Methodology: Understanding the pat- Results: To assess the model's performance, we subjected it
terns of the transcriptome in the brain is particularly hard to an extensive series of tests. These included the replication
since brain tissues mix numerous types of neurons and glia, of fifteen published results in sequence segmentation, arti-
and little is known about which genes are expressed in ficial grammar learning, and structure dependence, and the
which cells and brain layers. Here, we describe an approach estimation of the model's ability to learn a generative gram-
to detect genes whose expression is primarily localized to a mar from a corpus of natural language. In its generative
specific brain layer and apply it to the mouse cerebellum. abilities, the model compares favorably to a standard trigram
We learn typical spatial patterns of expression from a few model, achieving much higher scores on precision, but
markers that are known to be localized to specific layers, performing less well in perplexity scores. It was also found
and use these patterns to predict localization for new genes. to categorize linguistic units fairly well, showcasing its
We analyze images of in-situ hybridization (ISH) experi- exemplar-based learning and its equal treatment of syntax
ments and train classifiers for four layers of the cerebellum: and semantics, which occasionally results in units that strad-
the Purkinje, granular, molecular and white matter layer. dle traditional boundaries of constituency. Our model suc-
Results: On held-out data, the layer classifiers achieve ac- cessfully reproduced the reported effects in all but two of the
curacy above 94 % (AUC) by representing each image at experiments.
multiple scales and by combining multiple image scores into Conclusions: We propose a general model of learning,
a single gene-level decision. When applied to the full mouse which is biologically motivated and is applicable to a wide
genome, the classifiers predict specific layer localization for spectrum of animal learning tasks, and successfully apply it
hundreds of new genes in the Purkinje and granular layers. to language learning. Within the field of language learning,
Many genes localized to the Purkinje layer are likely to be this is the first model to accommodate such a wide range of
expressed in astrocytes, and many others are involved in tasks while preserving a modicum of biological realism.
lipid metabolism, possibly due to the unusual size of Pur-
kinje cells. Intra-individual variability of reaction time differentiates
Conclusions: Gene expression can be accurately localized between attention and reading disorders
to brain layers, using ISH images in an automated way. Kolodny T* 1, Seidel N 2, Azulai O 2, Shalev L 3
1
Also, we find a surprisingly large fraction (3.4 %) of the Dept. of Cognitive Sciences, the Hebrew University,
mouse genome localized to the Purkinje layer. This suggests Jerusalem 2School of Education, the Hebrew University,
that many molecular functions have special variants restrict- Jerusalem. 3School of Education and the Sagol School of
ed to this thin layer. Specifically, we identify the Bergmann Neuroscience, Tel Aviv University.
S64 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
Background: Attention deficit/hyperactivity disorder reducing gaps between finger movements in both groups,
(ADHD) is one of the most prevalent developmental disor- but Uncued training induced higher gains. The underly-
ders. Intra-individual variability of reaction time (IIV of RT), ing kinematic strategies producing these changes and
also conceptualized as an index of sustained attention abil- the representation of the trained sequence differed sig-
ity, has been demonstrated in ADHD in a variety of tasks nificantly across subjects, although net gains in speed
and has been suggested as a candidate endophenotype of were similar. The differences in long-term memory due
ADHD. However, it is questioned whether IIV of RT is to the type of training and the variation in strategies
specific to ADHD, rather than a more general characteristic between subjects, suggest that the different neural mech-
of clinical groups, as for example is the case with slow RT. anisms may subserve the improvements observed in
In this study we aimed at demonstrating specificity by overall performance.
comparing IIV of RT of adults with ADHD with that of
adults with reading disorder (RD), the most prevalent dis- Auditory response adaptation is not specific to the direction
order co-occurring with ADHD. IIV of RT was assessed of auditory motion
using the standard deviation of RT (SD of RT) in a conjunc- Kra Y* 1,2, Gutfreund Y 1
1
tive continuous performance test (CCPT), designed to mea- Dept. of Physiology and Biophysics, Faculty of Medicine,
sure sustained attention. The CCPT - a long monotonic task Technion 2Gonda Interdisciplinary Brain Research Center,
with a low frequency of target stimuli to which a response is Bar Ilan University
required, poses difficulty to maintain a constant level of
performance, while minimizing the involvement of working Two alternative hypotheses have been suggested with
memory and other cognitive factors. regard to auditory motion processing. The first hypoth-
Results: Participants with RD performed equally well as esis suggests that there is no dedicated auditory motion
control participants in all measures of the CCPT, including processing circuitry in the brain and that motion is
SD of RT- reflecting low IIV of RT, although reporting a encoded as a series of static localizations. A prediction
high rate of behavioral symptoms of inattention. The IIV of of this hypothesis is that the neural responses to motion
RT of participants with ADHD was significantly higher than are inseparable from the neural responses to static stim-
of participants with RD and controls. Interestingly, IIV of uli. The alternative hypothesis is that the central audi-
RT in the co-morbid group (participants with ADHD+RD) tory system contains neural circuitry that is dedicated to
was significantly lower than in the ADHD group. auditory motion processing and is exclusively sensitive
Conclusions: Pure sustained attention deficits, as to parameters such as direction and velocity. In this
reflected by high IIV of RT, are unique to ADHD. study we aim to examine the later hypothesis that sound
Symptoms of inattention experienced by participants motion is independently encoded in the brain. We used
with RD do not stem from deficient sustained attention, adaptation paradigms such as the oddball paradigm. In
and may be the outcome of reading difficulties rather the oddball paradigm, rare stimuli (deviants) are embed-
than their cause. It is recommended to use tools such as ded in a long sequence of common stimuli (standards).
the CCPT in order to obtain a discriminative diagnosis The role of the standards and deviants is then switched,
of attention and reading disorders. and neural responses to a stimulus when rare are then
compared with the responses to the same stimulus when
Kinematic strategies underlying improvement common. The standard stimulus was an auditory stimu-
in the acquisition of a sequential finger task lus starting at a position outside the auditory receptive
with self-generated vs. cued repetition training field (ARF), moving in a straight line through the ARF
Korman M 1, Freidman J* 2 and ending at a position outside the ARF. The deviant
1
University of Haifa 2Tel-Aviv University was a stimulus moving at the same velocity but in
opposite direction starting at the end-point and ending
Many motor skills, such as typing, consist of articulating at the start-point of the standard. Auditory stimuli were pre-
simple movements into novel sequences that are executed sented in virtual acoustic space. The results of these experi-
faster and smoother with practise. Dynamics of re- ments did not show specific adaptation to the direction of
organization of these movement sequences with multi- motion, the neural responses to deviant and standard direc-
session training and its dependence on the amount of self- tions were on average similar. This was in marked contrast to
regulation of pace during training is not yet fully under- the results obtained using the same adaptation paradigms but
stood. In this study, participants practiced a sequence of key using static stimuli with standards and deviants differing by
presses. Training sessions consisted of either externally the location of the sound. Our results therefore argue against a
(Cued) or self-initiated (Uncued) training. Long-term specialized auditory motion processing circuitry. This work
improvements in performance speed were mainly due to was supported by a grant from the ISF.
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S65
Protective effects of the novel multi-target iron chalator / object discrimination may involve microvibrissae- and non-
monoamine oxidase inhibitor drug, VAR, on age-related whisker tactile based discrimination. To determine whether
neurodegeneration: regulation of BDNF/CREB signaling the somatosensory cortex can code for surface coarseness
Kupershmidt L, Weinreb O*, Tamar A, Youdim MB through the microvibrissae, we recorded from the cortical
Eve Topf and USA National Parkinson Foundation Centers area representing the frontobuccal pad while presenting
of Excellence for Neurodegenerative Diseases Research and moving textures with varying coarseness. We found that
Dept. of Pharmacology, Technion surface coarseness is coded by the discharge rates of fronto-
buccal pad cortical neurons. This suggests that microvibris-
Background: Brain-derived neurotrophic factor (BDNF)/ sae or skin/fur cues can provide salient texture information.
tropomyosin receptor kinase B (TrkB)/cAMP response Supported by ISF to RA
element-binding protein (CREB) signaling pathway has been
shown to play a pivotal role in neuronal survival, differentiation K shell decomposition reveals the functional hierarchy
and synaptic plasticity, be highly implicated in the pathophys- of information integration in human brain
iology of aged-related cognitive decline and be positively reg- Lahav N 1, Ksherim B 1, Ben Simon E 2,3, Cohen R 4,
ulated by long-term antidepressant treatment. The main aim of Havlin S 1
1
this study was to investigate whether the positive impact of our Minerva Center and Dept. of Physics, Bar-Ilan University,
novel multi-target monoamine oxidase inhibitor and anti- Ramat Gan2Sackler Faculty of Medicine, Tel Aviv University,
depressant iron chelator, VAR, on cognitive deficits and brain Tel Aviv3 Functional Brain Center, Wohl Institute for Ad-
morphological deteriorations are accompanied with BDNF/ vanced Imaging, Tel-Aviv Sourasky Medical Center, Tel- Aviv
4
TrkB/ CREB pathway regulation and synaptic integrity preser- Dept. of Mathematics, Bar-Ilan University, Ramat Gan
vation in the hippocampus of the aged rats.
Results: Here, we report that a chronic systemic treatment The human brain has been shown to feature small world
of aged rats with VAR(5 mg/kg; 4 times weekly for network characteristics. In order to further analyze the
6 months), had a significant positive impact on anxiety unique structure of this network we applied a k-shell de-
levels and cognitive age-related impairment, as revealed composition analysis on a structural human brain network,
by forced swim, object recognition and open field tests. This derived from DTI\MRI imaging of 5 subjects. In this tech-
effect was accompanied by a marked brain MAOA and B nique, 998 cortical ROIs were used to construct the nodes of
inhibition and significant increase in hippocampal catechol- each network and 14,865 edges were derived from white
amines levels. Histochemical studies showed that VAR in- matter fibers. We confirmed that the whole network features
creased the number of viable cells detected by Nissl a 'small world network' and that the cortical network is
staining, as well as the levels of BDNF and phosporylated highly resilient. Using the K-shell decomposition analysis
CREB in hippocampal CA3 and dentate gyrus regions, we were able to reveal shells of growing connectivity within
compared with aged control rats. We have found thatVAR the network. In this way we identified that each shell can be
induced hippocampal levels of TrkB, growth associated attributed to specific functional network alongside its
protein (GAP) 43, synaptophysin and nerve growth factor corresponding organizational hierarchy. we revealed that
(NGF). VAR also significantly enhanced the levels of phos- the shells can be grouped into three hierarchial clusters.
phorylated extracellular-signal-regulated kinase (ERK) and For instance, primary visual areas were found in the lowest
Bcl2/Bax ratio in the hippocampus of aged rats. functional cluster (lower k-shells) while higher visual asso-
Conclusion: Our results indicate that VAR-induced neuropro- ciative areas were found in the highest cluster that we called
tection against age-related neurodegeneration and preservation the nucleus (highest shell). Furthermore, all known con-
of hippocampal neuronal integrity might be exerted by enhanc- sciousness supporting networks were included in the nucle-
ing the BDNF/TrkB/CREB signaling pathway in aged rats. us. it can be assumed that information flow in the brain
starts from the lowest functional cluster while being more
Microvibrissae based texture coding and more integerated in the higher clusters.
Azouz R* , Kurupath P , , Gugig E
Dept. of Physiology and Cell Biology, Faculty of Health Effects of gestational exposure to chlorpyrifos on motor
Sciences, Ben-Gurion University of the Negev development and social behavior in C57BL/6 J mice
Lan A* 1,2, Dori A 3, Kofman O 1,2
1
In their natural environment, rodents use their whiskers to Zlotowski Center for Neuroscience Ben Gurion University
locate and distinguish between objects of different textures of the Negev 2Dept. of Psychology , Ben- Gurion University
and shapes. They do so by moving their whiskers actively as of the Negev 3Talpiot Medical Leadership Program Dept. of
well as passively, through body and head movements. An Neurology and Joseph Sagol Neuroscience Center Sheba
alternative and relatively unexplored strategy for texture and Medical Center
S66 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
Background: Chlorpyrifos (CPF) is a widely-used organo- possibility, we measured change detection performance on
phosphate insecticide suspected to be a risk factor for au- two simultaneously presented stimuli, after resetting atten-
tism. Exposure to CPF in gestation was linked to lower birth tion to one of them. After a reset flash at one stimulus
weight, abnormal reflexes, increased risk for pervasive de- location, detection performance fluctuated rhythmically.
velopmental disorder and lower IQ in children. In rodents Additionally, different locations were associated with differ-
gestational CPF elicited decreased vocalizations in pups and ent phases of the rhythmic sampling supporting a sequential
enhanced agonistic responses in adults. In this study the model of exploration. This suggests that selective attention
long-term effects of gestational exposure to CPF on early entails exploration rhythms similar to other exploration
motor development and social behavior, in C57BL/6 J male behaviors. In my presentation, I will report new findings
mice were tested. combining the psychophysical task with MEG recordings.
Method: Pregnant female mice were randomly assigned to We utilized stimuli that elicit a strong sustained gamma
one of the four treatments: 5 mg/kg, or 2.5 mg/kg CPF, band response in visual areas. Previously gamma band
vehicle (oil) and no treatment, administered by gavage on synchronization has been proposed as a mechanism support-
gestational days 12 to 15. In order to test whether maternal ing inter areal communication of behaviorally relevant stim-
behavior was impaired by CPF, on postnatal day (PND) 5 uli. In our study, we investigated the possibility that MEG
maternal retrieval was tested. On PND 5-12, 3 neonatal responses measured from visual areas might display cross
reflexes were tested: righting, negative geotaxis and cliff frequency interactions reflecting both sustained neural syn-
avoidance. On PND 90 the social preference (SP) & social chrony at higher frequency as well as slower rhythmic
novelty (SN) tasks were administered. Preference toward modulation that supports attentional sampling.
a conspecific was measured by time spent in either
chamber of a three-chambered box, in which the two Exploring the role of synaptic proteins in tuning
side chambers contained either an unfamiliar conspecific synchronous neuronal network activity
an inanimate object (SP task). Thereafter, SN was mea- Lavi A 1,2, Sheinin A 1, Perez O 3,2, Shapira R 1, Yeshurun
sured by comparing time spent in a chamber with an Y 4,2, Ashery U* 1,2
1
unfamiliar mouse as opposed to a chamber with the Dept. of Neurobiology, The George S. Wise Faculty of Life
familiar mouse. Sciences, Tel Aviv University, Tel Aviv 69978, Israel 2Sagol
Results: CPF treatment did not impair maternal retrieval, School of Neuroscience, Tel Aviv University, Tel Aviv 69978,
suggesting delayed development of CPF exposed offspring Israel 3Sackler School of Medicine, Tel Aviv University,
was unlikely to be due to maternal behavior. Both doses of Israel 4Blavatnik School of Computer Science, Tel Aviv
CPF resulted in delayed development of reflexes: righting University, Tel Aviv.
reflex (F (21,98)02.21, p<.05), the negative geotaxis reflex
(F (3,14)012.87, p<.05) and cliff avoidance (F (3,15)0 The plasticity of the brain plays a key role in shaping
14.06, p.05), but were not impaired in the SN task. our behavior, learning and memory. It is well known
Conclusion: Gestational exposure to CPF elicits deficits in that plasticity is associated with alteration in synaptic
social behavior and motor development. strength and efficacy. Some of these effects correlate
Funded by Israel Science Foundation grant 1055/10 to OK. with changes in the levels of synaptic proteins. Howev-
er, the implications of genetic alteration in synaptic
Attentional Sampling: lessons from psychophysics proteins on the network activity of neurons are not
and MEG known. We previously used the MicroElectrode Array
Landau AN*, Schreyer HM, Fries P (MEA) technology to examine the effect of DOC2B
ESI for Neuroscience in Cooperation with Max Planck manipulation, a synaptic neuronal Ca2+ sensor that is
Society known for its ability to alter synaptic transmission, on
neuronal network activity. We found that overexpression
Overt exploration or sampling behaviors, such as whisking, of DOC2B lead to a distinctive increase in the spiking
sniffing, and saccadic eye movements are often character- activity and noticeable increase the participation rate of
ized by a theta rhythm (4-10Hz; Otero-Millan, Troncoso, neurons in the network burst. In this work, we used a
Macknik, Serrano-Pedraza and Martinex-Conde, 2008; Buz- unique in silico neuronal network to simulate the effect
saki, 2006). In addition, the electrophysiologically recorded of DOC2B on network activity. Our model takes into
theta or alpha phase predicts global detection performance account both cellular and network parameters in order
(Busch Dubois and VanRullen, 2009; Methewson, Gratton, to understand the impact of DOC2B overexpression on
Fabioani, Beck and Ro, 2009). These two observations raise the activity of the neuronal network. Preliminary results
the intriguing possibility that covert selective attention sam- suggest that DOC2B's effect on neuronal network burst-
ples from multiple stimuli rhythmically. To investigate this ing activity might be explained by its ability to increase
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S67
spontaneous neurotransmitter release in a calcium- NGF is a neurotrophin for which the role in the promotion
dependent manner. Furthermore, our network model of angiogenesis in neuronal tissue is still not completely
suggests that DOC2B might exert its physiological ef- understood. We found that NGF promotes the pathological
fect through localized buffering of pre-synaptic calcium. neovascularization process in glioma through a direct inter-
This approach extends our understandings of the role of action with α9β1 integrin, which is up-regulated on micro-
DOC2B in synaptic transmission and as suggested before by vascular endothelial cells in human glioblastoma brain
London et al., demonstrates how small changes in the cellular tumors. We isolated from these tumors microcapillaries
level can be translated to significant changes in the network and derived endothelial (gHMVEC) primary cells using a
level. This stresses the importance of understanding synaptic new method of immune-selection. These cell clones dem-
proteins in the network frame of work. onstrated in vitro α9β1 integrin-dependent binding of NGF
in a cell adhesion assay. Moreover, NGF induced gHMVEC
Early neural lesions following organophosphate poisoning proliferation and chemotaxis, processes inhibited by specific
in the rat: propagation of damage blockers of α9β1integrin, such as MLD-disintegrin (VLO5)
Lazar S*, Egoz I, Brandeis R, Bloch-Shilderman E and monoclonal antibody Y9A2. A matrigel tube formation
Dept. of Pharmacology, IIBR, P.O.Box 19, Ness Ziona, assay revealed that NGF significantly increased capillary-
74100, Israel like growth from gHMVEC to a level comparable to treat-
ment with vascular endothelial growth factor VEGF. The
Sarin, a highly toxic cholinesterase inhibitor, administered snake venom disintegrin VLO5, inhibited the angiogenic
at near 1LD50 dose causes severe signs of toxic cholinergic effect of both growth factors, whereas the effect of Y9A2
hyperactivity in both the peripheral and central nervous was not statistically significant. Angiogenesis exogenously
system. The early histopathological consequences occurring induced by NGF was also α9β1-integrin dependent in an
following sarin exposure have not been fully characterized. embryonic quail chorioalantoic membrane system. Howev-
In the present study, we analyzed the early histopathological er, angiogenesis pathologically induced by developing glio-
and biochemical events occurring following sarin exposure. ma tumor in this system was only sensitive for inhibition
Male Sprauge-Dawley rats were exposed to 1LD50 of sarin with VLO5, suggesting a more complex effect of cancer
(75 μg/kg, i.m.). Brains were removed 1, 2, 6, 24 and cells on the neovascularization process. The anti-angiogenic
48 hours following sarin intoxication and processed for effect of VLO5 is probably related to its proapoptotic activ-
biochemistry analysis and immunohistopathology examina- ity in activated tumor capillaries endothelial cells. These
tion. Results showed maximal ChE inhibition (97 %) within findings extend NGF effects from neurons and glia to cap-
1 h post exposure that remained elevated at 48 h. Trans- illaries endothelial cells emphasizing the important role of
locator protein (TSPO, a well established marker for brain this neurotrophin on the brain neurovascular unit. Moreover,
damage) mRNA reached maximal level 24 h post exposure the ability of VLO5 to antagonize NGF-induced angiogenic
while maximal receptor density observed at 48 h. Immuno- effect may be useful for developing new angiostatic phar-
histopathologic examination revealed a marked increase in maceuticals for application in glioma therapy.
astrocytes (GFAP staining) already 2 h post exposure in all * Walsh, E.M., Kim, R., Del Valle, L., Weaver, M., Sheffield,
brain regions. This elevation was particularly higher in the J., Lazarovici, P. and Marcinkiewicz, C. Importance of inter-
piriform cortex area. A sharp decrease in intact neuronal action between nerve growth factor and α9β1 integrin in glial
cells (NeuN staining) was noted as soon as 1 h post tumor angiogenesis. Neuro Oncol. 14:890-901. 2012
exposure in the piriform cortex, frontal cortex and tha-
lamus regions and 2 h post exposure in the hippocam- Single-digit multiplication in Generally Gifted
pus. A time dependent reduction in MAP2 (microtubule- and Excelling-in-mathematics adolescents: ERP study
associated protein 2) labeling indicated a propagating Leikin M 1, Waisman I 1, Shaul S 1,2, Leikin R 1
1
damage to the nerve dendrites and spines. These results University of Haifa 2Edmond J. Safra Brain Research
suggest an immediate onset of a propagating deteriora- Center for the Study of Learning Disabilities,
tion cascade of nerve cells damage following organo-
phosphate exposure. Background: This paper presents a small part of a larger
interdisciplinary study that investigates brain activity (using
Interaction between nerve growth factor (NGF) ERP methodology) of mathematically talented adolescents
and alfa9beta1 integrin in glial tumor angiogenesis* when solving mathematical problems of different types. The
Lazarovici P present study aimed to examine the differences in time course
School of Pharmacy Institute for Drug Research, Faculty of and form of activation between four ability groups of high
Medicine,The Hebrew University of Jerusalem, Jerusa- school students according to the combination of G
lem,91120,Israel. (giftedness) and E (excellence in mathematics) factors. ERPs
S68 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
were used in order to compare the process of brain activation Results: NXPH1 and NXPH3 were expressed in SCN cells
when students perform single-digit multiplication tasks. both in vivo and in vitro but only NXPH3 mRNA showed
Results: P1, N2, P3, N4 and P6 ERP components were strong and significant rhythm in both. In vivo, NXPH3 peak
identified in the RMS, and peak detection was performed lagged two hours after NRXN1-α and NRXN2-α mRNA
for the chosen electrodes. Significant effect of E factor on peak, while in the SCN2.2 cells, NXPH3 and NRXN1/2-α
differences in amplitudes and latencies of the peaks was expression patterns were similar.
found. Gifted (G) student differed from non-gifted (NG) Immunofluorescence labeling demonstrated colocalization
ones only on P1with significantly longer latency for stu- of NXPH3 and membranal NRXN2-α at all time points,
dents from group G as compared to students from group although NXPH3 levels varied diurnally in agreement with
NG. Significant main effect (with repeated measures MAN- the mRNA temporal expression pattern.
OVA) for E factor in the amplitude measures (F (1,74)0 Conclusions: These results show for the first time that
5.036, p0.028) of all ERP components with larger ampli- NXPH3 is transcribed rhythmically in the SCN in vivo and
tudes for students from group E as compared to group NE in SCN2.2 cells in vitro. Furthermore, we show that endog-
was found. Significant interaction between all selected elec- enous NXPH3 and NRXN2-α colocalize in SCN2.2 cells,
trodes and E factor (F (1.782, 133.930)06.497, p0.003) was with different levels of NXPH3 expression throughout the
also obtained. day. These results suggest that NXPH3 may have a role in
Conclusion: G factor does not affect performance on rela- the circadian rhythm disturbances typically seen in ASD and
tively simple arithmetical tasks. At the same time, effect of schizophrenia.
E factor is associated with the automatic retrieval of
information performed by E participants, and producing Breakdown of temporal hierarchy in neural processing
calculations by NE participants. The difference in am- of natural information: evidence from schizophrenia
plitude and latency of the N2 component may reflect Bleich-Cohen M 1, Giladi N 2,3, Hendler T 1,3, Lerner Y* 1
1
the difference in the attention mechanism between E Functional Brain Center, Tel-Aviv Sourasky Medical Cen-
and NE participants. For E students the solution process ter, Israel, 2Dept. of Neurology, Tel-Aviv Sourasky Medical
is faster with higher amount of activity and use of more Center, Israel, 3Tel Aviv University, Israel
areas but for less time.
Background: Real-life events, such as listening to a speech or
Neurexophilin 3 is expressed rhythmically watching a movie, unfold over many minutes. During such
in the suprachiasmatic nucleus (SCN) in vivo events, our brains absorb information continuously for the
and in immortalized SCN2.2 cells and is colocalized duration of the experience. However, the information gathered
with membranal but not intracellular Neurexin2-α at each particular moment only becomes meaningful in the
Lerner H, Zisapel N* context of previous events. The capacity to accumulate infor-
Dept. of Neurobiology, George S. Wise Faculty of Life mation over time, thus, is crucial to our functioning in an ever-
Sciences, Tel Aviv University, Israel changing world. Yet our knowledge about gathering and
parsing information over time is surprisingly limited. Recent-
Background: Neurexophilins (NXPH1/2/3/4) are secreted ly, in healthy subjects, we revealed hierarchy of information
neuronal glycoproteins, primarily expressed in mam- processing over time from early sensory areas toward high
mals. NXPH1/2/3 (but not NXPH4) bind specifically order perceptual and cognitive areas. Here, we investigate the
to Neurexins 1/2/3-α (NRXN1/2/3-α). NRXNs are issue in first-episode schizophrenia patients, who are known
members of a gene family encoding hundreds of alter- to exhibit deficient information processing.
natively spliced isoforms of presynaptic proteins that are Results: Results were derived from inter-subject correlation
involved in neurosecretion and excitatory/ inhibitory analysis, which measures the reproducibility of neural
synapse specification and mental disorders, e.g. autism responses across participants evoked by continuous and
and schizophrenia. The role of NXPHs in NRXNs' complex stimuli, such as stories and movies. The time-
functions is largely unknown. courses within each brain area in schizophrenia patients
We have recently shown circadian oscillations in NRXN1/2- were estimated against healthy controls and unaffected sib-
α in the suprachiasmatic nucleus (SCN) of the hypothala- lings of the patients, which are known to be more prone to
mus, that function as the main circadian clock in vivo and in the disease. Results in patient group demonstrated impaired
immortalized SCN cells (SCN2.2 cells), which retain the hierarchy with processing intact in low level but disturbed in
rhythmic properties of the SCN, in vitro. Bioinformatic high level, in both visual and auditory modalities. The
search suggested that NXPH1 might be a clock controlled sibling group showed an intermediate effect.
gene. We thus explored circadian rhythms in NXPH1/2/3 in Conclusion: We believe that better understanding of the
the SCN in vivo and SCN2.2 cells in vitro. underlying neural circuit involved in information
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S69
processing in schizophrenia patients may assist in early on a target stimulus when a mask stimulus is briefly presented
identification of functional neural markers for the dis- before, during, or after the target, at the same, or at flanking
ease and facilitate development of improved methods locations. Each crowding and visual masking effect represents
for early diagnosis. a very important stage in visual processing and both are widely
YL is supported by the IBRO Return Home Grant used as a tool to study visual processing in the brain. Yet the
relation between crowding and lateral masking is unclear. In
Dietary sodium, added salt - associations with depression our previous studies we showed that crowding is correlated
in NHANES with masking; a higher degree of crowding correlates with
Goldstein P* 1, Leshem M 2 higher masking. Previous studies showed that training on lat-
1
Dept. of Statistics 2Dept. of Psychology, University of eral masking improves some visual functions but the effect on
Haifa crowding is not yet clear. Here we explored whether training on
lateral masking can reduce the crowding effect as well as
Background: The possibility that enhanced salt intake protects improve other visual functions in the fovea and the peripheral.
against stress is a long-standing and attractive hypothesis deriv- Methods: Subjects were tested before and after undergoing
ing from the commonality of adrenal corticoids mediating both training in visual acuity, stereo acuity, letter crowding, spa-
salt appetite and stress response, and the intertwining endocrine tial alignment, and contrast sensitivity. The subjects were
systems regulating sodium appetite, serum sodium concentra- trained on detection tasks and on two types of masking
tion, fluid volume, and sympathetic tone. Mineralocorticoids (simultaneous, temporal). The target appeared randomly
and angiotensin II are activated by sodium deficiency and are either at the fovea or at the periphery (right or left).
anxiogenic. ACTH activation increases sodium intake in some Results: During the training sessions the extent of spatial and
species but not others, including humans. Rats on a sodium temporal masking was reduced. After training, the group im-
restricted diet, sodium depleted, or with endocrinologically- proved in visual acuity, spatial alignment, and contrast sensitivity
mimicked sodium depletion, evince increased modeled anxiety at all locations. In addition, stereo acuity was tested and it im-
and depression (reduced sweet hedonics and electrical brain proved in the fovea and crowding was reduced at the periphery.
self-stimulation). Here we examined the possible relationship Discussion: The results indicate that training that reduces
of salt intake and depression in humans, the masking effect is transferred to reduction in the crowd-
Method: We analyzed the National Health & Nutrition Exam- ing effect. Thus, the results support our hypothesis that
ination Survey (NHANES) 2007-2008 US database of ~10,000 crowding and lateral masking share similar mechanisms.
people for the relationship of dietary sodium, reported table salt The improvements in all trained locations, using lateral
use, and depression. masking, support our suggestion that similar basic process-
Results: We find, in women only, that depression is inverse- ing takes place in both peripheral and the foveal vision.
ly related to dietary sodium intake, and positively related to Israel Science foundation and Dept. of Defense, USA
table salt use.
Conclusions: It is possible that depression-induced anhedo- A mouse model of the gateway hypothesis: nicotine
nia may reduce choice of foods with sodium enhanced flavor. and cocaine
We have shown that rats in the chronic unpredictable stress Levine A* 1, Huang YY 1, Drisaldi B 1, Pollak DD 2,
model of depression consume less sweet and less salty solu- Griffin EA Jr. 3, Xu S 1, Schaffran, C. 3, Kandel DB 3,4,
tions, even when sodium restricted. On the other hand, our Kandel ER 1,3,5,6
1
findings can suggest that men are protected against depression Dept. of Neuroscience, College of Physicians and Surgeons
by their higher sodium intake, while in women low sodium of Columbia University, New York State Psychiatric Institute,
intake increases rates of depression. Adding salt might be self- 1051 Riverside Drive, New York, NY 10032, USA 2Dept. of
medication. Although the data are correlative, these possibil- Physiology, Center for Physiology and Pharmacology, Med-
ities should not be ignored. ical University of Vienna, Schwarzspanierstrasse 17, I A-1090
Support: to ML by the Salt Institute and the University of Haifa. Vienna, Austria 3Dept. of Psychiatry, College of Physicians
and Surgeons of Columbia University, 1051 Riverside Drive,
Training on visual masking improves visual functions New York, NY 10032, USA 4New York State Psychiatric Insti-
in fovea and periphery tute, 1051 Riverside Drive, New York, NY 10032, USA
Lev M 1, Sterkin A 1, Yehezkel O 1,2, Doron R 1, Fried M 1, 5
Howard Hughes Medical Institute, College of Physicians
Polat U 1 and Surgeons of Columbia University, New York State Psychi-
1
Tel-Aviv University 2UC Berkeley atric Institute, 1051 Riverside Drive, New York, NY 10032, USA
6
Kavli Institute for Brain Science, College of Physicians and
Background: Crowding impairs the ability to recognize an Surgeons of Columbia University, New York State Psychiatric
object in clutter. Visual masking refers to impaired performance Institute, 1051 Riverside Drive, New York, NY 10032, USA
S70 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
We present the results of mouse models of the Gateway Hy- perturbational approach using transcranial magnetic
pothesis, an epidemiological finding that describes the progres- stimulation (TMS) as a means to study stability and
sion from nicotine or alcohol to marijuana to the use of illicit dynamics of the schizophrenia network and suggested
drugs in human populations. We designed an alternate sequen- that TMS perturbations have considerably greater effects
tial treatment procedure involving nicotine and cocaine and on schizophrenia participants than on controls. Here we com-
examined the behavioral, electrophysiological and molecular bine TMS with electroencephalography (EEG) to measure the
effects of sequential treatments. Pretreatment with nicotine brain response to TMS perturbations in schizophrenia and in
alters the response to cocaine of both addiction-related behavior healthy controls. Using complexity system approach we char-
and synaptic plasticity in the striatum, a region critical for acterize the effect of these TMS perturbations on the dynamics
addiction. The ordering effect from nicotine to cocaine is and stability of the underlying networks.
unidirectional; there is no effect of cocaine on nicotine. Nico- Results: While in the Sham condition the schizophrenia brain
tine alters addiction related behavior and cellular physiology of network had less links than the control network, following
LTP in response to cocaine. Nicotine produces these effects by TMS perturbations the schizophrenia network exhibited more
initiating global histone acetylation, which leads to greater links than the TMS-perturbed healthy network. When analyz-
transcriptional activation of the fosB gene, a molecular marker ing the robustness of the schizophrenia and control networks to
for addiction. Pretreatment with the HDAC inhibitor SAHA intentional attack and to network failure (when nodes are
produces an enhancement of the effect of cocaine very similar removed in decreasing order of their degree or in a random
to that produced by pretreatment with nicotine. Conversely, manner, respectively), both healthy networks (Sham and TMS)
decreasing histone acetylation leads to a decrease in the effects behaved as expected from a scale-free network dominated by
of cocaine electrophysiologically and in fosB expression. His- hubs. However, while the Sham schizophrenia network was
tone acetylation is reduced genetically by using a mouse which even less robust than the healthy network to intentional attack,
lacks one functional allele of CBP (a histone acetyl transferase), the TMS-perturbed schizophrenia network behaved like a
or pharmacologically, by infusing low-dose theophylline (an random network.
HDAC stimulator) to the nAC. Nicotine enhances the effects of Conclusions: 7TMS perturbations applied to the schizo-
cocaine only when it is administered for several days prior to phrenia network lead to an abnormal increase in effective
cocaine treatment and is given concurrently with cocaine. A connectivity and shift the network to a random-like network
new analysis of epidemiological data indicates that the majority dynamics.
of cocaine users initiate cocaine use while still smoking active-
ly, and that initiation of cocaine after smoking increases the risk Font size effect on risk preferences
of becoming dependent on cocaine compared with initiation Levy DJ* 1,2
1
prior to smoking. The HDAC inhibitory properties of nicotine Marketing Dept., Faculty of Management, Tel-Aviv University
2
provide a possible molecular mechanism for the Gateway Sagol School of Neuroscience, Tel-Aviv University
Hypothesis.
Background: Many things influence risk preferences such
Impaired network stability in Schizophrenia as the magnitude of the reward to be chosen, its probability
Arzouan Y 1, Moses E 2, Peled A 3,4, Levit-Binnun N* 1 to occur and even the current and global wealth of the
1
Unit of Applied Neuroscience, Interdisciplinary Center, decision maker. Other more context dependent effects and
Herzliya, Israel 2Dept. of Physics of Complex Systems, higher order cognitive effects like reference points, stress,
Weizmann Institute of Science, Rehovot, Israel 3Institute framing of the questions and even the subject's internal state
for Psychiatric Studies, Sha’ar Menashe Mental Health have been found to influence risk preferences. However,
Center, Hadera, Israel 4Ruth and Bruce Rappaport Faculty much less is known if and how low-level sensory attributes
of Medicine, Technion, Israel influence risk preferences. In this study we examined the
effect of a low level visual attribute on subjects' risk
Background: Schizophrenia is a serious mental illness preferences.
that has been mostly studied from a bottom-up, biolog- Methods: Subjects were asked to choose between a certain
ical, anatomical, or neuropsychological approach. Re- small monetary reward ('reference') and a stated probability
cently, the urgent need for top-down approaches has of either winning a larger amount of money or getting
become evident, since abnormalities in global, emergent nothing ('lottery'). In all trials the reference option was
brain properties such as connectivity have been impli- always the same font size (22-meduim) while the lottery
cated in schizophrenia. Indeed, a growing body of work option could take one of three different font sizes: 18-small,
is concentrating on global network metrics and on dy- 22-medium, or 27-large. Subjects faced the same choice
namic systems computations to characterize abnormali- options for all three font sizes. From these trials we estimated
ties in schizophrenia. Recently, we have undertaken a each subject's risk preferences for each off the three font sizes.
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S71
Results: We found a systematic effect of font size on risk Conclusions: Elevation of SRA enhances EAE progression
preferences. As the font size of the lottery option increased by expresing SRA on APCs to CD4+ T-cells and increases
the propensity to choose the lottery option increased. Inter- their proliferation. Further studies of SRA-mediated cellular
estingly, this effect was still evident even after we controlled pathways in APCs may offer useful insights into the devel-
for the difference in reaction times between the three opment of MS and other autoimmune diseases, providing
conditions. future avenues for therapeutic intervention.
Conclusions: A low level visual attribute affected subjects'
risky behavior. This suggests that brain areas that encode Do past negative life events affect generalization learning
low-level visual attributes participate in value representation and symptoms improvement after cognitive behavioral
and choice. However, further studies need to be conducted therapy (CBT) in individuals with post traumatic stress
using additional visual attributes like contrast, and frequen- disorder (PTSD)?
cy, inside the fMRI scanner to examine if the effect we Levy-Gigi E* 1,2, Richter-Levin G 1, Kéri S 3,4
1
observed is because value is represented already at the level University of Haifa, Center of Affective Neuroscience, Haifa,
of sensory areas or rather the sensory areas send sensory Israel. 2National Psychiatry Center, Budapest, Hungary.
3
information to value areas per se. National Psychiatry Center, Budapest, Hungary 4Universi-
ty of Szeged, Faculty of Medicine, Dept. of Physiology,
Scavenger receptor A enhances disease progression Szeged, Hungary.
in MS mouse model through CD4+ T-cells activation
Levy-Barazany H. 1, Frenkel D* 1,2 Our previous studies have shown that Individuals with
1
Dept. of Neurobiology, George S. Wise Faculty of Life PTSD have a selective impairment in generalization learn-
Sciences, Tel Aviv University, Tel Aviv, Israel 2Sagol School ing. Most treatments for PTSD patients involve CBT. This
of Neuroscience, Tel Aviv University, Tel Aviv, Israel method is based on principles of associative learning and
generalization. Individual differences in generalization
Background: Multiple sclerosis (MS) is an autoimmune learning may influence the degree to which different PTSD
disease of the central nervous system (CNS) characterized patients are likely to benefit from CBT. The aim of the
by damage to the neuronal myelin sheath. The class A present study was to test the connection between general-
scavenger receptor (SRA), constitutively expressed on ization learning and responsiveness to CBT, and its correla-
antigen-presenting cells (APCs) in peripheral tissues and tion with past negative life events. We used a novel
the CNS, was shown to play a role in the phagocytosis of generalization task. The first phase of the task includes a
myelin; however, the role of SRA in the development of discrimination learning procedure in which stimuli consist-
experimental autoimmune encephalomyelitis (EAE) and au- ing of a cue and a context predict a specific outcome
toimmune reaction in the periphery has not yet been studied. (reward/punishment). In the subsequent reversal phase,
We measured the clinical score of EAE induced C57BL/6- there are two possibilities: (1) the cue is unchanged but
WT and SRA-/- mice and characterized CNS pathology appears in a new context; (2) a new cue is presented in the
using immunohistology staining. Furthermore we assessed original context. The new stimuli are associated with the
pro-inflammatory cytokine response in cell cultures and opposite outcome relative to the stimuli in the first phase.
measured SRA expression levels using RT-PCR and immu- Participants must reverse the original discrimination rule in
nohistochemistry; order to adapt to the new condition. 30 PTSD and 30
Results: We discovered that EAE progression and CNS trauma-exposed non-PTSD participants were tested in two
demyelination were significantly reduced in SRA-/-mice points of time. Participants with PTSD had significantly
compared to WT mice. In addition, there was a reduction more negative life events prior to trauma exposure com-
in infiltrating peripheral immune cells into the CNS lesion pared to trauma-exposed non-PTSD participants. These
of SRA-/- mice, which was associated with reduced astro- results may suggest that a history of negative events increases
gliosis. Immunological assessment showed that SRA defi- risk for later PTSD. In addition, as predicted PTSD partic-
ciency resulted in significant reduction of pro-inflammatory ipants showed a significant deficit in generalization
cytokines, such as IL-2, IFN-γ, IL-17 and IL-6. Further- learning specifically when had to reverse aversive con-
more, we discovered that SRA-/- APCs showed impairment text. At this stage all PTSD participants went through a three
in activation and in their ability to induce CD4+ T cell months of CBT including a total of 24 45-minutes individual
proliferation. Recently, we have shown development of sessions. Improvement was defined as a reduction of 50 % in
brain lesions in EAE induced non obies dibetic (NOD) mice PTSD symptoms as measured by the Clinician-Administered
(Levy et al 2010). Here we present an increase in SRA PTSD Scale (CAPS). Results show a possible connection
expression in infiltrated cells surrounding the brain lesion between past negative life events, generalization learning
in these mice. and symptoms improvement after CBT.
S72 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
Translational and genomic approaches to obesity, benefit by training with specific structural regularities, we
depression and their interface now ask whether learning transfers to novel contexts. Namely,
Licinio J* whether regularity is a means for facilitating a broader learn-
John Curtin School of Medical Research, The Australian ing process (like a gating mechanism) or, whether learning is
National University, Canberra, Australia specific to the trained regularity. Participants were randomly
divided to 6 groups, each practicing the same task and same
Drugs have been used by individual clinicians and medical stimuli and procedure, but with different proportions of trials
areas to treat all sorts of ailments for millennia. After World with Ref 1st versus Ref 2nd (0, 20 %, 50 %, 80 %, 100 %, and
War II the emergence of an organized academic medical without reference). After completing a 300 trials training
discipline of pharmacology led to a revolution in therapeutics. stage, they were all tested (in the following 100 trials) on the
Likewise, translation of discovery into treatments occurs daily same task 50 % Ref 1st and 50 % 2nd trials. Performance in
throughout the world as the outcome of cottage industries Ref 1st trials improved linearly across groups as the number of
working in a highly fragmented manner. The efficiency of Ref 1st trials increased, regardless of the intervening Ref 2nd
translational outcomes must be optimized. There is an emerg- trials. Although performance was maximally improved when
ing concept worldwide that as its logical outcome would lead training with Ref1 only, this improvement was structure spe-
to the creation of translational science as a novel bona fide, cific, and was substantially hampered in the test phase (50-
self-standing academic medical discipline aimed at facilitating 50). Performance in Ref 2nd trials improved only when there
and fostering translational outcomes across the full spectrum were no intervening Ref 1st trials (i.e. 100 % ref 2nd), but
of medicine, in integration with pharmacogenomics aimed at showed more transfer to the mixed condition. Our inability to
improving and personalizing treatment outcomes. In our own obtain low thresholds in both structures suggests that the
work we have focused on two common and complex diseases mechanisms "seeking" structure are competitive, biased in
of gene environment-interactions, depression and obesi- favor of the Reference 1st structure. Training with "favorable"
ty, as well as their interface, as case examples of how structures, as evident by their quick improvement, may block
to approach translation both from bench to bedside and the improvement with other structures.
bedside to bench. This work includes novel and provoc-
ative findings on the phenomenon of antidepressant- The role of TGF-β signaling in mediating cerebrovascular
induced weight gain. In these two disorders that are pathology: from cell culture to mouse model
rare cases with a strong genetic basis and other cases Lifshitz V 1, Levkov J 1, Shapira K 1, Ashatkina D 1, Galron
of clear environmental impact. We need to reframe the R 1, Henis Y.1, Frenkel D* 1,2
1
continuum of gene-environment interactions in the Dept. of Neurobiology, Faculty of Life Sciences, Tel Aviv
causes and treatments of common and complex diseases University, Tel Aviv, ,. 2Sagol School of Neuroscience, Tel
from a challenge to an opportunity for a variety of Aviv University, Tel Aviv, Tel Aviv,
exciting translational approaches that will lead to better
and personalized preventive and treatment strategies. Background: The accumulation of amyloid deposits on the
cerebral blood vessels, known as cerebral amyloid angiopathy
Learning 2–tone frequency discrimination – is fast (CAA), is associated with cognitive decline and is one of the
improvement an indication of success or a cause hallmarks of Alzheimer's disease (AD) pathology. Transform-
of alarm? ing growth factor beta 1 (TGF-β1) expression levels correlate
Lieder I 1,2,3, Jaffe-Dax S 1,2,3, Go A 3, Ahissar M* 1,2,3,4 positively with the degree of cerebrovascular amyloid in AD
1
Edmond and Lilly Safra Center for Brain Sciences, Hebrew cases. Furthermore, expression of TGF-β1 under GFAP pro-
University of Jerusalem 2Interdisciplinary Center for Neural moter in mice leads to an age-related deposition of amyloid,
Computation, Hebrew University of Jerusalem 3Dept. of such as β-amyloid (Aβ), around cerebral blood vessels. We
Psychology 4Dept. of Neurobiolody, Hebrew University of aim to define the role of TGF-β1 in mediating endothelial
Jerusalem cells pathology related to CAA.
Methods: We isolated EC from CAA mouse model and
Two-tone discrimination is traditionally viewed as a simple human CAA patients in order to target EC genes that related
discrimination task. However, it was recently shown that its to CAA pathology. We applied shRNA approach in mouse EC
performance varies substantially with the implicit strategy cell line in order to identify the contribution of different TGF-
chosen by listeners. Introducing regularities, such that a β1/Smad dependent signaling in ECs.
reference tone is presented in a fixed position (first or second Results: Using specific endothelial cells gene array we have
in every trial), enables listeners to categorize the informative identified genes that are regulated by TGF-β1 and may play a
tone rather than compare the tones, leading to substantially role in disease progression in a mouse model with CAA pathol-
improved discrimination ability. Having found that we can ogy. Using shRNA Smad2 and specific inhibitor we have shown
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S73
the important role of Smad1/5/8 pathway in mediating changes use gene expression measures from in situ hybridization
in the selected genes in EC line and in TGF-β1 mouse model. across the full developing mouse brain to quantify the
Conclusion: We suggest the important role of TGF-β1- specialization of regional gene expression profiles.
Smad1/5/8 signaling in the progression of CAA and we Results: We quantified expression specialization as the dis-
identify new target genes that may be used for future ther- similarity in expression profiles across brain regions and
apeutic intervention or for early diagnosis of CAA. looked at dissimilarity dynamics over development. Surpris-
Alzheimer's association, HFSP and ISF ingly, during the time that the brain becomes anatomically
regionalized in early development, its transcription special-
Repeated checking primes inhibition in healthy ization decreases, reaching a low point around birth, and
participants then rises postnatally. This hourglass shaped profile spans
Linkovski O* 1,2, Kalanthroff E 1, Anholt G 2,3, Henik A 1 many genes and brain regions. The early decrease of spe-
1
Dept. of Psychology and Zlotowski Center for Neurosci- cialization is mainly due to biological processes that are
ence, Ben-Gurion University of Negev, Beer Sheva, Israel involved in constructing brain circuitry, like axon guidance,
2
Dept. of Psychology, Ben-Gurion University of Negev, Beer while the rising post natal specialization is largely at-
Sheva, Israel3Dept. of Psychiatry and Institute for Research tributed to plasticity and neural activity processes. Post
in Extramural Medicine, VU-University Medical Center and natal specialization is particularly significant in the cer-
Academic Outpatient Clinic for Anxiety Disorders, GGZ ebellum, whose expression signature becomes increas-
InGeest, Amsterdam, the Netherlands ingly different from other brain regions. This effect is
also observed in the human cerebellum during the par-
Repeated checking is a common symptom of Obsessive allel developmental period.
Compulsive Disorder (OCD)—an anxiety disorder charac- Conclusions: Neural transcriptome diversity is minimized
terized by intrusive thoughts that are followed by compul- around birth, due to reduction of spatial divergence of genes
sive acts aimed to reduce anxiety. Various studies used a important in nervous system structure and function. The fact
repeated-checking manipulation to demonstrate that relevant that the cerebellum mostly develops after birth and becomes
checking affects subjective memory but does not harm functional following post-natal inputs is reflected in an
memory accuracy. This effect of repeated checking was abrupt change in its gene expression profiles, and a similar
found to be larger in individuals with poor inhibitory con- trend is observed in parallel human data, suggesting that
trol. The current study aimed to reveal how repeated check- similar specialization profiles of brain development may be
ing affects inhibition. Two groups of healthy participants abundant in mammals.
completed either a repeated-checking task or a simple de-
tection task. Both tasks were followed by a stop-signal task Convolution models for induced electromagnetic
designed to measure inhibition of a pre-potent response. responses
Results revealed that the repeated-checking task improved Litvak V*, Jha A, Flandin G, Karl Friston K
performance of the stop signal. It can be assumed that at The Wellcome Trust Centre for Neuroimaging, UCL Institute
least in healthy participants, repeated checking primes inhi- of Neurology, London, UK, WC1N 3BG
bition, thus making easier for the participants to recruit
cognitive control in the stop-signal task. Implications for Time-frequency analysis is a widely used method for study-
neuropsychological characteristics and theories of OCD are ing event-related (induced) neural responses. Conventional-
discussed. ly, event-specific time-frequency images are computed by
Meloul Desiree averaging time-frequency decompositions of data epoched
around the event in question. However, averaging of this
Dynamics of gene expression divergence during mammalian sort fails when the induced responses overlap or when there
brain development follow an 'hourglass' shape are multiple response components that have variable timing
Liscovitch N, Chechik G* within each trial (for example stimulus and response com-
Gonda Multidisciplinary Brain Research Center, Bar Ilan ponents associated with different reaction times). In these
University situations, it is advantageous to estimate response compo-
nents using a convolution model of the sort that is standard
Background: The transcriptome of the brain changes dur- in the analysis of fMRI time series. Here we describe one
ing development and across brain regions, reflecting pro- such approach, based upon ordinary least squares deconvo-
cesses that determine the structure and function of its lution of induced responses to input functions encoding the
circuitry. Despite the importance of these changes, little is onset of different components within each trial. There are a
still known about how brain regions become specialized in number of fundamental advantages to this approach: for
terms of their transcription profiles during development. We example; (i) one can disambiguate induced responses
S74 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
to stimulus onsets and variably timed responses; (ii) one neurons. This approach allows us to address fundamental
can test for the modulation of induced responses – over questions in the field of adult neurogenesis – do ABNs
peristimulus time and frequency – by parametric experimental mature to become like resident neurons, or do they form
factors and (iii) one can gracefully handle confounds – such as a special subpopulation? Does their contribution to odor
slow drifts in power – by including them in the model. We coding change as they mature? We find that ABNs
illustrate the utility of deconvolution estimators using simu- clearly respond to sensory stimuli, suggesting that they
lated and real MEG data. are an integral part of OB odor coding. Their sponta-
The Wellcome Trust funded this work neous firing characteristics do not substantially change
during the final stages of development. In contrast, we
Self-monitoring of social facial expressions find that odor responsiveness and selectivity reach a
in the primate amygdala and cingulate cortex peak during the final stages of development, and then
Livneh U, Resnik J , Shohat Y , Paz R eventually become similar to that of resident neurons.
Neurobiology Dept. Weizmann Institute of Science Our results suggest that ABNs mature to become like
any other OB neuron. The heightened responsiveness
Keeping track of self-executed facial expressions is essential and selectivity during development suggest that they
for the ability to correctly interpret and reciprocate social contribute differently to odor coding as they mature,
expressions. Yet, little is known about neural mechanisms and might also subserve an experience-dependent mech-
that participate in self-monitoring of facial expression. We anism of survival.
designed a natural paradigm for social interactions where a
monkey is seated in front of a peer monkey that is concealed Effect of injury severity on brain activation patterns
by an opaque LCD shutter positioned between them. Open- in survivors of traumatic brain injury: an fMRI study
ing the shutter for short durations allowed the monkeys to Livny-Ezer A* 1,2,3, Weiser M 4,3, Kushnir T 2,3, Harnof S 5,
see each other and encouraged facial communication. In Tomasi D 6, Hoffman C 2, Biegon A 6
1
order to explore neural mechanisms that participate in self- J. Sagol Neuroscience Center, Sheba Medical Center, Tel
monitoring of facial expression we simultaneously recorded Hashomer 2Diagnostic Imaging Dept., MRI Unit, Sheba
the elicited natural facial interactions and the neural activity Medical Center, Tel Hashomer 3Sackler Faculty of Medicine,
of single neurons in the amygdala and the dorsal-anterior- Tel Aviv University 4Dept. of Psychiatry, Sheba Medical
cingulate-cortex (dACC), two regions that are implicated Center, Tel Hashomer 5 Dept. of Neurosurgery, Sheba
with decoding of others' gestures. Neural activity in both Medical Center, Tel Hashomer 6 Brookhaven National
regions was temporally locked to distinctive facial gestures Laboratory, USA
and close inspection of time-lags revealed activity that either
preceded (production) or lagged (monitor) initiation of facial Survivors of Traumatic brain injury (TBI) suffer from a
expressions. This result indicates that single neurons in the range of cognitive deficits. Our objective was to assess
dACC and the amygdala hold information about self-executed the influence of injury severity determined by initial
facial expressions and demonstrates an intimate overlap be- Glasgow Coma Scale (GCS) on patterns of brain acti-
tween the neural networks that participate in decoding and vation during a working memory (WM) task in TBI
production of socially informative facial information. survivors compared to age and sex matched healthy
controls.
In vivo sensory physiology of adult-born neurons Brain activations were assessed with functional magnetic
Livneh Y 1, Mizrahi A* 1,2 resonance imaging (fMRI) using a 3 T MRI system (GE,
1
Dept. of Neurobiol., Inst. of Life Sciences, The Hebrew University HDxt). Twelve mild (mTBI), 10 moderate-severe
of Jerusalem 2The Edmond and Lily Safra Center For Brain (msTBI) patients and 19 controls were scanned while
Sciences (ELSC), The Hebrew University of Jerusalem performing an N-back task for letters. The task (0-, 1-
and 2-back conditions) was presented using E-Prime
The adult mammalian olfactory bulb (OB) is supplied with software and results were analyzed using SPM8. Activa-
adult-born neurons (ABNs) throughout life. ABNs are tions in the low memory load (1-back vs 0-back condi-
thought to have a special role in OB plasticity. However, their tion, p Overall, activation patterns were more dispersed
actual involvement in odor processing remains elusive, partly and less lateralized in the TBI groups compared to con-
because even the basic odor response profiles of ABNs have trols. These results indicate that TBI severity influences
never been documented. Here, we provide the first character- the pattern of brain activation, with moderate-severe but
ization of odor responses of ABNs in the mouse OB. To do so, not mild head injury associated with more dispersed and
we performed in vivo two-photon-targeted juxtacellular less lateralized activations in response to a WM task
recordings from virally labeled ABNs, and resident OB compared to healthy controls.
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S75
phenotypes. The anti-apoE4 mAbs were injected to apoE synaptic weights are characterized by a unimodal distribution.
targeted replacement (TR) mice in a preventive paradigm Above this point, the stability of the STDP dynamics is gov-
(10 weekly i.p injections of the mAbs, starting post- erned by the synaptic weight dependence of the STDP rule. In
weaning) and in a treatment paradigm (3 i.p injections of the latter case there is a different parameter with a critical value,
the anti-apoE4 mAbs, prior to sacrifice at 4 months old). above which, a bimodal synaptic weight distribution exists. We
Results: Examination of naïve 4 months old apoE4 mice show that the location of these critical points depends on
revealed distinct hippocampal pathologies, including tau general properties of the temporal structure of the STDP rule
hyperphosphorylation, Aβ neuronal accumulation, synaptic and not on its fine details. These results hold for both excitatory
impairments as well as behavioral deficits. The anti-apoE4 and inhibitory synapses. The symmetry in the learning dynam-
preventive approach revealed that weekly i.p injections of the ics of excitatory and inhibitory synapses is discussed.
anti-apoE4 mAbs to 1 month old mice, for 3 months, pre-
vented the tau hyperphosphorylation and partially reduced the Thrombin: a novel regulator of synaptic plasticity
Aβ neuronal accumulation in hippocampal neurons. In con- in the hippocampus
trast, the excitatory marker VGluT1 decrease in the apoE4 Maggio N* 1, Itsekson Z 1,2, Dominissini D 1,2, Blatt I 1,
mice was not affected by the injections. Preliminary results Amariglio N 1, Rechavi G 1,2, Chapman J 1,2
1
utilizing the treatment paradigm demonstrated that the apoE4 The Chaim Sheba Medical Center 2Tel Aviv University
associated Aβ accumulation can be reversed by 3 weekly i.p
injections of the anti-apoE4 mAbs, prior to sacrifice at Background: Thrombin, a serine protease involved in the
4 months old. The effects of treatment by the mAbs on tau, coagulation cascade has been recently shown to affect neuronal
VGlut1 and other markers are currently being investigated. function following blood brain barrier breakdown, therefore
Conclusion: i.p injected anti-apoE4 mAbs counteract the contributing to the stroke pathology. Several lines of evidence
pathological effects of apoE4 in TR mice. This suggests a have shown that thrombin may exist in the brain parenchyma
novel therapeutic approach for treatment of apoE4 carriers under normal physiological conditions, yet its role in normal
in AD and in other acute and chronic diseases. brain functions and synaptic transmission has not been estab-
lished. In an attempt to shed light on the physiological functions
The effect of STDP temporal window structure of thrombin and Proteases Activated Receptor 1 (PAR1) in the
on the learning dynamics of single excitatory brain, we studied the effects of thrombin and a PAR1 agonist on
and inhibitory synapses long term potentiation (LTP) in mice hippocampal slices.
Luz Y, Shamir M* Results: Surprisingly, different concentrations of thrombin
Dept. of Physiology and Neurobiology, Ben-Gurion University affect LTP through different molecular routes converging on
PAR1. High thrombin concentrations induced a NMDA
Spike-Timing Dependent Plasticity (STDP) is characterized dependent, slow onset LTP, whereas low concentrations of
by a wide range of temporal learning patterns, depending on Thrombin promoted a VGCCs, mGluRs dependent LTP
the studied network and the experimental conditions. These through activated Protein C (aPC). Remarkably, aPC facil-
characteristic patterns represent the change in the measured itated LTP by activating PAR-1 through an Endothelial
post-synaptic potentials or currents as a function of the forced Protein C Receptor (EPCR)-mediated mechanism which
time interval (Δt) between pre- and postsynaptic spikes during involves intracellular calcium stores.
the experiment. Long Term Potentiation (LTP) is marked by a Conclusions: These findings reveal a novel mechanism by
positive sign of the characteristic function and Long Term which PAR-1 may regulate the threshold for synaptic plastic-
Depression (LTD) by a negative sign. It is a common practice ity in the hippocampus and provide additional insights into the
to define this function in segments of the time interval – role of this receptor in normal and pathological conditions.
typically in two segments, one for positive Δt (the causal
branch) and the other for negative Δt (the acausal branch). Activity dependent neuroprotective protein (ADNP)
Here we suggest a model in which this pattern is constructed as an erythropoiesis regulator
from a superposition of two separate processes one for the LTP Malishkevich A1, Arviv C1, Dresner E1, Gozes I1 2 3
1
and the other for the LTD. We approximate these two functional Sackler Faculty of Medicine, 2Adams Super Center Brain
branches using a continuous non-segmented “probability like” Studies; 3Sagol Neuroscience School, Tel Aviv Univ., Israel
function that captures the essential features of the STDP. We
demonstrate how the various experimentally observed STDP The highly conserved Activity-Dependent Neuroprotective
temporal structures can be obtained by a gradual change of a Protein (ADNP) is a member of a novel protein family,
single continuous parameter in our model. Analysis of the containing zinc-finger motifs and a homeodomain profile.
STDP dynamics reveals a critical point. Below this critical point During mouse embryogenesis, ADNP was identified as
the STDP dynamics is governed by a negative feedback and the essential for brain development, and ADNP-knockout mice
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S77
exhibited marked growth retardation, defects in the closure cut-off the gene panel yielded a sensitivity and speci-
of the cranial neural tube, and death at embryonic day ~9.5. ficity in detecting PD of 90.3 and 89.1 respectively and
At embryonic day 9, ADNP was shown to regulate >400 the area under the receiving operating curve (ROC
genes, encoding proteins associated with organogenesis, AUC) was 0.96. patient medication had no significant
neurogenesis and heart development. ADNP was identified effect on the predictive probability (PP) of the classifier for PD
as a chromatin accessory protein, interacting with compo- risk The predictive ability of the model was validated in an
nents of the SWI/SNF chromatin-remodeling complex, in- independent cohort of 30 patients at advanced stage of PD,
cluding Brg1. Previous studies have demonstrated that Brg1 classifying correctly all cases as PD (100 % sensitivity).
is involved in erythropoiesis regulation, and is recruited to Notably, the nominal average value of the PP for PD (0.95
the β-globin locus by selective association with zinc-finger (SD00.09)) in this cohort was higher than that of the early PD
containing transcription factors. As ADNP belongs to the group (0.83 (SD00.22)), suggesting a potential for the model
zinc-finger protein family, we postulated that Brg1 might to assess disease severity. Lastly, the gene panel fully discrim-
mediate the effect of ADNP on erythroid development. Chro- inated between PD and Alzheimer's disease (n029).
matin immunoprecipitation (ChIP) assays revealed, for the Conclusions: The findings provide evidence on the ability
first time, recruitment of ADNP as well as Brg1 to the mouse of a five-gene panel to diagnose early/mild PD, with a
β globin promoter in murine erythroleukemia (MEL) cells. possible diagnostic value for detection of individuals at
However, MEL differentiated cells showed diminished bind- presymptomatic stages, who are good candidates for neuro-
ing ability on the third day after dimethylsulfoxide (DMSO) protective treatment.
treatment compared to control cells that were not exposed to
DMSO. These findings suggest that ADNP plays an important Endocannabinoid-like entities as neuroprotectants
role regulating development, mediating its functions through after traumatic brain injury
transcriptional regulation of various systems involved in or- Mann A, Shohami E*, Mechoulam R, Trembovler V,
ganogenesis, and specifically here, in erythropoiesis. Alexandrovich A
Gildor Chair, Adams Super Center, AMN, CFTAU, Allon The Institute of Drug Research, The Hebrew University of
Therapeutics (IG, Director, Founding Scientist) Jerusalem
A molecular signature in blood for early diagnosis Background: Traumatic brain injury (TBI) is a leading
of Parkinson’s disease cause of death and disability worldwide. It involves two
Mandel SA** 1, Molochnikov L 2, Grünblatt E 3, Bonucelli phases: 1.primary injury: irreversible, direct injury sustained
U 4, Aharon-Peretz J 5, Youdim MB 1, Rabey JM6,2 at the moment of impact including the disruption of brain
1
Eve Topf Center for Neurodegenerative Diseases Research, parenchyma with shearing of blood vessels and brain tissue,
Faculty of Medicine, Technion, Israel 2Sackler School of followed by a sequence of mechanisms which cause further
Medicine, Tel Aviv University, Tel Aviv, Israel 3Neurobio- brain damage, known as: 2.secondary injury, which includes
chemistry Laboratory, University Zurich-Irchel, Zurich, increased cerebral edema and permeability of the BBB,
Switzerland 4Dept. of Neuroscience, University of Pisa, axonal injury and neurodegeneration. In parallel, neuropro-
Pisa, Italy 5Dept. of Neurology, Rambam Medical Center, tective events also take place including the induction of the
Haifa, Israel 6Asaf HaRofeh Medical Center, Dept. of endocannabinoid (eCB) system, whose three main receptors
Neurology, Zerifin, Israel are: CB1, CB2 and TRPV1. Levels of 2-arachidonoyl glyc-
erol (2-AG), an eCB ligand, are elevated after TBI for at
Background: Neurodegenerative diseases like Parkinson's least 24 h. Moreover, treatment with 2AG after TBI was
disease (PD) and Alzheimer's disease (AD) are considered found to improve recovery, reduce edema, lesion volume,
disorders of multifactorial origin, inevitably progressive and BBB permeability and neuronal death. Similar results were
having a long preclinical period. Currently, the clinical obtained after treatment with Arachydonoyl-Serine (Ara-S),
diagnosis of PD can be made when motor symptoms occur, an eCB-like compound belonging to the Fatty Acid-Amino
though the disease has originated several years earlier. Fur- Acids (FAAAs). This study was aimed to investigate the
thermore, at its initial stages PD may be confounded by effect of two novel eCB-like compounds, belonging to the
other diseases, such as essential tremor, multiple system FAAAs, on functional outcome after TBI.
atrophy and progressive supranuclear palsy. Results: Palmitoyl-Serine (Palm-S) and Oleoyl-Serine do not
Results: The transcriptional expression of seven selected directly bind to eCB receptors. Yet, mice treated 1 h after TBI
genes was examined in blood samples from 62 early with these compounds displayed significant improvement of
stage PD patients and 64 healthy age-matched controls. their neurological outcome. Interestingly, the effect of Palm-S
Stepwise multivariate logistic regression analysis identi- was attenuated upon co-application with either CB1, CB2 or
fied five genes as optimal predictors of PD. At a 0.5 TRPV1 antagonists. Along the same line, preliminary
S78 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
results reveal reduced effect of Palm-S on CB2-KO Enhancement of neuronal growth and differentiation
mice. In contrast, when CB2-KO mice were treated with by the conjugation of β-NGF to maghemite nanoparticles
Ara-S, the drug-mediated neuroprotection was further Marcus M 1,2, Skaat H 3,2, Margel S 3,2, Shefi O* 1,2
1
improved, which implies that CB2 may be interfering Faculty of Engineering, Bar Ilan University, Ramat Gan,
to the Ara-S-mediated neuroprotective mechanisms. Israel 2Institute of Nanotechnology and Advanced Materi-
Conclusions: Taken together these findings suggest var- als, Bar Ilan University, Ramat Gan, Israel 3Dept. of Chem-
ied neuroprotective pathways mediated by indirect activa- istry, Bar Ilan University, Ramat Gan, Israel
tion of the eCB receptors by those eCB-like compounds,
following TBI. The ability to control and manipulate neuronal growth has
This study was supported by a NIH grant No. DA-9789 great implications in the tissue engineering field. Growth fac-
tors are critical components in nerve tissue development and
Spatial, temporal and mechanistic characterization repair. The nerve growth factor (β-NGF), a prototypical
of apoptotic death in the developing subventricular zone growth factor, functions as a signaling molecule and stimulates
Marcolino BF, Libby RT, Greene LA the growth, maintenance and survival of certain target neurons.
Univ. of Rochester Med Center, Columbia University In the present study, we describe a new approach to promote
neuronal differentiation and growth, by using a NGF-nano-
Background: We focused on developmental cell death in based tool. PC12 cells, a common model for primary neuronal
the neonatal subventricular zone (SVZ), a region that gen- cells, undergo cellular changes when exposed to β-NGF in
erates neurons and glia. While apoptosis is known to occur vitro, i.e., cease proliferation, grow long neurites, and show
in the SVZ, there is a lack of knowledge regarding its changes in cellular composition associated with neuronal dif-
temporal and spatial occurrence, the cell types affected, ferentiation. We study the effect of β-NGF conjugated to
and underlying mechanisms. maghemite (γ-Fe2O3) nanoparticles, fluorescently labeled, on
Results: Apoptotic cells were identified using immunohis- the growth and differentiation of PC12 cells, compared to the
tochemistry for cell death markers cleaved caspase 3 and free factor. We find that the stabilization of β-NGF by covalent
phospho-H2AX, At p0, the highest proportion of dying conjugation to the maghemite nanoparticles significantly en-
cells, 0.4 %, was in the medial subregion (mSVZ). By p7, hance PC12 neurites outgrowth, compared to free β-NGF at
most apoptotic cells were in the dorsolateral SVZ subregion. the same concentration. We also find an increase in the com-
Thus, the SVZ is a dynamic microenvironment, with a plexity of the branching tree and in the clustering behavior. We
changing distribution of dying cells. Results showed that test several concentrations of nanoparticles and find the effect
almost all dying cells at p0 and p7 are Ki67-, indicating that to be more significant at lower concentrations. Single cell
the apoptotic cells are postmitotic. NeuroD, a neuronal imaging reveals particles accumulation in the soma (but not
marker, was expressed in 69 % of the dying cells in the p0 in the nucleus), in the growth cones and at branching points.
mSVZ, while S100β, an astrocyte marker, and PDGFR We suggest that by covalently binding β-NGF to nanopar-
alpha, an oligodendrocyte marker, were expressed by a ticles, β-NGF's half-life is extended and therefore has a stron-
minority of dying cells. Experiments also showed the ger effect which leads to an increase in PC12 differentiation.
BH3-only proapoptotic protein, Bim, was expressed by
dying cells at p0, but not p7. Bim knockouts revealed Regional differences in the representation of “change”
protection from apoptosis at p0, but not p7. Lastly, we within the Hippocampus
investigated extracellular regulators of apoptosis. Trks are Markus EJ* 1, Schmidt BJ 1,2, Swanson A 1, Satvat E 3,
neurotrophin receptors implicated in SVZ function. We Marrone DF 4
1
found expression of TrkB receptors in the SVZ at p0 and University of Connecticut 2University of Minnesota
3
p7. Injection of a Trk antagonist in the p0 mSVZ resulted in University of Waterloo 4Wilfrid Laurier University
increased apoptotic cell number.
Conclusions: We identify the mSVZ and the dorsolateral SVZ Background: The link between the hippocampus and episodic
as the primary sites of apoptosis in the SVZ at p0 and p7, memory is well known. The hippocampus however, is not a
respectively. Postmitotic neurons are the primary cell type to homogenous structure. Determining the manner in which dif-
undergo cell death. Bim is expressed in the p0 mSVZ and its ferent regions work in parallel and/or interact will provide a
elimination offers transient apoptosis protection. TrkB is better understanding of how information is processed within this
expressed in the p0 and p7 SVZ. Inhibition of Trks in the p0 system. Given the importance of the hippocampus in navigation
mSVZ increases apoptotic cell death. Future studies will look at we provided an "episodic event" that included a "cognitive"
the cell types dying in the p7 SVZ, and the specific Trk involved manipulation (change in strategy/emotion/decision) while con-
in maintaining cell survival in the SVZ. trolling for the trajectory and motor behavior of the rats.
Ford Foundation Fellowship, NIH/NINDS-LGA Results: Using immediate early genes to identify individual cells
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S79
that differentiated between our task manipulations, we found Dietary modification of brain membrane phospholipid
heterogeneity both along the longitudinal axis (dorsal/septal vs. composition and signal transduction
ventral/temporal) and among sub-regions of the hippocampus Martsiano S, Vayman V, Weinstein M, Nachum-Biala Y,
(DG, CA1, CA3). Similarly local field potential recordings show Troen A*
differences in theta frequency, correlation with running speed, Institute of Biochemistry and Nutrition, Faculty of Agriculture,
changes in power and coherence along the longitudinal axis. Hebrew University of Jerusalem
Conclusions: These data support and extend upon previous
reports of regional differences in the hippocampal system. Our Brain microvascular pathology is a common feature of neu-
data indicate that both the dorsal and ventral regions of the rodegenerative disease and cognitive decline. In humans, poor
hippocampus are involved in processing a navigation task. Fur- folate status and elevated blood homocysteine are associated
thermore there may be more integration and cooperation through- with increased risk for these conditions. In animal models,
out the hippocampus with increased hippocampal task demands. folate deficiency has been shown to cause brain microvascular
damage and to decrease adult neurogenesis. These associa-
Optical probing of three-dimensional engineered tions may be due in part to the role of folate and homocysteine
neural-networks metabolism in maintaining normal membrane phospholipid
Marom A 1,2, Dana H 1, Shoham S* 1 composition. Previous work has shown that folate deficiency
1
Faculty of Biomedical Engineering, Technion-Israel Insti- can significantly lower the ratio of phospatidylcholine:
tute of Technology, Haifa, Israel 2The Interdepartmental phsophatidylethanolamine in brain membranes, and that this
Program in Biotechnology, Technion-Israel Institute of change can be mitigated by the addition of methionine to
Technology, Haifa, Israel diet. Methionine also mitigates the cognitive impairment
induced by folate-deficiency, without lowering the concen-
Background: Physiological and pharmacological studies of tration of homocysteine in blood. These findings are con-
the mammalian brain in situ are inherently limited, due to light sistent with the hypothesis that diet-induced alterations in
scattering as well as many other experimental difficulties, membrane-dependent signaling are important determinants
motivating the development of many in vitro preparations. of cognitive dysfunction. This study aims to identify trans-
These in vitro models are typically two-dimensional and thus membrane signaling pathways that are essential for neuronal
provide only a limited similarity to natural physiology. Con- and microvascular function, and which are disrupted by
versely, creating and working with three dimensional (3D), diet-induced changes in membrane composition. Here we
biologically relevant central nervous system (CNS) models focus on Notch protein, a trans-membrane regulator of neu-
also present major challenges, such as selecting a suitable 3D ral and endothelial development and differentiation which
scaffold and developing fast 3D imaging systems. has been implicated in both Alzheimer's and cerebrovascular
Results: In this study we introduce and present the funda- disease. Work is underway to determine the effect of diet-
mental characteristics of a dense 3D neuronal network com- induced changes in brain membrane composition on Notch
posed of rat primary cortical cells embedded in a hydrogel signaling, by measuring changes in pathway activity and
scaffold, and the 3D optical probing of the network using target gene-expression, in relation to diet, membrane compo-
optogenetic probes. The network was transfected with viral sition and other biochemical, anatomical and behavioral
agents for the calcium indicator GCaMP3 and for the light- outcomes. Identifying diet-sensitive signaling pathways
gated channel Channelrhodopsin 2, facilitating the probing in brain will assist in developing diet and drug-based
of a large population of neurons. We monitored the activity interventions for the prevention and treatment of dementia.
of large neuronal populations in our 3D network, using a
fast custom-developed, temporal-focusing based imaging The natural history of Alzheimer’s disease: strategies
system with frame rates of up to 200 Hz. We will present for diagnosis and therapy
the basic characteristics of network activity patterns and Masters Cl
correlations between activity patterns of different cells in Mental Health Research Institute, The University of
the network. Furthermore, we will present viability and Melbourne
immunohistological analysis of the forming networks.
Conclusions: This three-dimensional transparent neural en- Compelling evidence now shows that the Aβ-amyloid peptide
vironment allows optical monitoring and activation of the is the central biochemical marker of Alzheimer's disease (AD),
neural network. Combined with a fast custom-developed, and is the most likely cause of the neurodegeneration manifest
temporal-focusing based imaging system, this tool opens in synaptic dysfunction and eventual neuronal loss.
new opportunities for large-scale neuronal interfacing and Our central interest lies in the mechanism through which Aβ
for applications of 3D engineered networks ranging from undergoes toxic gain-of-function, inducing neuronal damage.
basic neuroscience to the screening of neuroactive substances. This provides the most direct route for therapeutic intervention,
S80 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
with least risk of therapeutic side-effects, since Aβ toxicity is The novel multi-target neuroprotective drug, M30
unlikely to mimic any normal function. Various hypotheses have modulates the insulin signaling pathway in the brain
emerged to explain Aβ toxicity: redox chemistry associated of APP/PS1 double-transgenic Alzheimer’s disease mice
with the Cu metal binding sites on Aβ, zinc-mediated oligomer- Mechlovich D, Amit T, Weinreb O, Bar-Am O, Mandel SA,
ization at glutamatergic synapses and lipid interactions associat- Youdim MB*
ed with the α/β conformation of the hydrophobic C-terminus. Eve Topf Center for Neurodegenerative Diseases Research,
Currently, we are purifying and characterizing the Aβ oligomeric Faculty of Medicine, Technion
species found in human AD brain and blood. The membrane
associated fractions of Aβ may hold the key to understanding the Background: Increasing evidence suggests that dysregula-
complex relationship between the smaller pool of toxic oligo- tion of brain insulin receptor (InsR) and insulin signaling
meric species the larger pool of fibrillar species locked into the cascade are associated with the pathogenesis of Alzheimer's
amyloid plaques and congophilic angiopathy. Assays for moni- disease (AD). Our group has recently designed and synthe-
toring the oligomeric species of Aβ in blood may be useful for sized a series of multifunctional non-toxic, brain permeable
the development of drugs which directly modulate the assembly compounds for AD. One leading multi-target compound, M30
of these oligomers. In vitro, PBT2, an 8-hydroxy-quinoline, has possesses the neuroprotective N-propargyl moiety of our anti-
efficacy in reducing higher order Aβ oligomers. This drug is Parkinsonian drug, monoamine oxidase (MAO)-B inhibitor,
currently in clinical development. rasagiline (Azilect®) and the antioxidant–iron chelating moi-
ety of an 8-hydroxyquinoline derivative of the iron chelator,
The association between creativity and the 7R VK28. Positive outcomes for the neuroprotective effects of
polymorphism in the dopamine receptor M30 were recently obtained in preclinical experimental stud-
D4 gene (DRD4) ies, regarding pathological aspects relevant to ageing and AD.
Mayseless N* 1, Uzefovsky F 2, Shalev I 3, Ebstein R P 2,4, Results: We report a significant increase in brain insulin and
Shamay-Tsoory SG 1 InsR, transcript and protein, respectively and glycogen synthase
1
Dept. of Psychology, University of Haifa 2Dept. of Psycholo- kinase-3β phosphorylation in a double-transgenic (Tg) AD
gy, The Hebrew University of Jerusalem, Jerusalem, Israel mouse model carrying mutations in the amyloid precursor pro-
3
Center for the Study of Rationality and Interactive Decision tein (APP) and presenilin 1 (PS1) genes, systematically treated
Theory, Jerusalem, Israel 4S. Herzog Memorial Hospital, with M30 (1 mg/Kg for 9 months). In addition, we demonstrate
Jerusalem, Israel that M30 up-regulated the levels of hypoxia-inducible factor
(HIF)-1α and expression of its target genes involved in glycol-
Creativity can be defined as the ability to produce ysis, aldolase, enolase-1 and glucose transporter-1 (Glut-1), in
responses which are at the same time novel and appro- the cortex of APP/PS1 mice, compared with vehicle-treated Tg
priate. One approach for assessing creativity is measur- mice. Treatment with M30 also lead to an increase in the hepatic
ing divergent thinking (DT) abilities which involve protein expression levels of InsR and Glut-1 and lowered the
generating multiple novel and meaningful responses to increase in blood glucose levels following glucose tolerance test.
open ended question. DT abilities have been shown to Conclusions: Taken together, the findings suggest that the ben-
be associated with dopaminergic activity and may be eficial effects of M30 on central behavioral and pathological
impaired in attention deficit hyperactivity disorder hallmarks of AD may be associated, at least in part, with the
(ADHD). Given that there is a strong association be- ability of this multifunctional iron chelating drug to regulate
tween the dopamine D4 receptor gene (DRD4) and main brain glucose metabolism parameters.
ADHD, the current study examined the role of a repeat
polymorphism in exon3 of the DRD4 (7R DRD4) in EEG profile of dyslexic readers during a serial reaction
creativity in a group of healthy individuals (N0186). time task.
Scores on two DT tasks (Alternate Uses Task and a Meiri H*, Breznitz Z
subset of the figural Torrance Tests for Creative Think- Edmond J. Safra Brain Research Center for the Study of
ing) were used to assess different aspects of creativity Learning Disabilities, University of Haifa
(fluency, originality). Results showed that individuals
carrying the DRD4-7R allele, as compared to non- Background: Developmental dyslexia is largely character-
carriers, scored significantly lower on tests of divergent ized by a lack of accurate and fluent reading which persists
thinking, and that this effect was evident in all measures into adulthood. Past research has investigated whether or not
of creativity including fluency and originality. The cur- dyslexic readers (DRs) are impaired when performing tasks
rent results support a novel explanatory model of crea- of implicit learning, such as serial reaction time (SRT) tasks.
tivity, which centers upon the role of the dopaminergic However, studies have revealed contradictory findings and
system in divergent thinking. no consensus has been reached on whether or not dyslexic
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S81
readers have a general deficit in implicit learning or if their accumulation of Abeta42 and hyperphosphorylated tau in hip-
difficulties are restricted to reading-related paradigms. Further- pocampal neurons and down regulates the levels of the presyn-
more, the use of EEG has not been employed to understand the aptic glutamate transporter, Vglut1. Weekly i.p. injection of anti
cognitive processing involved during implementation such apoE4 mAbs to one month old mice for three months prevented
tasks. This study used EEG with ERP methodology to compare the accumulation of hyperphosphorylated tau in hippocampal
the performance of dyslexic university students and control neurons of the apoE4 mice and partially reduced the accumu-
participants during an SRT task. lation of neuronal Abeta 42. In contrast the apoE4 driven
Results: DRs experienced a decrease in N170 amplitude over decrease in Vglut1 was not reversed by the anti apoE4 mAbs.
the course of the task, suggesting that they classified the target Conclusions: ApoE4 driven tau hyperphosphorylation of
stimulus as "novel" for a longer duration than did controls. Both hippocampal neurons is prevented by i.p. injection of anti
groups experienced a decrease in latency of the P2 component, apoE4 mAbs. The extent to which such mAbs can also
but only controls exhibited a decrease in amplitude as well. reverse the effects of apoE4 when applied following the
This suggests that early processing of the target stimulus was appearance of the apoE4 phenotype and the degree to which
still relatively effortful for DRs by the end of the task. While up regulation of the levels of apoE4 by Bexarotene modu-
both groups showed a decrease in amplitude for the P3i com- lates the effects of apoE4 will be discussed.
ponent, only the controls showed an amplitude decrease for the
P3ii component. This further implies that stimulus novelty had Theta rhythm alterations during epileptogenesis: a novel
not worn off for the DRs as much as it had for the control group, biomarker for the prediction of seizures
thereby implying that less learning had occurred. Milikovsky DZ 1,2, Weissberg I 1,2, Kamintsky L 1,3,2,
Conclusions: DRs have a specific problem with implicit Bar-Klein G 1,2, Friedman A* 1,2
1
learning when material is presented sequentially. They ex- Dept. of Physiology and Neurobiology, Ben-Gurion
hibit the ability to learn implicitly, but not in the same way University of the Negev, Beer-Sheva, Israel 2Zlotowski
or with the same efficiency as nondyslexic readers. Center for Neuroscience, Ben-Gurion University of the
This study was supported by the Edmond J. Safra Negev, Beer-Sheva, Israel 3Dept. of Biomedical Engineering,
Philanthropic Foundation and the Azrieli Foundation. Ben-Gurion University of the Negev
Development of ApoE4 targeted therapy of Alzheimer's Background: Blood-brain barrier (BBB) dysfunction and
disease. the associated extravasation of serum albumin were demon-
Michaelson DM* 1, Luz I 1, Liraz O 1, Boehm A 1, strated to underlie the induction of epileptogenesis. Here we
Smorodinsky NI 2 explore the potential of electroencephalographic (EEG) fea-
1
Dept. of Neurobiology, The Segol School of Neurobiology tures as biomarkers for epileptogenesis in animal models,
Tel Aviv Israel 69978 2Dept. of Cell Biology and Immunology, aiming to develop a method for identifying at-risk patients.
Tel Aviv University Results: Mice were implanted with epidural electrodes and
intraventricular pump infused either albumin, TGF-β, IL-6 (all
Introduction: Apolipoprotein E4 (apoE4) is the most preva- shown to induce epileptogenesis) for one week. EEG was
lent genetic risk factor of Alzheimer's Disease (AD) and at recorded continuously for 14 days. Mean of relative power in
present there is no apoE4 targeted treatment. The apoE4 risk five frequency bands: θ (3-8 Hz), α(8-12 Hz), β (12-20 Hz), low
for AD may be due to either loss of "good" apoE3 allele(s) or (20-40) and high (30-100) γ, was calculated for every 60 s EEG
to dominant negative effects of the "bad" apoE4 allele. We segment. Linear regression of the means was calculated for day
will presently address the hypothesis that the effects of apoE4 2-4 post surgery. Mice showing seizures within the first 4 days
are mediated via gain of a cytotoxic effects. Accordingly, after treatment were excluded from the analysis. Since θ was
mAbs directed specifically against apoE4, which we have shown by previous studies to be decreased among epileptic
recently prepared, will be injected i.p. into apoE4 and apoE3 animals, we used K-means algorithm to cluster groups of "θ
mice and the extent to which they can counteract the effects of slopes", and a statistical significant difference was revealed be-
apoE4 will be determined. The possibility that elevating the tween epileptic and non-epileptic mice: θ power was unchanged
levels of apoE4 either exacerbates or diminishes the effects of for 13 out of 16 animals without epilepsy (slopes were within a
apoE4 will be assessed utilizing the RXR ligand Bexarotene. tight range around zero), whereas among 10 out of 11 epileptic
The experiments will be performed utilizing young apoE4 and animals, θ slope was outside of this range. A significant inverse
apoE3 targeted replacement mice and an unbiased approach in correlation was found between the rates of θ change and the day
which the effects of apoE4 evolve spontaneously and are not of first seizure. The change in θ was found to be inversely
manipulated via a hypothesis driven paradigm. correlated with changes in power within the high γ band slope.
Results: Experiments uitilizing 4 months old targeted replace- Conclusion: To our knowledge, this is the first study to
ment apoE3 and apoE4 mice revealed that apoE4 triggers the identify a specific EEG pattern as a predictor for
S82 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
epileptogenesis. The similar results obtained in the three not necessarily for unbounded colloids or solutes. Thermal
animal models give hope that such a pattern may be diffusion mixes all molecules by random collisions caused
found in other models of the disease, and could be by the thermal energy. Diffusion is sufficient for material
translated to human studies. distribution in small cells, but it is impractical as means of
transportation through axonal length scales. To the best of
Modulation of synaptic plasticity in the hippocampus our knowledge, no driving force was ever suggested for
by sensory deprivation the transport of axoplasmic molecules that are not attached to
Milshtein H 1,2, Dolev I 1, Amitai Y 3, Slutsky I* 1,2 motor proteins. We suggest that a flow mechanism is central
1
Depatment of Physiology and Pharmacology, Sackler Fac- for the distribution of materials not carried by vesicles. In
ulty of Medicine, Tel Aviv University 2Sagol School of Neu- addition we describe how the active movement of organelles
roscience, Tel Aviv University 3Ben Gurion University of the drags the surrounding fluid, thus inducing a cytoplasmic flow,
Negev, Beer-Sheva, Israel similarly to observations in plant cells. The flow is predicted
to depend mainly on the distribution of microtubules, the
A fundamental feature of neural circuits is the capacity for separation distance between organelles and a few physical
plasticity in response to experience or learning. Primary properties of the axonal external layer.
sensory cortices display a 'critical period' (CP), an early
postnatal epoch of enhanced plasticity during which large- The role of methyl donor nutrition in epigenetic
scale changes in response selectivity can be induced by mechanisms in the brain
changes in sensory experience. Sensory input promotes Nachum-Biala Y, Martsiano S, Vayman V, Weinstein M,
maturation of cortical synapses, while sensory deprivation Troen A*
delays and prolongs CP. Later adult plasticity in sensory Institute of Biochemistry and Nutrition, Faculty of Agriculture,
cortices is limited and depends on attention and behavioral Hebrew University of Jerusalem
outcome. In contrast, hippocampus is known to maintain its
high capacity to undergo activity-dependent synaptic plas- Recent work has shown that experience dependent, revers-
ticity throughout life. While cortical efferents from all major ible epigenetic modification of neuronal DNA (i.e. DNA
sensory areas converge to the hippocampus via the perirhi- methylation) is required for the cellular changes that under-
nal and postrhinal and then the entorhinal cortices, it is lie cognitive function and learning and memory, including
completely unknown whether sensory experience regulates synaptic plasticity and possibly neurogenesis. Dietary fac-
synaptic plasticity in hippocampal networks. tors such as high fat intake, folate deficiency and obesity can
We explored the effect of visual and somatosensory deprivation alter and disrupt DNA methylation in non-neural tissue. In
on synaptic dynamics in hippocampal networks by comparing light of the above, diet has been hypothesized to mediate
synaptic local field potentials in hippocampal slices from control brain function, development and aging through similar epi-
and sensory-deprived animals. Our data show that visual and genetic mechanisms. Nevertheless, the extent to which this
whisker deprivation during the corresponding cortical CP alters occurs remains largely hypothetical. We propose to address
short-term synaptic plasticity in several hippocampal pathways. this hypothesis by examining the effect of dietary folate on
Short-term facilitation in Schaffer Collateral synaptic connections brain DNA methylation and pathways of brain plasticity,
was enhanced by both dark rearing and bilateral whisker trim- using an animal model of folate-dependent cognitive im-
ming. Furthermore, whisker trimming increased synaptic facili- pairment. Our aims are to identify molecular and epigenetic
tation in the medial temporoammonic and lateral perforant changes on neuronal processes responsive to dietary methyl
pathways, while it did not alter synaptic dynamics in the lateral donor availability (i.e. folate deficient (FD) diet) and deter-
temporoammonic and medial perforant pathways. These results mine whether Methionine (Met) supplementation, an essen-
demonstrate that sensory deprivation during cortical CP affects tial amino acid whose metabolic salvage is a product of
hippocampal synaptic processing by promoting short-term syn- folate-dependent metabolism, would ameliorate FD effects.
aptic facilitation in a pathway-specific manner. We observed changes in mRNA levels of TET1 and TET3,
suggesting an alteration of DNA methylation/demethylation
Cytoplasmic flow as a transport mechanism in nerve cells processes in FD rats. In addition, there was a pronounced
Mussel M, Zeevy K*, Nevo U change in genes related to neuronal plasticity (e.g. DCX,
Dept.of Biomedical Engineering, Tel Aviv University VEGF) all of which was restored by adding Met to the diet.
Work is underway to determine the effect of diet-induced
Two mechanisms are believed to participate in the move- changes in total brain DNA methylation pattern. This result
ment of molecules inside the axon: thermal diffusion and gives an initial insight into the effect of nutrition on gene
axonal transport. Axonal transport is an active organized expression related to neuronal plasticity and DNA methyla-
movement for material transportation within vesicles, but tion. An additional investigation is necessary to determine the
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S83
alteration in DNA methylation dynamics as a result of changes The peripheral sensory systems are constantly bombardment
in nutrition and the effect of those on cognitive function. with stimuli, only a fraction of which induce behavioral
responses. A major challenge in behavioral neuroscience is
Towards retinal stimulation with spatio-temporal to predict which stimulus and when will be selected or in
patterns of ultrasound other words to identify the neural mechanisms that gate the
Naor O 1,2, Margalit E 3, Shoham S* 1 sensory information. An emerging hypothesis is that the
1
Faculty of Biomedical Engineering, Technion 2Interdisci- evolutionary role of the superior colliculus, and its avian
plinary center for neural computation, Hebrew University homolog the Optic tecum (OT), is to sort stimuli based on
3
Dept. of Ophthalmology and Visual Science, University of saliency and send this information to the appropriate brain
Nebraska Medical Center, Omaha, NE, USA regions to direct orienting movements, attention and auto-
nomic responses. We tested this hypothesis by recording the
Background: Ultrasound (US) waves are commonly used neural activity in the OT simultaneously with pupil dilation
in many medical applications, but have also been shown to responses (PDRs), a behavioral indicator for stimulus per-
stimulate neurons. These developments open new possibil- ception. We presented long sequences of auditory stimuli
ities for non-invasive modulation of brain activity, however, and correlated on a trial-by-trial basis the fluctuations of the
for applications attempting to mimic physiological activa- PDR with the neural activity in the OT. The main finding
tion patterns, accurately controlled spatio-temporal patterns was that the PDR was correlated with the ongoing activity in
of excitation are required. Our study is aimed at demonstrat- the OT prior to stimulus presentation, but not with the neural
ing US spatio-temporal patterned stimulation of the retina. response itself (post minus pre stimulus onset activity).
Results: We approached the spatially-patterned US field Following this surprising finding, we characterized ongoing
problem by adapting methods from computer generated activity in the OT. We report that ongoing activity was
holography, addressing the generation of sparse and contin- highly variable and was characterized by spontaneous epi-
uous patterns using Gerchberg-Saxton type algorithms. The sodes of high activity. Using dual recordings we show that
algorithms were tested in simulations and resulting fields these episodes were correlated between the OT and the
were measured using serial hydrophone scanning, conclud- entopallium (E), the forebrain recipient of the tectofugal
ing that US spatial distributions may be generated efficient- pathway. Moreover, during episodes of high ongoing activ-
ly. Generalizations of the method, allowing propagation ity the cross-correlations between spike trains in the OT and
through composite media and geometrical constraints have the E tended to increase. These results support the recently
been formulated, bringing the method closer to operation in suggested hypothesis that the coupling between neural ac-
a realistic environment. The US effect on the retina was tivity in the OT and the forebrain is dynamically controlled
studied in-vivo and in-vitro. In-vivo, full-field US pulse and plays a role in gating of sensory signals. The level of
trains were transmitted to eyes of anesthetized rats, while ongoing activity in the OT may reflect an internal state
measuring the evoked potentials (EPs) via subcutaneous during which such coupling is increased.
electrodes. This US stimulation led to significant EPs with The generous support of the Israel Science Foundation is
a power of ~25 % that of flash EPs and no damage was gratefully acknowledged
found to the stimulated retinas. In addition, responses to US
stimulation of the eye were found in local field potentials Antidotal efficacy of MMB-4 compared to other oximes
measured from rat V1. In-vitro, isolated rat retinas were against nerve agents poisoning – in vitro and in vivo
placed on multi-electrode-arrays and excited with either studies
full-field or spatially-patterned US pulse-trains. Preliminary Nili U, Katalan S, Yacov G, Rabinovitz I, Chapman S,
data show responses of the retinas to these stimuli. Raveh L, Bloch-Shilderman E, Amitai G*
Conclusions: Our results indicate that the retina is excitable Dept. of Pharmacology, IIBR, P.O.B 19, 74100, Ness-Ziona,
by acoustic stimulation and that acoustic fields can flexibly Israel
patterned. Thus, vision restoration strategies based on US
excitation of the retina may lead to non-invasive prosthetics. The bisquaternary oxime MMB-4 (methoxime) has been
InSightec LTD., Professor Ido Perlman suggested as an efficacious oxime in the antidotal treatment
against organophosphorus (OP) nerve agents. The in vitro
Ongoing activity in the Optic Tectum is correlated reactivation of various OP-inhibited AChE by MMB-4, 2-
on a trial-by-trial basis with the pupil dilation response PAM, TMB-4, Toxogonin, HI-6 and HLö-7 (pH 07.4,
Netser S, Gutfreund Y* 23oC) was studied. The reactivation kinetics by oximes of
Dept. of physiology and biophysics, the Rappaport faculty AChE inhibited by sarin displayed superiority of MMB-4
of medicine and research Institute, the Technion–Israel compared to Toxogonin, TMB-4 and 2-PAM (kr03.2, 0.17,
institute of technology, Haifa, Israel 0.15 and 0.1 × 103, M-1 min-1, respectively). Further,
S84 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
MMB-4 was found equipotent to TMB-4 but 25-fold faster most likely important parts of the mechanisms underlying
than 2-PAM toward VX-inhibited AChE (kr 01.5 × 103, the beneficial effects of, for example, cardiovascular train-
3.5×103, 60 M-1 min-1, respectively). Non-aged soman- ing and different cognitive challenges on functional recov-
inhibited AChE could be reactivated only by HI-6, HLö-7 ery after stroke. Our work on environmental enrichment
and MMB-4 (kr09.2, 4.7, 0.9×103 M-1 min-1, respective- (EE) post stroke includes a meta-analysis demonstrating
ly). The antidotal efficacy in rats of MMB-4 (M, 25 mg/kg, the effectiveness of EE in experimental stroke, and a pilot
im) was compared to TMB-4 (T, 7.5 mg/kg, im) against clinical trial of EE, which showed significant increases in
sarin poisoning in conjunction with atropine (A, 3 mg/kg, overall, cognitive and social activity in patients exposed to
im) and benactyzine (B, 1 mg/kg, im), following pretreat- an EE. Further, recent data from our population-based stud-
ment (30 min) with pyridostigmine (Pyr, 0.1 mg/kg, im). ies demonstrated that physical fitness is correlated with
The protection ratios (PR) obtained for MAB and TAB, 2.8 cognitive performance and mood. In ongoing studies, we
(2.3-3.3), 1.7 (1.5-2.0), respectively, indicate higher efficacy are currently exploring the effects of a music and rhythm-
of MMB-4 vs. TMB-4. MMB-4 (M) was also used in based intervention in a cohort of stroke patients in chronic
combination with atropine (A) and caramiphen (C, 20 mg/ phase. These and other translational aspects of EE will be
kg, im) (MAC without pretreatment). The MAC mixture, presented and further discussed.
provided higher survival rate than TAB against either 1.5 or
2xLD50 sarin (im). The PR of MAC with Pyr pretreatment Auditory responses and stimulus-specific adaptation
against soman poisoning was higher than TAB, 2.9 (2.5-3.4) in rat auditory cortex are preserved across wakefulness,
vs. 2.0 (1.7-2.4). However, in the absence of Pyr, MAC NREM and REM sleep
displayed similar antidotal efficacy to TAB against soman Nir Y* 1,2, Vyazovski V 1,3, Cirelli C 1, Banks M 4, Tononi G 1
1
poisoning, PR: 1.6 (1.5-1.7), 1.4 (1.2-1.6), respectively. The Dept. of Psychiatry, University of Wisconsin, Madison, WI,
efficacy of MAC and MAB mixtures against VX poisoning 53719, USA 2Dept. of Physiology and Pharmacology, Sack-
displayed remarkably high PR values 72(58-95) and 37(16- ler School of Medicine, and Sagol School of Neuroscience,
85), respectively, vs. TAB and TAC, PR: 25(19-33) and 29 Tel Aviv University, Tel Aviv 69978, Israel 3Dept. of Bio-
(12-70). The antidotal data obtained with sarin and soman chemistry and Physiology, University of Surrey, Guildford,
using MMB-4 instead of TMB-4 could be anticipated from Surrey, GU2 7TE, UK 4Dept. of Anesthesiology, University
the in vitro reactivation data. of Wisconsin, Madison, WI 53706, USA
New approaches to stroke recovery Sleep entails a disconnection from the external environment.
Nillson M* By and large, sensory stimuli do not trigger behavior, are not
Hunter Medical Research Institute (HMRI), University of consciously perceived, and do not induce plastic changes as is
Newcastle and Hunter New England Health, Newcastle, typically the case in wakefulness. It has been suggested that
Australia thalamic 'gating' may disrupt relay of sensory signals, but the
extent of signal propagation along ascending sensory pathways
There is an urgent need to increase the effectiveness of in sleep remains unclear. In this study, neuronal responses in
rehabilitative therapies after stroke. Environmental enrich- core auditory cortex were compared as freely moving WKY
ment (EE), a multimodal approach comprising physical, rats (n06) spontaneously switched between wakefulness and
social and cognitive activity, is very promising as a strategy sleep states. Local field potentials (LFPs), and single-unit ac-
that is broadly deployable. There are very few, if any, tivity (SUA, n0520) were recorded continuously along with
pharmacological or non-pharmacological approaches to EEG, EMG and video for determining vigilance states. In the
stroke recovery that have been shown in experimental stud- first experiment, a wide battery of stimuli included tones, clicks
ies to be as consistently effective as EE. Convincing evi- and click-trains, complex environmental sounds and rat vocal-
dence exists that EE improves cognitive reserve and izations, FM sweeps, and 'chirp AM' tones. Baseline neuronal
functional activity and reduces anxiety-like behaviours in activity showed robust differences between vigilance states
normal rodents and in different disease models. Multimodal (e.g. firing rate in NREM was 80.5 % of that in wakefulness,
stimulation promotes brain plasticity. Studies of brain plas- p<10-43). By contrast, both the selectivity and the magnitude
ticity have traditionally focused neuronal functions, in par- of auditory-evoked responses were comparable across wake-
ticular the roles of the synapse. However, astrocytes, fulness, NREM and REM sleep (non-significant pair-wise dif-
microglia, different progenitors and vasculature are key ferences <8 % between states), and this was confirmed
elements in plasticity and are also profoundly influenced separately for onset, offset, and sustained responses. In a second
by EE. We now also begin to understand how to translate the experiment, the processing of deviant tones was compared in
positive effects of EE in experimental animal research to sleep and wakefulness using an oddball paradigm. Robust
humans. The effects of multisensory stimulation constitute stimulus-specific adaptation (SSA) was observed following
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S85
the onset of repetitive tones, whose strength (>15 %) was Regenerative response of optic nerve axons while using
indistinguishable across vigilance states. a specifically designed hydrogel
These results suggest that responses in core auditory cortex Nitzan A 1, Aviv M 2, Buzhansky L 3, Einav S 4, Nevo Z 2,
are preserved across sleep states, supporting the notion that Gazit E 3, Solomon AS* 1
1
neuronal activity in primary sensory cortices are primarily The Goldschleger Eye Research Institute, Sheba Medical
driven by external physical stimuli. During sleep, a func- Center, Tel Aviv University 2Dept. of Human Molecular
tional disconnection within cortex may possibly prevent this Genetics and Biochemistry, Sackler School of Medicine,
activity to effectively drive high-order cortical regions. Tel Aviv University 3Dept. of Molecular Microbiology and
Funded by NIH Director's Pioneer Award to G.T. and the Biotechnology, George Wise Faculty of Life Science, Tel
HFSPO long term fellowship to Y.N. Aviv University 4Dept. of Biomedical Engineering, Fleisch-
man Faculty of Engineering, Tel Aviv University
Role of the translational machinery in antioxidant-
induced reversal of cocaine psychomotor sensitization Background: Regeneration of the CNS in mammals is lim-
Nisimov E, Kohen R, Yaka R* ited by the generation of physical and chemical inhibitory
Institute for Drug Research (IDR), School of Pharmacy, barriers that are formed following injury and the absence of
Hebrew university Jerusalem positive cues that elicit and guide repair. Hydrogels are con-
sidered to be good materials for CNS repair because of high
It is well known that the use of cocaine cause various oxygen and nutrient permeability and low interfacial tensions.
physiological changes in different organs, including the Hyaluronic acid (HA) is a natural polymer used as a building
CNS. These changes caused severe damage and a variety block for hydrogel formation. This polymer is appealing for
of behavioral effects, and many studies are dedicated for medical use owing to its similarity to the natural extracellular
investigating this phenomenon. In more recent studies, it has matrix (ECM) and to its biocompatible and biodegradable
become evident that oxidative stress plays an important role qualities. Peptide-based scaffolds represent another very im-
in cocaine toxicity and cocaine induced addictive behaviors. portant biocompatible material that can support cell growth.
Previously we have shown that the acute or chronic admin- Results: Hyaluronic acid (HA) based composite containing
istration of cocaine induces massive oxidative stress in self assembled, small peptide nano-tubes (FmocFF) was se-
principle areas of the reward system such as the pre frontal lected for the in vivo study based on its net-like 3D structure.
cortex (PFC) and the nucleus accumbens (NAc). We found Cell culture analysis showed that the composite was non-toxic
that the antioxidant Tempol abolished cocaine-induced ele- and allowed cell attachment. The right optic nerves (ONs) of
vation of oxidative stress in these areas both in vitro and adult rats were completely transected while sparing the vas-
following cocaine injection. Importantly, Tempol at a dose culature and the meninges. The HA-FmocFF composite was
that does not affect the basal levels of locomotor activity, implanted at the lesion site. The control group was implanted
attenuated both the development and expression of cocaine- with 2 % unmixed HA. The HA-FmocFF composite was
induced psychomotor sensitization and prevented the in- found to be non-toxic and biocompatible to the optic nerve,
crease in oxidative stress following withdrawal. We also with no evidence of degeneration. Two months after injury,
found that Tempol increases the phosphorylation of eukaryote immunofluorescence analysis and MRI analysis were pre-
elongation factor 2 (eEF2) in cocaine sensitized rats. However, formed. . In most ONs a small number of axons were found
the molecular mechanism by which Tempol acts remain poorly adjacent to the injury site. However, about a third of the ONs
understood. We therefore hypothesized that antioxidants such treated with the HA-FmocFF composite showed a more
as Tempol exerts their neuroprotective effects via activation of substantial regeneration towards the optic chiasm.
the translational machinery using eEF2 KI mice (D273A), in Conclusions: HA-FmocFF hydrogel appeared to contribute
which the protein is present but defective. more to axonal regeneration than hyaluronic acid alone. Par-
We found an age dependent difference in cocaine psycho- tial regeneration can be achieved with specifically designed
motor sensitization; while adolescent mice showed de- hydrogels, which present the regenerating axons with a rela-
creased in both the development and expression of tively clear pathway and net-like 3D scaffold to maintain their
sensitization compare to their littermates controls, adult progress beyond the lesion site.
mice showed a significant increase in sensitization. These
results suggest that eEF2 indeed play an important role in Neuronal electrical activity patterns depend on the axon
the neuroadaptations that leads to cocaine sensitized re- morphology – analysing the Hodgkin Huxley cable model
sponse and currently we are exploring whether antioxi- Ofer N 1,2, Shefi O 1,2
1
dants such as Tempol acts via this molecular pathway. Faculty of Engineering, Bar Ilan University, Ramat Gan,
National Institute for Psyochobiology in Israel (NIPI) and the 52900. 2Bar Ilan Institute of Nanotechnologies and Ad-
Rosetrees Trust. vanced Materials, Bar Ilan University, Ramat Gan, 52900.
S86 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
The Hodgkin Huxley model which was published in 1952, (143 vs. 113 in untreated mice). Moreover, the treatment
describes the mechanism and principles of electrical con- prolonged the lifespan by 14 % (152 vs. 133 days in untreated
duction of neuronal membranes. This model revolutionized mice). In contrast, transplantation of MPC alone or MPC
our understanding of how the nervous system processes overexpressing just one of the four NTFs did not elicit any
information. The model provides a mathematical depiction improvement. We also found that the supernatant of a condi-
of the formation of the action potential, and its propagation tioned media mixture from MPC populations expressing the
along the axon. Using the Hodgkin Huxley model, we four NTFs increased, in motor neuron cell line (NSC-
explore the axonal response to external current stimuli. We 34), the phosphorylated AKT and BAD by 6-8 fold
investigate the space clamp and cable models and present a compared to MPC expressing a single NTF. We conju-
novel detailed bifurcation analysis. In this study we focus on gated Qdot605 streptavidin to biotinylated GDNF and
two borderline cases of electrical responses. In the first added it to the axon endings of primary motorneurons
regime, a finite number of spikes are generated followed cultured in compartmental microfluidic devices, to study
by constant voltage. We demonstrate that the number of the possible axonal transport to the cell body. Strikingly, we
action potentials is controllable and can be adjusted to any observed that the Qdot-GDNF undergo highly directed axonal
finite number. In the second regime, located between current transport in the retrograde direction and accumulated in the
stimuli that cause a train of action potentials and current cell body compartment.
stimuli that cause single spikes, spike series followed by Conclusion: We built a novel powerful strategy enabling the
failures are generated. We demonstrate the ability to control stable, long-term administration of a cocktail of the four NTFs
the number of action potentials before a failure. For specific factors. The constant release of the critical NTFs from the
current stimulus regimes, chaotic behavior was observed. muscle fibers through the neuromuscular junction into the
In addition, we examine the influence of axonal morphology, motor neuron system and the retrograde transport to the cell
namely the axon radius and branching points, and the influence bodies in spinal cords, probably inhibit death pathways. We
the temperature on activity patterns. The investigation of the hope that our study will lead to a novel strategy to slow down
electrical response for different axonal radii draws on a detailed the progress and alleviate the symptoms of ALS and extend
non-linear analysis of the Hodgkin Huxley cable model. We find the life expectancy and quality of affected patients.
a strong correlation between the axonal radius and the activity The study was partially supported by Muscular Dystrophy
pattern. These two borderline phenomena and the effect of Association (MDA), USA
morphology on the electrical response illustrate ways in which
the pattern of axonal activity can be controlled, and suggest that Automated long-term tracking and analysis of social
this behavior may be instrumental in information coding. The behavior in groups of mice
study of the non-linear behavior of the neuronal electrical re- Ohayon S 1 , Avni O2* , Taylor AL 2, Egnor R 2, Perona P
1
sponse may thus contribute to a better understanding of dynam- Computation and Neural Systems, California Institute of
ical neuronal diseases such as epilepsy and Parkinson's. Technology, 1200 E California Blvd, Pasadena, CA 91125,
USA 2Howard Hughes Medical Institute, Janelia Farm Re-
Cell/gene therapy in a mice model of ALS delay the onset search Campus, 19700 Helix Drive, Ashburn, VA 20147,
of symptoms and prolong lifespan USA
Offen D* 1, Dadon-Nachum M 1, Ben-Zur T 1, Barhum Y 1, 3
Division of Engineering and Applied Science, California
Gluska S. 2, Perlson E 2, Yaffe D 3 Institute of Technology, 1200 E California Blvd, Pasadena,
1
Felsenstein Medical Research Center, Tel Aviv University CA 91125, USA
2
Dept. of Physiology and Pharmacology, Sackler Faculty of
Medicine, Tel Aviv University, Israel. 3 Dept. of Molecular Social interaction in a group of animals has been a difficult area
Cell Biology, Weizmann Institute of Science of study since behavior develops over long periods of time,
requires laborious time consuming manual annotation, and
Background: Neurotrophic factors (NTFs) preserve and suffers from subjective scoring. We present a computer vision
protect motor neuron in ALS mice models. However, clin- based method for tracking multiple mice over long periods of
ical studies administering NTFs in ALS patients have all time (days) without mixing individual identities within the
failed. We have developed muscle progenitor cells (MPCs) group. Our system computes the trajecotry of each individual
population expressing BDNF, GDNF, VEGF or IGF-1. and reconstructs high order statistical ethograms (e.g. relative
MPC populations, each expression one of the four NTFs, posture, preferred locations, following, approaching, etc.).
or a mixture of the four populations was transplanted into These correlates of social interaction can be used to study
the hind legs of ALS (SOD1) mice model. courtship, dominance and aggression, which may develop over
Results: We found that transplantation of the MPC mixture the course of days and may not be observable in acute experi-
significantly delayed the onset of the symptoms by 30 days ments. We show the applicability of our method in studying
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S87
how social hierarchy develops between a group of two males Background: CPF is the most widely used organophosphate
and two females over the course of 5 days. pesticide in the world that can interact with brain acetylcho-
linesterase (AChE) activity. Human and animal studies indi-
Neural control of vascular reactions: the impact of emotion cate that CPF is a developmental neurotoxicant able to cause
and attention early cognitive and behavioral deficits at doses well below the
Okon-Singer H* 1,2,3, Mehnert J 2,4,5, Hoyer J 2, Hellrung L threshold of systemic toxicity. However, the exact mecha-
2
, Dukart J 2,6, Villringer A 2,3,4 nisms of action underlying the developmental neurotoxicity
1
University of Haifa, Israel 2Max Planck Institute for Hu- by which CPF alter brain development are still unclear. In
man Cognitive and Brain Sciences, Leipzig, Germany addition, less attention was paid to the potential risk of sub-
3
Mind and Brain Institute and Berlin School of Mind and toxic dose of OPs during postnatal period and their persistent
Brain, Berlin, Germany 4Charité Universitätsmedizin, Ber- consequences on fear learning in adults. In this study, adult
lin, Germany 5Berlin Institute of Technology, Machine Balb/C and C57 mice pretreated with CPF during early pre-
Learning Dept., Berlin, Germany 6LREN, Département des natal period were tested on cued fear conditioning and on
Neurosciences Cliniques, CHUV, Université de Lausanne, active avoidance learning task. Our objectives were (1) to
Lausanne, Switzerland investigate if repeated subthreshold exposure to CPF disrupts
the expression of acetylcholinesterase splice variants (AChE-
Background: Recent evidence suggests that the brain is S and AChE-R) on pup brains during the critical postnatal
causally involved in the initiation and progress of cardio- period and (2) to determine if early prenatal exposure to CPF
vascular diseases, by failing to regulate blood pressure can alter fear learning in adulthood.
responses to emotional events. This study examines the Results: A sub-toxic dose of CPF (1 mg/kg) was administered
neural regions regulating blood pressure reactions to nega- on post-natal day (PND) 4-10 to Balb/C and C57 mice. No
tive stimuli, and their possible modulation by attention. signs of toxicity and weight changes were shown. In addition,
Methods: 24 healthy subjects (11 females; age024.75± no significant effect was observed on AChE-R and AChE-S
2.49 years) participated in an affective perceptual load task transcript expression in pup brains treated with CPF compared
that manipulated attention to negative/neutral distracting to controls. However, adult Balb/C mice pretreated with CPF
pictures. fMRI data was collected in a 3 T-Siemens scanner failed to learn cue fear conditioning and had a significant lower
simultaneously to continuous recording of peripheral blood rate of learning in the active avoidance task. In contrast, C57
pressure. A parametric modulation analysis examined the mice pretreated with CPF showed facilitated conditioned fear
impact of attention and emotion on the relation between learning and no effect was found in the active avoidance test.
neural activation and blood pressure reactivity in the task. Conclusion: Early exposure to CPF induces persistent long
Results: In attended conditions, distracting negative pic- term effects on fear learning in adult mice, nonetheless, no clear
tures resulted in behavioral interference, neural activation relation was found to the expression of acetylcholinesterase
in an emotion-related network, and a positive correlation mRNA following injection in the immature brain.
between peripheral vascular reactivity and activation in a ISEF Foundation – PhD scholarship from the National
cortico-limbic network. The effects were modulated by atten- Education Foundation.
tion: behavioral and neural responses to highly-negative pic-
tures were smaller or diminished in unattended conditions. Time scale adaptation for evidence integration in human
Conclusions: These results emphasize the role of atten- vision
tion mechanisms in reactions to emotional information. Ossmy O*, Usher M
Thus, the findings suggest that attention can serve as a School of Psychological Sciences, Sagol School of
therapeutic tool for decreasing abnormally enhanced Neuroscience, Tel-Aviv University, Tel Aviv, 69987, Israel
vascular reactions to aversive stimuli, a main risk factor
for cardiovascular diseases. Background and Methods: Recent research in decision-
making has focused on the process of evidence-integration and
Early postnatal exposure to chlorpyrifos caused strain its neural substrate. Converging evidence from experimental
dependent changes in fear learning in adult mice. psychology and neuroscience has revealed that observers accu-
Oriel S 1, Dori A 2, Amar S 3, Kofman O** 1 mulate sensory evidence to a response criterion. The time scale
1
Dept. of Psychology, Ben-Gurion University of the Negev, of this process is reported to go from about half a second to few
Beer-Sheva, IL 84105, Israel. 2Talpiot Medical Leadership seconds. In most studies that examined the integration range, the
Program, Dept. of Neurology and Joseph Sagol Neuroscience evidence stream was stationary. In such conditions the optimal
Center, Sheba Medical Center, Tel Hashomer, IL 52621, strategy is to integrate for as long as the stimulus is available. In
Israel. 3Soroka University Medical Center, Ben-Gurion this study we examined evidence-integration with visual non-
University of the Negev, Beer-Sheva, IL 84105, Israel stationary evidence, subject to temporal uncertainty. 6 observers
S88 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
were presented with 2 circles of fluctuating brightness. During system, a significant curative effect on the behavioral symp-
each 5 sec trial, the brightness fluctuates randomly around a toms of the flies and on a-synuclein aggregation in their brain
baseline (noise), except for a specific interval (t<<5 sec) of observed.
signal, in which one of the spots is brighter, and detection is Conclusions: We conclude that CEppt affect the process of
required. In such a situation integrating for the whole interval is aggregation of a-synuclein without changing its secondary
un-optimal, leading to an excessive integration of noise and structure and suggest that increasing amounts of CEppt
resulting in elevated False Positives. Optimally, the observers slow this process by stabilizing the soluble oligomeric
should adapt the evidence integration time to the time-scale of phase. When administered to Drosophila fly model, CEppt
the signals. To probe for the ability to adapt the integration time- appears to have a curative effect on the defective flies.
scale, we carried out two types of sessions: i)with a predomi- General significance: Our results indicate that CEppt can
nance of long signals (900 ms), and ii) of short-signals (150 ms). be a potential therapeutic agent for Parkinson's disease.
Results: For all observers, hit rates increased monoton-
ically as a function of signal-strength and signal-duration. Mutation in TECPR2 reveals a role for autophagy
Critically, all participants showed time-scale adaptation of in hereditary spastic paraparesis
temporal integration to the characteristic signal duration: bet- Oz-Levi D* 1, Ben-Zeev B 2, Ruzzo EK 3, Hitomi Y 3,
ter accuracy (lower thresholds) in long predominance com- Gelman A 4, Olender T 1, Alkelai A 1, Ben Asher E 1, Elazar
pared to short predominance sessions, on long signals, and Z 4, Goldstein D 3, Pras E 2, Lancet D 1
1
vice versa for short signals. Department of Molecular Genetics, Weizmann Institute of
Conclusions: This study demonstrates that human observers Science, Rehovot, 76100 Israel 2Sheba Medical Center, Tel
can successfully detect signals under conditions of temporal Hashomer, Israel 3Center for Human Genome Variation,
uncertainty by integrating for a time interval that is adapted to Duke University School of Medicine, Durham, North Caro-
the environmental contingencies. lina 27708, USA 4Department of Biological Chemistry,
Weizmann Institute of Science, Rehovot, 76100 Israel
Differential inhibition of a-synuclein oligomeric
and fibrillar assembly in Parkinson disease model We studied five individuals from three Jewish Bukharian
by cinnamon extract families with an apparently autosomal recessive form of
Shaltiel-Karyo R 1 , Davidi D 1 , Frenkel-Pinter M 1, Segal hereditary spastic paraparesis, accompanied by severe intel-
D 1, Gazit E 1, Ovadia M* 2 lectual disability, fluctuating central hypoventilation, gastro-
1
Biotechnology, Faculty of Life Sciences, Tel-Aviv University, esophageal reflux disease, wake apnea, areflexia and unique
2
Zoology, Faculty of Life Sciences, Tel-Aviv University dysmorphic features. Exome sequencing identified one ho-
mozygous variant shared among all affected individuals and
Background: The oligomeriztion of a-synuclein into or- absent in controls, a 1 bp frame shifting deletion in TECPR2
dered assemblies is associated with the symptoms of leading to a premature stop codon and predicting significant
Parkinson’s disease. Yet, it is still debatable whether degradation of the protein. TECPR2 has been reported as a
oligomers are formed as part of a multistep process towards positive regulator of autophagy. We thus examined the
amyloid fibril formation or alternatively as "off-pathway" autophagy-related fate of two key autophagic proteins,
aggregates. SQSTM1 (p62) and MAP1LC3B (LC3) in skin fibroblasts
Methods: 100 mM a-synuclein was incubated with decreas- of an affected individual , as compared to healthy control,
ing amount of cinnamon extract precipitation (CEppt). The and found that both protein levels were decreased, with a
fibril formation was measured using spectroscopy and micros- more pronounced decrease in the lipidated form of LC3
copy and oligomers were detected using blot analysis. The (LC3II). siRNA knockdown of TECPR2 showed similar
secondary structure of the protein was analyzed using CD. changes, consistent with aberrant autophagy. Our results
Brains of the Drosophila we studied using immunostaining are strengthened by the fact that autophagy dysfunction
and confocal microscopy. has been implicated in a number of other neurodegenerative
Results: Here we probed the inhibition pattern of oligomeric diseases. The discovered TECPR2 mutation implicates
and fibrillar forms of a-synuclein, using a natural substance, autophagy, a central intracellular mechanism in spastic
CEppt which was previously shown to effectively inhibit paraparesis.
aggregation of b-amyloid polypeptide. We demonstrated that
CEppt has a differential inhibitory effect on the formation of Conveying the impact of the input from the RMTg
soluble and insoluble aggregates of a-synuclein in vitro. This onto the VTA on cocaine addiction
inhibition pattern revokes the possibility of redirection to "off- Ozeri N, Michaeli A, Yaka R*
pathway" oligomers. When administering to Drosophila fly Institute for Drug Research (IDR), School of Pharmacy,
model expressing mutant A53T a-synuclein in the nervous Hebrew university Jerusalem
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S89
The reward system is of crucial significance in our everyday Methods: Here we present a simple algorithmic approach for
life since it mediates important behaviors for survival. It is data extraction from blurred images acquired by a dual two-
well known that the rewarding effect and the feeling of photon laser scanning-TF microscope, which offers additional
euphoria depend on dopamine levels. Since the ventral information regarding the cells' geometrical location. The algo-
tegmental area (VTA) is the major source for dopamine in rithm uses a forward model of scattering and light propagation to
the reward system and because initiation of drug addiction predict the blurred images acquired by the camera and a regu-
was demonstrated to occur in the VTA, its regulation is of larized inverse solution to reconstruct the underlying activity.
great importance. Recently, focus was shed on the RMTg- a Results: forward model results for increasing scattering depths
midbrain structure that exerts GABAergic input onto the show a gradual degradation of the blurred images quality. Sep-
VTA. Neuronal excitation in the RMTg was observed con- aration between adjacent cells becomes challenging from depth
current with foot shock, leading to the speculation that this of 200 μm and prevents direct analysis of the cells activity
area is involved in the processing of negative rewards. patterns. Simulations show that the use of this algorithm allows
We hypothesize that a temporal coupling between an infu- extraction of activity patterns for depths of more than 700 μm
sion of cocaine and RMTg stimulation will strengthen the inside brain-like tissues, even in cases of severe noise.
GABAergic tone on the VTA, which in turn will interfere Conclusions: We have tackled the major challenge of ap-
with regular synaptic plasticity processes that occur with plying parallel excitation methods inside scattering biolog-
drug reception and partly mediate the formation of addic- ical media that rely on detection by a CCD. The framework
tion. Furthermore, in accordance RMTg's role in the signal- we have developed enables to expand this work to study
ing of negative reward we expect future avoidance from the different tissue characteristics, different optical parameters,
drug. Studying Sprague-Dawley rats, we used optogenetic different noise models, and different inverting and regular-
and behavioral tools to probe the effects of activation of the ization techniques. In addition, the algorithm can be imple-
RMTg while the rats were injected with cocaine. Since the mented for investigating large-scale networks in vivo.
borders of the RMTg are vaguely defined, we injected a
nonspecific channel rhodopsin-containing virus that Improving cell based therapy for Parkinson’s disease
infected a broad area that included the RMTg. Contrary with Parish Cl
our expectations, the stimulation enhanced the preference to the The Florey Institute of Neurosciennce and Mental Health,
place the rats received the drug in the conditioned-place pref- Melbourne Brain Centre, The University of Melbourne
erence (CPP) protocol. Moreover, in a CPP to the stimulus itself
rats preferred the place where they received the stimulus. Our Parkinson's disease is characterized by the progressive de-
results indicate that midbrain posterior areas, including the generation of midbrain dopamine neurons, resulting in mo-
RMTg, provide important input to the VTA and exert a role tor dysfunction. While current therapies are limited, clinical
in the reward system. However, in order to certainly define the trials have demonstrated that new dopamine neurones trans-
impact of RMTg activation on the rewarding effect of cocaine planted directly into the brain can structurally and function-
we will next use further methods for obtaining specificity. ally compensate for those lost in the disease. While
Israel Science Foundation (ISF) and Bretller Center at the providing proof-of-principle, these trials have also shown
School of Pharmacy. extensive variability amongst patients and exposed a number
of caveats in the technology including limited tissue availabil-
Neural activity extraction from blurred light sheet ity, poor cell survival and insufficient reinnervation of target
microscopy images tissues. These hurdles highlight the need for further research,
Paluch S, Elbaz R, Dana H, Shohan S* and provide the foundation for our research. Our focus is on
Faculty of Biomedical Engineering, The Technion – I.I.T., optimising donor material, improving graft survival and pro-
Haifa, Israel moting integration of transplanted dopamine neurons.
In order to tackle these problems we rely heavily on knowl-
Background: Significant enhancement of data acquisition rate edge of developmental biology. How are dopamine neuro-
in functional neuronal microscopy may be obtained by using nes normally born in the developing foetus and what
parallel optical excitation methods, such as multifocal multi- regulates the growth and guidance of their axons to appro-
photon microscopy (MMM), selective plane illumination mi- priate targets? Understanding these processes and exploiting
croscopy (SPIM), and temporal focusing (TF). However, since them in a stem cell transplantation context could significant-
these methods usually detect the fluorescence signal using a ly improve this technology. We are additionally exploring
camera, they are sensitive to tissue scattering effects, which blur the potential for bioengineered scaffolds to promote neural
the images, reduce the spatial resolution, and eventually limit repair. Our research addresses a number of these issues and
the maximal imaging depth. Therefore, an efficient method for adopts diverse approaches to improve and advance the field
de-scattering of the acquired data is needed. of cell transplantation.
S90 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
and synaptic plasticity. Recently, a further downstream mech- Results: To enhance sensitivity for repeated clip presentations
anism of AKT involvement in long-term depression (LTD) we analyzed data from the initial 15 % of the experiments
prevention and late phase long-term potentiation (LTP) has (1:36 min). A novel multivariate machine learning analysis was
been revealed. Moreover, AKT is also known to be involved applied to classify which action sequence each subject performed
in early phase LTP; however no solid knowledge has been prior to entering the scanner, based on the differential response to
accumulated regarding the downstream effectors mediating the two types of videos. This analysis achieved high cross
AKT's effects on LTP. Here, we present our preliminary find- validation accuracy (92 %), signifying a cluster in the Retrosple-
ings describing a mechanism of AKT's effect on LTP. nial Region, as the most informative area for classification.
Results: Using different regimes for application of the AKT Conclusion: We show that it is possible to probe differences
inhibitor A6730 (30 min drug exposure before high frequency related to recently performed actions by using the proposed
stimulation (HFS), drug for 30 min before and 20 min after multivariate approach. This data driven analysis marked a rela-
HFS, drug for 20 min 30 min after HFS), to acute hippocam- tively small cluster in the Retrosplenial Region as most indicative
pal slices trained with the HFS paradigm, we observed that of the prior experience of the subject. The Retrosplenial Cortex
AKT regulates LTP expression without affecting its induction has been shown to be consistently active during the recall of
and maintenance. The effects of AKT inhibition was similar to autobiographic episodic memories (especially recent ones), thus
that of PI3K inhibitors (worthmannin and LY294002). Fur- supporting the memory assumption regarding the neural mech-
ther, we delivered an AKT activator in order to combine with anism that underlies our sense of self-experience recognition and
inhibitors of various signaling pathways to prevent AKT - the maintenance of the "autobiographical self".
induced effect on LTP and to characterize a potential down-
stream mechanism of LTP regulation. Unexpectedly, SC79 (a An odor-dispensing device for the treatment of sleep
novel activator of AKT), which also prevents AKT transloca- apnea
tion to the plasma membrane, induced a significant decrease Perl O 1, Plotkin A 1, Weissbrod A 1, Oksenberg A 2, Vander
in basal synaptic activity and in expression of LTP. T 2, Hairston I 3, Sobel N 1
1
Conclusions: We consider that translocation of AKT towards Dept. of Neurobiology, The Weizmann Institute of Science,
the plasma membrane is necessary for regulation of synaptic Rehovot, Israel 2Loewenstein Rehabilitation Hospital,
activity and LTP. Moreover, AKT related LTP expression is Ra'anana, Israel 3Dept. of Behavioral Sciences, Tel-Aviv
not dependent on downstream cytosolic factors, but is Yaffo Academic College, Tel Aviv, Israel
mediated via direct effects of AKT on post-synaptic
density components and glutamate receptors. Obstructive sleep apnea (OSA) is a prevalent sleep disorder
characterized by repetitive cessation or decreased amplitude
Local brain activity in the retrosplenial region probes of breathing lasting 10s or more. Clinical consequences
our own prior experience cover a wide spectrum of cardiovascular, neurocognitive,
Perez O* 1,2, Jamshy S 2,3,4, Talmor A 3, Intrator N 2,3, and metabolic dysfunction. Current standard of care is con-
Yeshurun Y 2,3, Hendler T 1,2,4,5 tinuous positive airway pressure (CPAP), which is effective
1
Sackler School of Medicine, Tel Aviv University 2Sagol butfsd characterized by low compliance due to encum-
School of Neuroscience, Tel Aviv University 3Blavatnik School brance. Studies of olfactory processing during sleep suggest
of Computer Science, Sackler Faculty of Exact Sciences, Tel that pure olfactory and mildly trigeminal odorants do not
Aviv University 4Functional Brain Center, Tel Aviv Sourasky arouse or wake, but nevertheless induce a sniff response.
Medical Center, Tel Aviv 5Dept. of Psychology, Gordon With this in mind we set out to test the hypothesis that odors
Faculty of Social Sciences, Tel Aviv University can be used to "jump start" respiration during OSA without
waking. We developed a computer-controlled touch-screen-
Background: A neural trace of our recent experiences is interfaced home device that delivers pulses of odorants at
necessary for the sense of reality and continuity in our either fixed intervals, or in response to apnea. Using an array
life. There is an ongoing debate whether the neural of sensors, the device monitors and records nasal and oral
marking of prior experience is mediated by action per- respiration, heart rate, O2 saturation, and snoring. Overall
ception or cognitive-memory systems. The current fMRI activity is monitored by wrist-worn actigraph. The device
study aims to identify the neural trace of recently per- obtains daily subjective measures of sleep quality through
formed actions. an interactive touch-screen, as well as an objective measure
Prior to scanning, 26 subjects performed one of two short derived from a reaction time test. The device is placed in the
action sequences, both in a context of stealing an object participant's home for 2 weeks, recording data for 3 consec-
from a room. Then in the scanner subjects passively viewed utive nights in each week, one week with odors and one
36 short video clips, each describing one of the two action week without (counter-balanced, participants uninformed to
sequences, shown from a self-perspective point of view. order). We used 5 odorants, which were delivered in pulses
S92 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
of 15 s, both in a random order once every 13 minutes, and Forgetting what was where: behavioral, neuropsychological
automatically in response to an apnea. We have studied and neuroimaging investigations
8 individuals of various OSA severity. Odor significantly Pertzov Y*, Husain M
improved reaction time during morning-after tests. Odor UCL Institute of Cognitive Neuroscience & UCL Institute of
reduced apneic events and improved O2 saturation levels Neurology, Queen Square, London, UK
in some of the subjects. Sleep quality and activity reports
suggested odors did not reduce number of wakes. Current An influential view of working memory (WM) proposes
effort is focused on improving the device, as well as replacing that objects are maintained in visual WM as an integrated
some of the odors for the sake of continued experimentation. unit. Therefore, when objects are forgotten they are lost as a
This work was supported by a grant from Johnson & Johnson whole, in their entirety. Here we investigate this claim by
examining how object identity, location and - crucially -
Avoiding a 'close talker': an EEG/ERP study object-location associations are differentially susceptible to
of preferred interpersonal distance (part of a symposium forgetting in healthy people, in patients with focal lesions of
on social behavior) the medial temporal lobe (MTL) and in individuals with
Perry A* 1, Rubinstein O 2, Peled L 1, Shamay-Tsoory S 1 familial Alzheimer's disease. Our studies in healthy individ-
1
Dept. of Psychology, University of Haifa 2Faculty of uals demonstrate that when objects are rapidly forgotten
Education, University of Haifa they do not disappear completely from memory, but rather
it is the links between identity and location that become
Background: Despite the vast knowledge, both behavioral vulnerable over time. When multiple items reside in mem-
and neural, of the mechanisms defining space around a sin- ory for a few seconds, patients with focal MTL lesions were
gular body, little is known about the neural mechanisms that just as likely as controls to identify a previously presented
encode space between bodies. Yet, the space between people item. However, contrary to some prevailing accounts of MTL
creates and defines the social dynamics of our interactions function, they were significantly worse at localizing objects to
with others. Although different between cultures, within each their remembered locations. Crucially, this impairment was
culture interpersonal distance is implicit but clearly felt, espe- specifically associated with a systematic bias to misreport an
cially if one stands nearer or further than expected. To assess object as having previously occupied the location of another
the neural dynamic of interpersonal distance preferences we object in memory. Our findings suggest that when objects are
used a revised version of the Comfortable Interpersonal Distance forgotten they do not vanish from memory but rather the links
paradigm, in which participants imagine either a friend or to their locations are gradually severed. Furthermore, MTL
stranger approaching (visualized on a computer screen) and does not participate in retaining the identity of objects, but it is
are asked to stop the figure when feeling uncomfortable. Be- necessary for binding object identities to their correct loca-
havioral findings in 100 students indicated that preferred inter- tions. These results, supported with parallel fMRI findings,
personal distance is correlated with both measures of empathy provide important evidence for the view that the MTL is not
and of social anxiety. We then used the same paradigm to strictly involved in long-term declarative memory but also
explore how interpersonal distance modulates EEG suppression over far briefer retention intervals in binding object location-
over sensory-motor cortex in the mu/alpha range. Analyzing the identity information. Assessing misbinding of object location
ERPs elicited by the same stimuli, we investigated how early in and identity provides an important new way to diagnose
the perception time-course these factors affect perception. individuals at risk of developing familial Alzheimer, tracking
Results: Mu suppression, a suggested marker of mirror their progress and monitoring response to treatment.
neurons activity, was modulated by the type of figure Supported by The Wellcome Trust and the NIHR BRC at UCL/
approaching (friend or stranger). ERP differences be- UCLH.
tween conditions were evident as early as about
300 ms, as demonstrated by a modulation of P3 by Functional and spatial correlation structure
the same experimental factors. in the primary visual cortex of monkey
Conclusions: Individual differences affect how comfortable Piamenta-Mendels O 1, Kohn A 2,3, Shamir M* 4,5
1
we feel when being approached by a friend or stranger. Dept. of Cognitive Neuroscience, Ben-Gurion University of
These differences are determined early in perception, and the Negev, Be'er-Sheva, Israel 2Dom Purpura Dept. of Neu-
modulate brain regions which have been shown to be en- roscience, Albert Einstein College of Medicine, NY NY USA
3
gaged in understanding other people's actions and inten- Dept. of Ophthalmology and Visual Sciences, Albert
tions. Future studies are planned to look at similar Einstein College of Medicine, NY NY USA 4Dept. of
paradigms with individuals with difficulties in determining Physiology and Neurobiology, Ben-Gurion University of the
appropriate interpersonal distance, such as individuals with Negev, Be'er-Sheva, Israel 5Dept. of Physics, Ben-Gurion
Asperger's syndrome. University of the Negev, Be'er-Sheva, Israel
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S93
Theoretical studies have shown that correlations in the Reciprocal interactions between perceptual learning
trial to trial fluctuations of the neural responses to and adaptation in texture discrimination
external stimuli may limit the information content that Pinchuk-Yacobi N, Sagi D*
can be extracted from the neural responses. Here we use Dept. of Neurobiology, Weizmann Institute of Science, Rehovot,
simultaneous recordings of large neural populations in Israel
the primary visual cortex of monkey to study these
correlations and investigate their effect on the ability Background: Perceptual learning and adaptation are two
of the population response to reliably encode the orien- instances of perceptual plasticity in the visual system. Al-
tation visual stimuli. though the two phenomena are intermixed during the learn-
We find that most cell pairs show significant correla- ing process, the dynamics of the reciprocal interactions
tions. Analysis of the spectrum of the correlation matrix between them is unclear. Intensive training on a texture
reveals a non-trivial correlation structure. However, an- discrimination task (TDT) leads to performance deteriora-
alyzing the accuracy of the population vector and opti- tion which has been suggested to result from stimulus ad-
mal linear readout we find that the considerable noise aptation. This study explicitly examines adaptation in TDT
correlations do not limit their accuracy, in contrast to by measuring (1) behavioral tilt aftereffects (TAE) and (2)
the theoretical prediction. Further analysis of the under- Electroencephalographic (EEG) adaptation effects.
lying structure of the correlations reveals that this non- Results: (1) Intensive training in TDT with a target composed
trivial structure is spatial (i.e., structure that respects the of three bars tilted 20° clockwise from the vertical axis caused
physical position of the neurons) rather than functional a repulsive TAE, in which a near-vertical test bar appeared to
(i.e., structure that respects the stimulus features which be tilted counterclockwise. The TAE was much stronger at the
the neuron is most sensitive for). trained location. (2) Analyzing EEG signals recorded during
Supported in part by the US-Israel BSF (grant 2009302). AK training revealed significant differences in amplitudes of
was funded in part by NIH grant EY016774. early-vision event related potentials (ERP) components be-
tween the early and later phases of within session training. The
Epigenetic inheritance of a cocaine resistance phenotype amplitude of occipital N1 decreased in later training compared
Pierce C* to early training, while the amplitude of posterior P2 in-
University of Pennsylvania creased. The rapid adaptive changes in the amplitudes of the
early ERP components were significantly correlated with the
A rat model was developed in order to delineate a heritable psychophysical discrimination thresholds in the TDT task.
phenotype resulting from the self-administration of cocaine. Thus, more adaptation resulted in higher discrimination
Delayed acquisition and reduced maintenance of cocaine thresholds. Training the next day resulted in reduced adaptive
self-administration was observed in male, but not female, changes in early ERP components.
offspring of sires that self-administered cocaine. Previous Conclusions: Reciprocal interactions between perceptual
work indicated that increased brain derived neurotrophic learning and adaptation exist in TDT. While adaptation dete-
factor (BDNF) in the medial prefrontal cortex (mPFC) riorates performance in TDT, sleep dependent consolidation
blunted the behavioral effects of cocaine. The current results of perceptual learning seems to reduce adaptation effects.
showed enhanced mPFC BDNF mRNA and protein as well
as increased association of acetylated histone H3 with Dominant and submissive mice respond differentially
BDNF promoters only in the male offspring of cocaine- to distinct psychotropic agents
experienced sires. Administration of a BDNF receptor an- Pinhasov A* 1, Nesher E 1,2, Gross M 1,2, Lisson S 1,2, Yadid
tagonist (i.e. the TrkB receptor antagonist ANA-12) reversed G 2, Tikhonov T 1
1
the diminished self-administration of cocaine in male cocaine- Dept. of Molecular Biology, Ariel University Center of
sired rats, which suggests that enhanced BDNF expression in Samaria, Ariel, Israel 2Dept. of Life Science, Bar Ilan
the mPFC reduced cocaine reinforcement in the male off- University, Ramat Gan, Israel
spring of cocaine-experienced sires. In addition, the associa-
tion of acetylated histone H3 with BDNF promoters was Dominance and submissiveness are functional elements sit-
increased in the sperm of sires that self-administered cocaine. uated at opposite poles of the behavioral spectrum which are
Collectively, these findings indicate that voluntary paternal important to the establishment of social hierarchy and to the
ingestion of cocaine results in epigenetic reprograming of the development of social interactions. Research in humans and
germline resulting in profound effects on mPFC gene expres- animals suggests that extreme expressions of dominance
sion and resistance to cocaine reinforcement in male offspring. and submissiveness may be involved in the etiology of
Supported by US National Institute on Drug Abuse grants behavioral disturbances. We previously demonstrated the
DA15214, DA22339, DA33641 and DA18678. inheritability of these traits by selective breeding based upon
S94 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
the dominant-submissive relationships (DSR) food compe- myelinated axons can also be explained by incorporating
tition paradigm. Continued multigenerational selection this model with the cable theory equations.
yielded populations of mice with strong and stable features Conclusions: The model provides a systematic means to
of dominance and submissiveness. investigate different manipulation modes of LIUS on excit-
We found that these animals react differentially to stressogenic able tissues, for many future therapeutic applications, using
factors, antidepressants and mood stabilizing agents. The anxi- a noninvasive and targeted technology.
olytic compound diazepam (1.5 mg/kg, i.p.) reduced anxiety- This research is funded by a Johnson & Johnson Grant.
like behavior of submissive animals, but showed paradoxical,
anxiogenic effects among dominant animals. In the Forced Learning to avoid saccadic suppression
Swim test, the antidepressant paroxetine (1, 3 and 10 mg/kg, Porat Y* 1, Carlebach N 1, Zohary E 1,2,3
1
i.p.) markedly reduced immobility of submissive animals, dem- Dept. of Neurobiology , Life Sciences Institute, Hebrew
onstrating antidepressant-like effect. In contrast, when admin- University of Jerusalem, Jerusalem 91904, Israel 2Interdis-
istered to dominant animals, paroxetine caused maladaptive, ciplinary Center for Neural Computation, Hebrew Univer-
frenetic activity. The mood stabilizer lithium (0.4 %, p.o.) sity of Jerusalem, Jerusalem 91904, Israe 3The Edmond &
selectively influenced dominant mice, without affecting the Lily Safra Center for Brain Sciences, Hebrew University of
behavior of submissive animals. In summary, we describe here Jerusalem, Jerusalem 91904, Israel
two distinct animal populations possessing strong dominant
and submissive phenotypes. We suggest that these animals hold Background: Humans naturally scan the visual scene by
potential as tools for studying the molecular basis and pharma- making fast, ballistic eye movements at about three times
cogenetics of dominant and submissive behavior. per sec. These saccades could potentially result in a smeared
and jerky image of the world, but visual perception is clearly
Low intensity ultrasound can affect neurons immune to such effects. One suggestion is that this percep-
through nanoscopic membrane vibrations tual constancy is accomplished by saccadic suppression: a
Plaksin M* 1,2, Eitan K 1, Shoham S 1 sharp drop in visual sensitivity during a saccade. Saccadic
1
Faculty of Bio-Medical Engineering, Technion, Haifa, Israel suppression has repeatedly been demonstrated, but the
2
Russell Berrie Nanotechnology Institute, Technion, Haifa, neural mechanisms underlying it are less clear (e.g. at
Israel what level in the visual pathways does suppression
occur). Specifically, it is unknown if saccadic suppres-
Background: It is known that low intensity ultrasound sion can be gated by higher level mechanisms such as
(LIUS) can generate action potentials in excitable tissues, selective attention.
yet, to the best of our knowledge until now no rigorous Methods: Subjects performed a visual discrimination task
explanation was given for this phenomenon. Hereby, we while their eye movements were being recorded. Using a
present a novel biophysical- biomechanical model for action gaze-contingent paradigm, a visual stimulus (elliptic
potential generation by LIUS in a nerve cell membrane, contour) was briefly presented during the execution of
based on the modified Hodgkin and Huxley (H&H) model a horizontal saccade. In each trial, upon saccade com-
of rat neural cortical cell. The model incorporates the dy- pletion, subjects reported the orientation of the ellipse
namics of the intra-membrane cavitation (see the recent (horizontal vs. vertical). Specificity to the location of
bilayer sonophore (BLS) model), with the bio-electric equa- the stimulus and the direction of the saccade were
tions of the ions transports through different trans- assessed by testing the degree of learning transfer to
membrane voltage gated channels (VGC). As the two leaf- novel untrained conditions. Results: Performance was
lets' distance varies with the ultrasound pressure they mainly measured by the slope of the psychometric function
affect directly the membrane potential through changes in (the percent of vertical choices as a function of the
membrane capacitance; they also have a much weaker in- ellipse axes aspect-ratio). Preliminary results suggest
fluence on the electric response of the membrane through that subjects improve considerably in this peri-saccadic
modulation of the rate constants of each type of the VGC, discrimination task.
that happen to be also sensitive to mechanical tension. Conclusion: Perceptual learning is possible even when
Results: Model simulations show that action potential in- stimuli are presented only during a saccade. Thus,
duction in neural cells by LIUS is mainly the result of Cl- peri-saccadic visual information can be processed at
ion flux out of the cell; and that the probability to induce will. This suggests that at least some of the behavioral
action potential increases with pressure amplitude and pulse suppression is caused by high-level cortical mechanisms.
duration and decreases with frequency. Interestingly, the Further research and analysis would help us to better
already known phenomenon of Compound action potentials understand the nature of peri-saccadic learning and the
(CAP) suppression by Ultrasound (US) at the peripheral mechanisms that allow it.
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S95
Compromised neuro-vascular coupling under blood- space and by intraneuronal accumulation of neurofibrillary
brain barrier dysfunction: a role in the pathogenesis tangles. Both active and passive immunization studies have
of brain diseases? shown that antibodies against amyloid-β peptides (AβPs) are
Prager O 1,3, Schoknecht K 4, Chassidim Y1,3, Kamintsky L 2,3, effective in decreasing cerebral AβP levels, beta-amyloid
Friedman A1,3 (Aβ) accumulation, inflammatory adverse effects and attenu-
1
Dept. of Physiology& Cell Biology, 2Dept. of Biomedical ating cognitive deficits in animal models of AD.
Engineering, 3 Zlotowsky Center for Neuroscience, Our lab previously described a novel approach to inhibit AβP
Ben-Gurion University of the Negev, Beer-Sheva, 4Institute production via antibodies against the β-secretase (BACE 1)
of Neurophysiology, Charite University Medicine, Berlin, cleavage site on the APP. These antibodies (BBS1) were
Germany found to block the β-secretase site on APP, interfere with
APP-BACE interaction, exploiting their presence at the cell
The brain uses more energy than any other organ of the surface prior to their internalization to the early endosomes
body and relies almost exclusively on delivery of oxygen where BACE1 cleaves APP.
(O2) and glucose through the vascular system. A regional Results: Here, we investigate the effect of BBS1 on Aβ
increase in the metabolic demands of active neurons is aggregation and on tau phosphorylation in triple transgenic
supported by elevated blood flow, a phenomenon termed mice model of AD (3× Tg-AD). The 3× Tg-AD mice harbor-
neuro-vascular coupling (NVC) or functional hyperemia. ing consequently, the concomitant manifestation of
The blood-brain barrier (BBB) is the regulated interface be- PS1M146V, APPSwe, and tauP301L transgenes were
tween the peripheral circulation and the central nervous sys- assigned into 2 groups. One group was immunized with the
tem (CNS). It's composed of endothelial cells which monoclonal antibody BBS1 and the second group was immu-
connected by tight junctions, and together with astrocytes, nized with same dose of OK1, a non relevant antibody. For the
pericytes, neurons and the extracellular matrix, constitute the immunization we used mini osmotic pumps adjusted intra-
"neurovascular unit" that is essential for proper function of the cerebroventricular (i.c.v) of right hemisphere, and pumping its
CNS. Recent recordings in patients with sub-arachnoid hem- content for one month. The experimental data demonstrated
orrhage demonstrated high incidence of BBB dysfunction behavior improvement of treated mice, reduction in tau phos-
together with impaired vascular response during neuronal phorylation explained by significant reduction in GSK3β
activation. We thus hypothesized that BBB dysfunction pre- which phosphorylates tau, as well as significant decrease in
dispose the brain to disturbed neuro-vascular coupling which plaques burden and reduced inflammation.
may further contribute to cellular damage. BBB dysfunction Conclusions: This data, showing that tau pathology was
was introduced with either photothrombosis or with exposure significantly reduced by BBS1 antibodies suggest a close
of the cortex to artificial "serum like" electrolytic solution interaction between tau and Aβ in the development of AD,
containing physiological concentration of albumin, the most and may serve as an efficient novel immunotherapy against
common blood protein. Neuro-vascular coupling was tested both hallmarks of the disease.
by imaging vessels diameter changes in the open-window The monoclonal antibody BBS1 is under a patent applica-
method while corticographic recording of seizures-induced tion licensed to NasVax. Ltd, Israel
using 4-aminopyridine (4-AP). BBB integrity was estimated
using angiography as previously reported. Our results show a Targeted delivery of membrane-impermeable cytotoxic
pronounced and reversible dilation of cortical vessels during compounds via TRP channels into specific cells
seizures in the healthy brain. In contrast, in the BBB dysfunc- Raizel H 1, Lev S 1, Honigman A 2, Binshtok AM* 1
1
tional brain (or in the brain exposed to artificial serum), Dept. of Medical Neurobiology, Institute for Medical Re-
vascular response to neuronal activation was significantly search Israel Canada and Center for Research on Pain, The
impaired, emphasizing the importance of intact BBB in the Hebrew University, Faculty of Medicine, Jerusalem, Israel
2
normal neuro-vascular coupling. Dept. of Virology Faculty of medicine, The Hebrew Uni-
versity,Jerusalem, Israel
Beneficial effect of antibodies against beta secretase
cleavage site of APP on Alzheimer's like pathology We have previously demonstrated that the pore of the tran-
in triple-transgenic mice sient receptor potential channels, TRPV1 and TRPA1, is
Rabinovich- Nikitin I, Rakover I, Becker M, Solomon B* large enough to pass QX-314, a permanently charged deriv-
Dept. of Molecular Microbiology & Biotechnology Tel-Aviv ative of lidocaine into neurons. Thus, activation of TRPV1
University, Tel-Aviv 69978, Israel and TRPA1 channels applied with QX-314, allows selective
entry of QX-314 into pain sensing neurons, producing inhi-
Background: Alzheimer's disease (AD) is characterized by bition of excitability while sparing non-painful sensory and
the accumulation of senile plaques in the brain extracellular motor neurons. Using this platform we were able to affect
S96 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
other sensory modalities such as itch in which we demon- classification error of 30 % at the optimal time. Next, we
strated specific inhibition of activity of itch sensing neurons. have constructed a classifier that uses the time course of the
Since TRP channels are expressed differentially among EEG traces. In addition, we performed dimensionality re-
various types of cells, we are able to utilize this cell specific duction on the electrode array by using only the top 15-20
"machinery" and extend the platform not only to selectively most informative electrodes. This method yielded a classi-
silence specific neuronal populations but also to affect in- fication success rate of 87 %, ranging from 80 % perfor-
tracellular metabolic pathways. Here we present a proof of mance in 'poor' subjects to 95 % for the 'best' subject. For
concept of this novel platform, by targeting charged chemo- the task studied here, we show that single-trial EEG data
therapy agent, Adriamycin, into cancer cell-lines expressing contains sufficient information to perform an accurate bina-
large pore cation-non selective TRP channels. We demon- ry classification of intended movement. Interestingly, it was
strated that mouse hepatocellular carcinoma cells (BNL1ME not necessary to build a separate classifier for each subject.
cell line) express functional TRPV2 channels. Activation of On the other hand, information about the EEG dynamics
these channels by 2-Aminoethoxydiphenyl borate (2-APB) was crucial for good performance. These results may bear
applied together with Adriamycin leads to selective entry of important implications for Brain-Computer Interface appli-
this charged chemotherapeutic agent into BNL1ME cells, cations, as well as for understanding the nature of the EEG
facilitating Adriamycin-induced cell death. signaling of movement preparation.
This method for selective facilitated delivery of chemothera-
peutic agents is expected to reduce their toxicity by decreasing Effector and regulatory T cells play distinct but beneficial
concentrations, limiting side effects and ultimately leading to roles in recovery from central nervous system trauma
a better clinical readout. Moreover, these results enable im- Raposo C, Schwartz M*
plementation of this strategy on neuronal populations not only The Weizmann Institute of Science
for killing specific cells but also for modulation of a pathway,
in basic research and in neuronal based pathologies. Background: Spinal cord injury (SCI) results in immune
Supported by Marie Curie Grant and Rosetrees Foundation activation and immune cell entry into the injured tissue.
While macrophages are major players during wound healing
Single-trial decoding of intention from EEG of the injured CNS, the role of T cells is still debatable.
Ramaswamy V* 1,2, Furstenberg A 1,2, Breska A 3, Deouell, Studies have found that autoreactive T lymphocytes impair
L 3,1,2, Sompolinsky H 4,1,2 recovery of locomotor function and contribute to tissue
1
Interdisciplinary Center for Neural Computation, The He- injury. On the other hand, CNS-specific autoimmune T cells
brew University of Jerusalem 2The Edmond and Lily Safra were shown to promote neuronal survival and functional
Center for Brain Sciences, The Hebrew University of Jer- recovery from acute and chronic neurodegenerative condi-
usalem 3Dept. of Psychology , The Hebrew University of tions. Part of the controversy draws from a general overview
Jerusalem 4Racah Institute of Physics, The Hebrew Univer- of the T cell response, disregarding the specific subsets of T
sity of Jerusalem cells, the dynamics of the healing response and the location.
In our work, we dissected the CD4+ T cell response in order
Brain Computer Interface applications require single-trial to understand this intricate network of events.
decoding of brain activity. Electroencephalography (EEG) Results: Here, we demonstrated that recovery from SCI is
holds promise for such applications, since it is non-invasive dependent on the fine-tuned crosstalk between T cells and
and has high temporal resolution. However, due to low macrophages. In particular, we found that both effector and
signal-to-noise ratio, classification of intentions on single- regulatory T (Treg) cells have important roles in the recov-
trial EEG with high accuracy has been a challenge. In this ery process. Mice deficient in Th1 cells showed impaired
work we consider a task, where the subjects had to press a recovery, which was correlated with a reduced recruitment
right (left) hand button rapidly and accurately in response to of M2 macrophages at the injured site. Consequently, we
a right (left) arrow cue. Our goal was to examine if single- found that an impaired M2 response led to deficiency in
trial data from this experiment contained sufficient informa- Treg cells, involved in the later phase of remyelination.
tion to infer the type of intended movement. If so, could we Conclusions: The results described here demonstrate the
design a classifier that would work well across different intricate interactions between the innate and the adaptive
subjects? Does the EEG dynamics provide important infor- immune system, following spinal cord injury. The optimized
mation for this task? We have studied a classifier based on action of this network was found to work at two levels; first,
Fisher Linear Discriminant (FLD) applied to the pooled by controlling the local inflammation and thus decreasing
EEG data from all subjects. Our first finding is that the the secondary degeneration, and second, by promoting the
performance of FLD classifier that takes as input a single critical step of white matter remyelination, thereby reducing
time-point EEG activity vector is relatively poor with the functional deficit in the CNS and promoting
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S97
regeneration. This physiological response can be fine-tuned We investigated the laminar profile of synaptic activity
to improve recovery, as a therapeutic approach for CNS in A1 to determine the effect of isoflurane (ISO) on
trauma. visual versus auditory evoked local field potentials
(LFP) in rats chronically implanted with electrode arrays
Attention shifts the location of fixation toward attended in A1, and in thalamo-cortical (TC) mouse A1 brain
stimuli in a slices. Current source density (CSD) of the columnar
Rappel P 1, Britz J 2, Deouell LY 1,3 response was estimated and analyzed for changes in
1
Dept. of Psychology, The Hebrew University of Jerusalem, profile and magnitude.
Israel 2Dept. of Fundamental Neuroscience, University of Results: Auditory stimuli in vivo elicited early current sinks
Geneva, Switzerland 3Edmond and Lily Safra Center for in middle layers that spread to supragranular (SG) and infra-
brain sciences (ELSC), The Hebrew University of Jerusalem, granular (IG) layers. Visual stimuli elicited longer latency
Israel sinks in IG layers followed by sinks in SG layers. ISO dose-
dependently decreased the responses, with a greater effect on
Background: The "Posner Cueing Task" is a task often used visual (V) versus auditory (A) responses [0.4 %: V-71 %, A-
to estimate spatial attention effects. During the task subjects 15 %; 0.8 %: V-96 %, A-20 %; 1.6 %: V-114 %, A-42 %]. In
view two stimuli (boxes, letters, etc.) and are cued by an slices, TC afferents stimuli elicited an early sink in middle
arrow to attend to one of the stimuli, while fixating on a layers, whereas cortico-cortical (CC) stimuli elicited early
central cue, and respond to target stimuli. Traditionally, any superficial sinks. ISO suppressed TC and CC responses to a
difference between subjects' behavioral or neuronal re- similar extent [0.25MAC: TC-94 %, CC-108 %; 0.5MAC:
sponse to a given stimulus when it is attended versus when TC-52 %, CC-81 %; 1MAC: TC-60 %, CC-66 %]. High and
it is unattended, is interpreted as an attentional effect. This is intermediate ISO levels decreased paired pulse depression
based on the assumption that the stimulus had an equal low- (PPD) following TC stimulation but increased PPD following
order impact on the visual system in both conditions. Our CC stimulation.
work examined this assumption. Conclusions: ISO decreased TC responses in vitro and audi-
Results: Subjects performed a Posner Cueing Task while tory responses in vivo similarly. The greater suppression by ISO
having their eye movements monitored. The results showed of visual responses in A1 versus CC responses in vitro suggests
a significant bias of subjects' fixation toward the attended additional cortical mechanisms of anesthetic disruption of mul-
location, so that attended stimuli fell closer to the fovea then timodal processing, such as the visual cortical responses.
unattended stimuli. This work was funded by the NIH (DC006013-01) and the
Conclusions: Given that the visual system is characterized UW Dept. of Anesthesiology
by a computational gain to central stimuli, our results suggest
that effects of cueing may result in part from a fixational bias Behavioral and neural correlates of emotional Intelligence:
leading to greater proximity of attended stimuli to the center of an event-related potentials (ERP) study
the retina, rather than a top-down "endogenous" attentional Raz S* 1,2, Dan O 1, Zysberg L 2
1
benefit. Dept. of Psychology, The Center for Psychobiological
Research, Yezreel Valley College 2Dept. of Psychology, Tel
Effects of isoflurane on sensory integration of different Hai College
synaptic pathways in auditory cortex
Raz A* 1,2,3, Krause BM 1, Grady SM 1, Banks MI 1 Background: The present study aimed to identify potential
1
Dept. of Anesthesiology and Neuroscience Training Pro- behavioral and neural correlates of Emotional Intelligence
gram, University of Wisconsin - Madison, Madison, WI, (EI) by using scalp-recorded Event-Related Potentials
USA 2Dept. of Anesthesiology, Rabin Medical Center, Bei- (ERPs). We identified ERP correlates of emotional processing
linson Hospital, Petah Tikva, Israel 3Tel-Aviv University, by comparing ERPs elicited in trials using pleasant, neutral
Tel-Aviv, Israel and unpleasant pictures. These emotional picture effects were
then compared across groups with low and high EI levels.
Background: Sensory awareness involves comparison of Results: Behavioral results revealed a significant va-
cortically-generated predictions with incoming sensory in- lence×EI group interaction effect since valence ratings
formation. An example of this in core auditory cortex (A1) were lower for unpleasant pictures and higher for pleas-
is modulation of auditory responses by input from extras- ant pictures in the high compared with the low EI
triate visual cortex. Evidence suggests that upon anesthetic- group. The groups did not differ with respect to neutral
induced loss of consciousness, ascending sensory pathways picture ratings. The ERP results indicated that high EI
are relatively unaffected, but descending pathways are participants exhibited significantly greater mean ampli-
disrupted, leading to a failure of the prediction process. tudes of the early attentive P2 (195–285 ms post-
S98 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
stimulus) ERP component in response to emotional and Semantic influence on episodic encoding: evidence
neutral pictures, at posterior-parietal as well as at frontal from fMRI repetition suppression
scalp locations. Reggev N 1, Maril A* 2
1
Conclusions: The present study is the first to demonstrate Cognitive Science, Hebrew University 2Psychology &
ERP correlates of EI in response to visual emotional stimuli. It Cognitive Science, Hebrew University
also underscores the usefulness of the ERP methodology as a
sensitive measure for the study of emotional processing in the It has long been acknowledged that congruency with semantic
research field of emotional intelligence. knowledge has a robust positive effect on episodic memory
encoding. Although recent empirical work highlights possible
Coupling sound to movement – design and assessment brain systems involved in this process, the mechanisms un-
of learned auditory-proprioceptive integration derlying superior episodic encoding of semantically-
Regev TI* 1,2, Duff A 3, Jordá S 4 congruent items remain largely unknown. In the current study,
1
The Edmond and Lily Safra Center for Brain Science, The we attempt to examine one possible structural account of the
Hebrew University of Jerusalem 2Inter Disciplinary Center effect: According to our hypothesis, items presented in a
for Neural Computation, The Hebrew University of Jerusa- congruent context result in enhanced excitation in the seman-
lem 3Synthetic Perceptive Emotive and Cognitive Systems, tic network (compared with items presented in an incongruent
Universitat Pompeu Fabra, Barcelona 4Music Technology context), which subsequently leads to enhanced episodic
Group, Universitat Pompeu Fabra, Barcelona encoding. To examine the first part of the semantic excitation
proposal, we scanned participants using fMRI in a repetition
Background: Sensory integration plays an important role in suppression paradigm that was aimed at studying the amount
the perceiving our own body. Proprioceptive knowledge of semantic-related suppression caused by congruent and
regarding, e.g., the movement of one's own arm, arises from incongruent items. Participants were presented with congruent
distinct sources that are combined together - somatic infor- (e.g., "Yellow Banana") or incongruent (e.g., "Blue Banana")
mation originated in sense receptors within body tissues, and noun-adjective pairs which were later followed by a presen-
visual information that comes from viewing the arm. Not tation of the noun alone (e.g., "Banana"), while performing an
much research has been done on auditory-proprioceptive in- incidental encoding task which did not require attending to the
tegration, despite the clear relation of sound to body move- congruency status of the items. Initial results provide support
ment. In this study we hypothesize that auditory information for our hypothesis concerning the superior semantic status of
can be integrated into proprioception by means of an artifi- congruent items: Congruent items elicited a stronger suppres-
cially designed system. Our objective is to investigate sound- sion of the concept ("Banana") than did incongruent items.
body perceptual interaction and suggest possible application These differences in levels of suppression were observed
for physical therapy. In the experiments presented, sound is mainly in brain regions known to be involved in semantic
synthesized in real-time according to movement parameters processing, including left inferior frontal and left temporal
captured by a sensor attached to the arm. Specifically, we regions. These results provide evidence that congruent and
couple the dimensions of arm elevation and auditory pitch. incongruent items result in differing amount of excitation of
Results: We operationalize our hypothesis using a motor task, concepts in the semantic network. Additional studies currently
in which subjects lift their arms towards a target point. Con- conducted in our laboratory examine the relationship between
tinuous sonification of arm elevation angle is present, or not the level of suppression of items presented in a congruent
(control condition), during movement trajectory. First, we context and the successful episodic memory for these items.
show that after a short learning period with a fixed angle-to-
pitch mapping, sonification improves accuracy in the motor Synaptic activity of the Abelson family of non-receptor
task, compared to control. Second, we distort the learned tyrosine kinases
mapping without informing participants. Mean hand positions Reichenstein M 1, Sheinin A 1,2, Borovok N 1, Michaelevski
are significantly affected by the mapping manipulation, while I* 1,2
1
most subjects do not report awareness of it. Dept. of Biochemistry and Molecular Biology, Tel-Aviv
Conclusions: Auditory pitch can be integrated into body University; Tel-Aviv 69978, Israel 2Sagol school of Neuro-
perception rapidly and efficiently. Distorting the learned science, Tel Aviv university, Tel Aviv
movement-to-sound mapping results in a complex auditory-
somatic competition. We propose that such distortions could Background: The Abelson family of non-receptor tyrosine
be applied to amplify the range of movement in motor neuro- kinases is best characterized in cancer, and also possesses
rehabilitation. We demonstrate how advanced interface tech- important physiological roles in neural development as well
nology can be used for the design of novel experimental as the regulation of synaptic structure and function, mediat-
scenarios and application in cognitive science. ed via interaction with the F-actin cytoskeleton, signaling
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S99
adaptors, and scaffolding proteins. In the hippocampus, Abl spatial memory and neurogenesis and OE improved olfac-
kinases modulate neurotransmitter release, affect paired pulse tory recognition and neurogenesis, however neither EE nor
facilitation/depression related short-term synaptic plasticity, OE further improved memory functioning in CX3CR1-/-
co-localize with PSD-95 and regulate its clustering. In the mice. Consistently with the behavioral findings, the number
prefrontal cortex, Arg, an isoform of Abl kinase family, of microglia in the hippocampus of non-enriched CX3CR1-/-
orchestrates spine maturation and cocaine-induced plasticity. mice was greater than in CX3CR1+/- mice and their soma size
An important role of Abl kinases in Ab production and sig- was increased, suggesting mild activation status. Furthermore,
naling has been also shown. Despite the accumulating evi- following EE the number and soma size of hippocampal
dence, not much is known about their direct involvement in microglia in CX3CR1+/- was significantly increased, whereas
the regulation of synaptic activity/plasticity processes. Hence, no further microglial changes were found in the hippocampus
to investigate the role of Abl kinases in synaptic transmission, of CX3CR1-/- mice. In contrast, the number and morphology
we recorded spontaneous miniature excitatory postsynaptic of microglia in the OB of CX3CR1+/- OE-exposed mice was
currents (mEPSCs) in the presence of TTX and PTX from not different than controls.
primary hippocampal neurons after 14-16 days in culture. Conclusions: These results imply that microglia activation
Results: We found that acute treatment of cultured rat hip- status and microglial interactions with neurons via the
pocampal neurons with STI571 (imatinib mesylate /Glee- CX3CR1 play an important role in memory and neurogen-
vec), a selective irreversible Abl kinase activity blocker, esis. Furthermore, the effects of EE on microglia and the
significantly increased mEPSC amplitudes comparing to possible role of these cells in enrichment-associated neuro-
control with no effect on interepisode intervals distribution behavioral functioning is region-specific.
of mEPSCs. Moreover, a new Abl kinase specific activator
DPH produced an opposite effect from significant reduction Modulation of auditory cortex during action execution
to complete elimination of mEPSCs in a drug dose and Reznik D 1, Mukamel R* 1,2
1
exposure time dependence manner. Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv
Conclusions: We suggest that Abl kinases may be involved 69978, Israel 2School of Psychological Sciences, Tel-Aviv
in regulation of basal synaptic activity of excitatory neuro- University, Tel-Aviv 69978, Israel
transmission in hippocampal neurons, having potential
implications on the processes of learning and memory Background: The notion of a corollary discharge that is
formation. sent by the motor cortex to sensory regions prior to
voluntary action has long been suggested to modulate
The role of microglia and signaling via their CX3C neural activity in sensory cortices. Most physiological
receptor-1 in hippocampal and olfactory bulb plasticity data demonstrate reduction but some suggest enhance-
Reshef R 1, Kreisel T 1, Beroukhim D 1, Jung S 2, Yirmiya R* 1 ment of activity in sensory cortex. The aim of the
1
Dept. of Psychology, The Hebrew University, Jerusalem, current study was to further examine the putative role
Israel. 2Dept. of Immunology, The Weizmann Institute of of a corollary discharge in modulation of auditory cor-
Science, Rehovot, Israel tex during keyboard playing.
Results: Healthy subjects (N015) played short musical
Background: Recent studies suggest that microglia are in- sequences on an MR compatible piano keyboard with
volved in hippocampal-related behavioral and neural plasticity either their right or left hand while auditory feedback
and that the number of microglia is increased following expo- was provided. Identical auditory feedback was subse-
sure to environmental enrichment (EE). CX3CR1 is a receptor quently replayed to the subjects during passive listening.
which in the brain is exclusively expressed by microglia, binds The functional MRI signal in auditory cortex (superior
the neuronally-derived CX3CL chemokine, and mediates tonic temporal gyrus; STG) was enhanced during playing
inhibition exerted by neurons over microglial activation. To compared to passive listening of identical auditory
examine the role of microglia activation and CX3CR1 signal- sequences. Control experiments exclude habituation as
ing in plasticity, we exposed heterozygous CX3CR1-GFP mice a possible explanation for the reduced activity during
(CX3CR1+/-) and mice with homozygous expression of GFP listening. Importantly, enhancement was lateralized. The
in which the CX3CR1 gene is functionally deleted (CX3CR1-/- signal in left STG was stronger during playing with the
) to either EE or to odor enrichment (OE) and assessed memory, right (contra-lateral) hand than during playing with the
neurogenesis and microglia status in the hippocampus and left (ipsi-lateral) hand. Symmetrically, the signal in right
olfactory bulb(OB). STG was stronger during playing with the left hand
Results: Non-enriched CX3CR1-/- mice displayed better compared with playing with the right hand. Similar
hippocampal spatial memory and olfactory recognition than laterality effects were obtained when identical auditory
CX3CR1+/- controls. In CX3CR1+/- mice, EE improved feedback during left and right hand playing was
S100 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
provided – excluding the possibility that the laterality Abnormal neuronal differentiation and mitochondrial
effects are due to octave differences between the two dysfunction in hair follicle-derived induced pluripotent
hands during normal playing. stem cells of schizophrenia patients
Conclusions: Our results show that a) performing an Robicsek O 1, Karry R 1, Petit I 2,3, Salman Kesner N 2,
action enhances neural activity in the sensory cortices Müller FJ 4, Klein E 1, Aberdam D 2,3, Ben Shachar D* 1
1
relevant to the perception of action consequences and b) Laboratory of Psychobiology, Dept. of Psychiatry, Ram-
this enhancement is lateralized. Taken together, these bam Medical Center, B. Rappaport Faculty of Medicine and
data support the notion of a corollary discharge from B. Rappaport Research Institute, Technion, Haifa Israel
2
motor cortex enhancing activity more strongly in ipsi- INSERTECH, B. Rappaport Faculty of Medicine, and B.
lateral sensory cortex, suggesting a more low-level Rappaport Research Institute, Technion 3INSERM U898,
source of the corollary discharge. University of Nice Sophia Antipolis, France 4Zentrum für
The authors thank the Israeli Center of Research Excellence Integrative Psychiatrie, Kiel, Germany
(ICORE), and HFSP for financial support.
Background: Schizophrenia is currently conceptualized as a
Wiring the brain for function neurodevelopmental disorder, involving dysfunction of dopa-
Richards L minergic and glutamatergic systems. Accumulating evidence
Queensland Brain Institute, The University of Queensland suggests mitochondria as an additional pathological factor in
schizophrenia. An attractive model to study neurodevelop-
The brain must be wired correctly in order to function. Brain mental related processes in schizophrenia is reprogramming
wiring forms through a series of highly orchestrated molec- of somatic cells into induced pluripotent stem cells (iPSC) and
ular, cellular and activity-dependent events. Axonal connec- differentiating them into different neuronal lineages.
tions between the two sides of the nervous system are Results iPSC from 3 schizophrenia patients and from 2 controls
known as commissural projections. The development of were reprogrammed from hair follicle keratinocytes, due to their
these connections is regulated by a number of different accessibility and common neuroectodermal origin with neurons.
mechanisms including the formation of midline tissue called iPSC were differentiated into Pax6+/Nestin+ neural precursors
the commissural plate, the guidance of commissural axons and then further differentiated into b3-Tubulin+/TH+/DAT+ do-
by midline glial and neuronal populations, and the expres- paminergic neural cells. In addition, iPSC were differentiated
sion of specific axonal guidance molecules. There are three through embryonic bodies into β3-Tubulin+/TBR1+ glutama-
commissural projections in the forebrain of placental mam- tergic neural cells. Schizophrenia-derived dopaminergic cells
mals; the corpus callosum, the hippocampal commissure showed severely impaired ability to differentiate, whereas gluta-
and the anterior commissure, all of which function to inte- matergic cells were unable to maturate. Mitochondrial respiration
grate information between the two hemispheres. Recent data and its sensitivity to dopamine-induced inhibition were impaired
from our laboratory indicates that the correct patterning and in schizophrenia-derived keratinocytes and iPSC. Moreover, we
formation of the commissural plate provides an essential observed dissipation of mitochondrial membrane potential
substrate for commissure formation in the telencephalon. (Δym) and perturbations in mitochondrial network structure
As commissural axons arrive at the midline they must nav- and connectivity in dopaminergic and in glutamatergic neural
igate through an environment of both attractive and repul- cells and along the differentiation process.
sive molecular axon guidance cues. These molecular cues Conclusions: Mitochondrial dysfunction in Schizophrenia
are expressed by midline glial populations and are crit- was highly correlated with the extent of differentiation im-
ical for commissure formation. As such, midline glia are pairment in both neural lineages. Our data unravel perturba-
associated with commissural projections throughout the tions in neural differentiation and mitochondria function,
nervous system of all bilaterally symmetrical animals which are possibly interconnected and may be of relevance
and the molecules they express are highly conserved. to early neurodevelopmental processes in schizophrenia.
A family of transcription factors called the Nuclear NARSAD, Chief Scientist of the Israeli Ministry of Health
Factor One (Nfi) genes regulate the development of
these glia and are thus indirectly crucial for commissure Chromatin remodeling – a novel strategy to control
formation. After crossing the midline, callosal axons excessive alcohol drinking
must find their target in the contralateral hemisphere, Ron D*
and both molecular and activity dependent cues are Ernest Gallo Research Center, University of California, San
likely involved in their targeting. Overall, the formation Francisco
of the corpus callosum provides an excellent model
system for understanding how the brain becomes wired Background: Alteration in gene expression is a central
up during development. feature underlying neuroadaptations that result from chronic
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S101
drug and alcohol use. One means of controlling gene ex- the 2 manners he solved the puzzle: incremental or by insight.
pression is the remodeling of chromatin structure. Specifi- In the "hint" group the average time until insight was
cally, chromatin condensation and decondensation block or 1.41 minutes (sterr00.23 min). In the control group (without
allow, respectively, the accessibility of gene promoters to a hint) the average time was 2.97 minutes (sterr00.46), Results
the transcriptional machinery. Results: Here, we report that were significant, p00.0045. 13 subjects reported an insight
changing the level of chromatin condensation by affecting solution in the hint group and 4 reported an incremental solu-
DNA methylation or histone acetylation limits excessive tion. In the control group, 9 reported an incremental solution
alcohol drinking and seeking behaviors in rodents. Specifi- and 7 reported an insight solution (p00.0799).
cally, we show that inhibiting the activity of DNA methyl- Conclusions: A "supportive" unaware hint might speed up
transferase prevents excessive alcohol drinking. Similarly, insight processes and within a group might increase the prob-
we show that systemic treatment with several histone deace- ability to achieve insight. We suggest that the information
tylase (HDAC) inhibitors reduces binge-like alcohol drink- inherent in the hint is integrated in the problem's representation
ing. We further report that systemic administration of the and influence reconstuction.
FDA-approved HDAC inhibitor, SAHA, inhibits the moti-
vation of rats to seek alcohol. Importantly, the actions of the Neuronal D-serine and glycine release through Asc-1
chromatin modifiers are specific for alcohol, as no changes transporter regulates NMDAR-dependent synaptic activity
in saccharin or sucrose intake were observed. Rosenberg D 1, Artoul S 1, Segal CA 1, Kolodney G 1,
Conclusion: Together, our findings demonstrate that DNA Radzishevsky I 1, Foltyn NV 1, Inoue R 2, Mori H 3, Billard
methylation and histone acetylation control the level of JM 4, Wolosker H* 1
1
excessive alcohol drinking and seeking behaviors in preclin- Technion-Israel Institute of Technology 2Graduate School
ical rodent models. Our study therefore highlights the pos- of Medicine and Pharmaceutical Sciences, University of
sibility that HDAC and DNMT inhibitors can be used to Toyama 3 Graduate School of Medicine, University of
treat alcohol abuse disorders. Finally, a molecular mecha- Toyama 4INSERM U894
nism underlying epigenetic changes induced by alcohol
exposure will also be described. Background: D-Serine and glycine are co-agonists of
Supported by NIAAA (R01AA016848) and State of California. NMDA receptors (NMDAR), but their relative contributions
for NMDAR-dependent processes are unclear. D-Serine was
Changes in frequency and duration of insight following initially thought to originate from astrocytes, but recent
exposure to unaware clues studies show a preferential neuronal localization of the D-
Rosen A, Reiner M* serine biosynthetic enzyme. We have shown that neuronal
Israel Institute of Technology, Dept. of Education in Tech- D-serine is released through alanine-serine-cysteine
nology and Science, Technion City, Haifa, 32000, Israel transporter-1 (Asc-1) but the physiological importance of
this pathway was not evaluated.
Background: Insight is a problem solving process, in which Results: We now report that the Asc-1 mediates release of
the solution happens suddenly after unique characteristic both D-serine and glycine from neurons, and this modulates
stages such as incubation and reconstuction that do not occur NMDAR synaptic activity. Asc-1 antiporter activity is en-
in incremental process. Insight involves unconscious thought hanced by D-isoleucine (D-ile), which releases D-serine and
processes. We suggest that unaware hints might have an effect glycine from neurons but not astrocytes in primary neuronal
on two parameters: 1.The length of time required to achieve a cultures and hippocampal slices. We show that D-ile enhan-
solution 2.The group frequency of achieving insight. ces the long-term potentiation (LTP) at hippocampal CA1
Results: Participants solved the "10 coin" puzzle. 17 subjects by stimulating Asc-1-mediated D-serine release. D-Ile
were exposed to an unaware visual hint. The hint was displayed effects on synaptic plasticity are abolished by enzymat-
in a sequence of three screens: 1. The initial setup of the puzzle ically depleting D-serine or by employing serine race-
(a triangle). Duration of exposure was for 1 second. 2.The hint mase knockout (SR-KO) mice, confirming its specificity
screen: the 10-coin triangle with the 7 central coins painted and supporting the notion that LTP depends mostly on
gray, emphasizing the invariant factors in the puzzle, for 30 D-serine release. On the other hand, our data also disclose a
milliseconds. 3. A "noise" image (masking), for 250 millisec- role of glycine in activating synaptic NMDARs. Although
onds. The sequence was repeated three times in a row. After- enzymatic depletion of D-serine also drastically decreases
wards, the subject was asked to solve the puzzle. After solving, the isolated NMDAR synaptic potentials, these responses are
all subjects were tested and found to be unaware to the hint. In still enhanced by D-ile. Furthermore, the NMDAR synaptic
the control group, 16 subjects solved the puzzle without being potentials are preserved in adult SR-KO mice and can be
exposed to the hint. The time unstill solution was measured for enhanced by D-ile as well, indicating that glycine overlaps
both groups. After solving, each subject was asked in which of with D-serine at synaptic NMDARs.
S102 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
Conclusions: Altogether, our results disclose a novel role of experience. Thus, the object-related lateral occipital com-
Asc-1 in regulating NMDAR-dependent synaptic activity by plex (LOC) is typically more invariant to parameter changes
mediating concurrent non-vesicular release of D-serine and (e.g. contrast, viewpoint, etc.) than early retinotopic areas.
glycine. Our data also highlight an important role of neuron- Here, we use a complementary approach to highlight
derived D-serine and glycine, and challenge recent models changes in brain activity that result solely from a perceptual
that suggest astrocytic D-serine as the sole responsible for state shift. We focus on LOC and early visual cortex (EVC)
activating synaptic NMDARs. and compare their fMRI responses to degraded object
images, prior to, and following perceptual learning that
CaMKII is differentially regulated in striatum and cortex renders initially unrecognized objects, identifiable. Using
Rostas JAP 1,2, Skelding K A 1,2, Fluechter L 1,2, Dickson three complementary analyses, we find that in LOC, learned
PW 1,2, Spratt NJ 1,2 recognition is associated with a change in the multi-voxel
1
School of Biomedical Sciences and Pharmacy, University response pattern to degraded object images, such that the
of Newcastle 2Hunter Medical Research Institute response becomes significantly more correlated with the
pattern evoked by the intact version of the same image. This
CaMKII is involved in ischemic/excitotoxic cell damage. Stria- provides further evidence that the coding in LOC reflects the
tum is more sensitive than cortex to ischemia/excitotoxicity. Gestalt, perceptual level of representation of visual objects.
Whether this is due to differences in perfusion or intrinsic Supported by The HU-EPFL Collaboration Program
factors is unknown. We investigated changes in CaMKII acti-
vation in striatum and cortex following MCA (middle cerebral Amalgamating positional and directional signals
artery) occlusion in vivo and excitotoxic stimulation of micro- by hippocampal place cells
slices in vitro. Phosphorylation changes in Thr286-αCaMKII, Rubin A*, Yartsev M, Ulanovsky N
Thr253-αCaMKII, Ser831-GluA1 and Ser1303-GluN2B were Dept. of Neurobiology, Weizmann Institute of Science
measured by western blotting in: microslices of striatum and
cortex from Sprague Dawley (SD) rats after stimulation with Most theories of navigation rely on the concept of a mental
100 μM AMPA, 100 μM NMDA + 50 mM glycine, or 2.5 mM map-and-compass. Hippocampal place cells are neurons
glutamate + 50 mM glycine; and micropunch homogenates of thought to be important for the neural implementation of
striatum and cortex after varying periods of MCA occlusion the mental map; these neurons fire when the animal traverses
and reperfusion. Autophosphorylation of Thr253-aCaMKII in- a specific location in the environment (the 'place field').
duced by in vivo ischemia occurred more rapidly, to higher Head-direction cells are neurons found outside the hippo-
stoichiometry, and lasted longer in striatum than in cortex campus, whose activity encodes the animal's head orienta-
whereas the changes in Thr286-αCaMKII autophosphorylation tion, hence implementing a neural compass. The prevailing
were equal between the regions. In vivo ischemia also induced view posits that head-direction cells do not encode the ani-
more rapid, larger and longer lasting increases in phosphoryla- mal's position, while place cells do not encode the head-
tion of Ser831-GluA1 and Ser1303-GluN2B by CaMKII in direction. However, little work has been done to date to
striatum than in cortex. These phosphorylation changes were investigate in detail the possible head-directional tuning of
mimicked in vitro following excitotoxic stimulation of micro- hippocampal place-cells. Here we addressed this by record-
slices. These results show that there are intrinsic differences ing the activity of single neurons in the hippocampus of two
between striatum and cortex in the regulation of CaMKII and evolutionarily distant bat species, the Egyptian fruit bat and
implicate tissue differences in Thr253-αCaMKII phosphoryla- the big brown bat, which crawled in 3 different arenas. We
tion in the differential sensitivities of striatum and cortex to found that a large proportion of hippocampal neurons, in
ischemia/excitotoxicity. both bat species, showed a conjunctive tuning to the animal's
position in space (place field) and to its head direction. The
Learning to recognize degraded objects is associated head-direction tuning was significant even after controlling
with a greater match to the objects' template patterns for the behavioral coupling between position and head-
in lateral occipital cortex direction. Surprisingly, some hippocampal neurons pre-
Roth Z* 1,2, Zohary E 1,2,3 served their head directional tuning outside of the neuron's
1
Edmond and Lily Safra Center for Brain Sciences 2Inter- place field – suggesting that the 'spontaneous' spikes outside
disciplinary Center for Neural Computation 3Dept. of Neu- of the place-field are not noise, but in fact carry head-
robiology, Hebrew University, Jerusalem direction information. These findings suggest that hippocam-
pal neurons can provide the brain's navigational system with
One feature of visual processing in the ventral stream is that both map information and compass information, and are
cortical responses gradually depart from the physical aspects therefore ideally suited to serve as the hub of spatial represen-
of the visual stimulus and become correlated with perceptual tation in the brain.
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S103
Specific cognitive and anatomical alterations some form among infants and animals. Kaufman et al.
in post-traumatic patients highlight the importance (1949) named the perception of a small number of items
of intra-hemispheric connectivity for associative memory "subitizing" (meaning "sudden" in Latin) to reflect the no-
Saar-Ashkenazy R 1,2,3,4, Cohen J* 4,5,6, Gasho C 7, Guez J tion of one's sudden perception of small numbers. We
3,8
, Shelef I 7, Friedman A 1,4,5, Shalev H 8 (Goldfarb & Treisman, submitted) recently suggested that
1
The program for Cognitive Sciences, Ben-Gurion Univer- perceiving the quantity in a subset (e.g., perceiving "2"
sity of the Negev, Beer-Sheva, Israel 2The school of Social- when two plates and one cup are displayed on a table) is
work, Ashkelon Academic College, Israel 3Dept. of Behav- qualitatively different from perceiving the total number of
ioral Science, Achva Academic College, Shikmim 79800, items (e.g., perceiving "3" in the previous example). We
Israel 4Zlotowski center for neuroscience, Ben-Gurion Uni- suggested that the number of items in the subset is perceived
versity of the Negev, Beer-Sheva, Israel 5Dept. of Physiology via an attentional path and it is effortful. The aim of the present
and Neurobiology, Ben-Gurion University of the Negev, study was to explore an important aspect of this theoretical
Beer-Sheva, Israel 6Sharett Institute of Oncology, Hadassah notion in which the number of distractors effects the percep-
Medical Organization, Jerusalem, Israel 7Dept. of Radiolo- tion of subset items even within the subitizing range.
gy, Soroka University Medical Center, Beer-Sheva, Israel Results: According to the assumptions, we found that in
8
Dept. of psychiatry, Soroka University Medical Center, a jumbled distractors display, RT for counting subset
Beer-Sheva, Israel target items within the subitizing range was faster when
there were few distractors in comparison to many dis-
Background: Memory deficits are a common complaint tractors. However, when distractors were organized in a
reported by patients with post-traumatic stress disorder specific pattern, allowing quantity pop-out (in contrast
(PTSD). Despite their vivid trauma-related memory, studies to effortful subset counting), there was no difference in
confirmed memory impairment for non-trauma related stim- RT for counting subset target items between few and
uli when compared to controls; specifically in associative many distractors.
memory (Guez et al., 2011). Studies in healthy individuals Conclusions: The results indicate that when distractors are
showed hemispheric memory asymmetry with left prefrontal disorganized, and subset counting is required, serial effortful
lateralization of encoding and right prefrontal lateralization counting is required even for items in the subitizing range.
of episodic retrieval, suggesting a role for inter-hemispheric This serial counting doesn't occur when distractors appear in
communication in memory-related tasks (Gazzaniga, 2000; an organized manner and pop-out counting can be per-
Ringo, Don, Demeter, & Simard, 1994). Since brain mag- formed. It seems that for different arrangements of distrac-
netic resonance imaging (bMRI) in PTSD patients sug- tors different cognitive processes are require in order to
gested volume alterations in various regions, including count target items in the subitizing range.
white matter changes, we aimed to test the relationship
between cognitive memory deficits and volume of the white Local electrical stimulations of the ventral prelimbic
matter corpus callosum (CC) in PTSD patients. cortex ameliorates depressive-like behavioral traits
Methods: We probed for specific alterations in associative in a genetic rat model for major depression
memory in PTSD and measured the volume of sub portions Saida H 1,2, Kravets E 1, Gersner R 1, Gal R 1, Sredni B 2,
within the CC employing bMRI. Zangen A* 1
1
Results: Our results highlight a reduction in CC white Faculty of Natural Sciences, Dept. of Life Science, Ben-
matter volume in PTSD as compared to controls that was Gurion University of the Negev 2The Mina & Everard
correlated to lower associative performance. Goodman Faculty of Life sciences, Bar Ilan University
Conclusion: We propose that CC volume reduction is a
potential substrate for the associative memory deficits found Background: Approximately 25 % of all patients suffer-
in PTSD. Supported by The German Science Foundation ing from Major Depressive Disorder (MDD) fail to
(DFG, Trilateral Program). respond to traditional antidepressant pharmacotherapy,
thus raising the need for novel therapeutic alternatives.
The effect of number of distractors on perception One approach that is highly effective in treating drug-
of items within the subitizing range resistant MDD is electroconvulsive therapy (ECT), how-
Sadan S*, Goldfarb L ever such extensive and wide-spread brain stimulation
Edmond J. Safra Brain Research Center for the Study of often induces severe side effects which may outweigh
Learning Disabilities, University of Haifa the therapeutic benefit. It has been suggested that re-
peated local stimulations of specific brain circuits may
Background: The brain is tuned to perceive quantities. This achieve a similar therapeutic effect while minimizing the
basic ability exists not only among human adults but also in associated side effects, thereby offering a novel
S104 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
therapeutic approach for MDD. The current study inves- has been a topic of dispute (Sanes et al., 1995). How-
tigated how local subconvulsive electrical stimulations ever, previous investigations of finger somatotopy may
(SCES) affect depressive-like behaviors in a genetic rat have been hindered by the spatial resolution of the
model for MDD. Methods: an extracellular stimulating imaging devices employed. Here we investigated the
electrode was unilaterally implanted in the left ventral functional architecture of the sensimotor cortex using
prelimbic cortex (vPLC) of Depressive Rat Line (DRL) 7- tesla fMRI. Several experiments were conducted in-
rats. These rats have been selectively bred in our lab to cluding: high resolution (1.3 mm) and super high reso-
express depressive-like behavioral traits, which are re- lution (0.75 mm) mapping of motor somatotopy,
sistant to Desipramine treatment but not to ECT. DRL somatosensory finger mapping, and high resolution rest-
rats received 10 sessions of SCES or sham stimulations, ing state scans. Thirteen subjects participated in part or
after which depressive-like behaviors were quantified. all of the experiments. The results revealed representations for
Results: compared with sham stimulations, repeated single digits within the motor cortex, with high selectivity for
SCES of the vPLC in DRL rats increased sucrose pref- specific finger movements. Sampling of different cortical
erence and swimming duration in the Forced Swimming depths, functional connectivity, and inter-hemispheric rela-
Test. tionships between finger regions were examined. These find-
Discussion: we show that the vPLC can be locally stimu- ings shed new light on the functional organization of the
lated to ameliorate genetically-induced depressive-like be- motor cortex during both activity and rest.
havioral traits in rats. RS is supported by the Swiss National Science Foundation
(NCCR Synapsy).
Tapping into the brain: An ultra-high resolution
investigation of the sensory-motor system using 7-Tesla An atypical form of neuronal cell death in neuronopathic
fMRI Gaucher disease
Salomon R* 1,2, Van Der Zwaag W 3, Gruetter R 4,5, Blanke Vitner EB 1, Salomon R 1, Farfel-Becker T 1, Ali M 1,
O 1,2,6 Shinder V 2, Dobrenis K 3, Futerman AH* 1
1 1
Center for Neuroprosthetics, School of Life Sciences, Ecole Dept. of Biological Chemistry, Weizmann Institute of Science,
Polytechnique Fédérale de Lausanne, Switzerland 2Labora- Rehovot, Israel 2Dept. of Chemical Research Support, Weiz-
tory of Cognitive Neuroscience, Brain Mind Institute, Ecole mann Institute of Science, Rehovot, Israel 3Dept. of Neuro-
Polytechnique Fédérale de Lausanne, Lausanne, Switzer- science, Albert Einstein College of Medicine, NY, USA
land 3Dept. of Radiology, University of Lausanne, Lau-
sanne, Switzerland 4 Laboratory for Functional and Background: Gaucher disease (GD) is the most common
Metabolic Imaging, EPFL, Switzerland 5Radiology, Univer- lysosomal storage disorder. This metabolic disorder is
sity of Lausanne, Switzerland 6Dept. of Neurology, Univer- caused by mutations in the gene encoding glucocerebrosi-
sity Hospital, Geneva, Switzerland dase and as a result, glucosylceramide (GlcCer) accumulates
within the cell. Type 2 and 3, the most severe forms of the
Advances in magnetic resonance technology now allow disease, are characterized by neurological impairment and
us to probe the functional architecture of the human neuronal cell death. However, the molecular mechanisms
brain at increasing spatial resolutions. High field scan- leading from GlcCer accumulation to neurodegeneration
ners make it possible to image brain activity at sub- and/or neuronal cell death are as-yet unknown.
millimeter voxel sizes permitting noninvasive imaging Results: We have recently characterized severe neuronal
of functional structures such as ocular dominance col- loss in several brain areas in a murine model of neurono-
umns (Yacoub et al., 2007) or auditory tonotopic maps pathic GD (nGD). Although profound cell death was
(Formisano et al., 2003). These ultra-high resolution detected by both Nissl and FluoroJade B-staining, no
scans also allow segregation of different depths of the TUNEL-positive cells were observed in the affected brain
cortical sheet, providing a glimpse at differential neural areas. Moreover, cell death was not accompanied by eleva-
activity corresponding to activity within different corti- tion in caspase 8 and 9 activities and only a slight increase in
cal layers (Zimmermann et al., 2011). Though the func- caspase 3 was detected in the latest stage of the disease,
tional architecture of the visual cortex has been suggesting that neuronal cell death in nGD is caspase-
extensively explored (Grill-Spector and Malach, 2004), independent. However, although there is no up-regulation
the functional organization of the sensory-motor cortex of caspase 8 activity in nGD mice, RIP1 Kinase, the sub-
is still under debate. For example, though a general strate of caspase 8, appears to undergo cleavage in nGD
somatotopic organization of the motor cortex has been mice brain possibly by an alternative protease, and its cleav-
well documented (Penfield and Boldrey, 1937), the ex- age correlates with disease progression. Moreover, RIP1
istence of somatotopic maps representing single digits Kinase undergoes cleavage in brains from GD type 2 human
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S105
patients in the same manner as in nGD mice. RIPK1 cleav- Towards using MFB stimulation for studying
age was not common to all lysosomal storage disorders, the hippocampal space code in flying bats
suggesting a specific cleavage mechanism in which GlcCer Saraf- Sinik I, Las L*, Ulanovsky N
is involved rather than a general lysosomal-related mecha- Weizmann Institute of Science
nism. Neuronal ultrastructure as detected by transmission
electron microscopy revealed markers of both apoptosis and In recent years, we introduced the bat as a new mammalian
necrosis in nGD brains. model for studying neural codes for space in the hippocampus.
Conclusion: Together, our results suggest an atypical We characterized the functional properties of space-mapping
form of neuronal cell death in neuronopathic Gaucher cells in 2-D and 3-D environments, using a custom neural-
disease. telemetry recording device for freely-flying bats. However,
the repertoire of possible 3-D behavioral tasks for bat hippo-
Cognitive impairments in young ApoE4 targeted campal experiments is currently limited by the experimenter's
replacement mice ability to manually reward fast-flying bats; therefore, it is
Salomon-Zimri S, Boehm A, Michealson DM* desirable to develop a rapid, potent, long-lasting motivator
Tel Aviv University, Tel aviv, Israel for training – such as electrical stimulation of the medial
forebrain bundle (MFB). Indeed, past work in rats showed
Introduction: ApoE4 is the most prevalent genetic risk that MFB stimulation, which releases dopamine, allows train-
factor of Alzheimer disease. ing of rats on highly complex tasks. Here we set out to create
The pathological effects of ApoE4 start decades before the methodology for MFB stimulation in bats. For this purpose,
onset of the disease. We have recently shown, utilizing we developed a lightweight, wireless neural stimulator, which
4 months old ApoE3 and ApoE4 targeted replacement mice, is head-mounted on the bat and is remotely triggered to deliver
that ApoE4 is associated with distinct hippocampal pathol- programmable electrical stimulation via up to 7 independent
ogy (e.g Tau hyperphosphorylation and the accumulation of electrodes. We also characterized anatomically the VTA-MFB
Aβ42 in hippocampal neurons as well as and lower levels of dopaminergic pathway in the bat. We found that MFB stimu-
the presynaptic glutamatergic transporter Vglut). In the lation shaped the bat's behavior very effectively in two-
present study we examined the extent to which the patho- alternative forced choice flight experiments. In future work
logical effects of ApoE4 are associated with cognitive we plan to incorporate MFB stimulation into hippocampal
impairments. This was performed by subjecting 4 months recording experiments, in order to train bats on complex tasks
old ApoE3 and ApoE4 male mice to in battery of cognitive (such as repeatedly flying through a defined 3-D volume), as
tests and assessing the extent to which the performance is well as to prolong recordings by using the long-lasting effec-
affected by the ApoE genotype. tiveness of MFB stimulation. To allow this combination of
Results: Morris water maze revealed that ApoE3 mice per- stimulation and recordings, we are now developing a "Neuro-
formed better than the corresponding ApoE4 mice both in Logger" – wireless device that will include a 7-channel wireless
learning and memory tasks. Further studies utilizing the stimulator, as well as a high-quality headstage and amplifier for
object recognition test. This revealed that the ApoE4 mice 16-channel neural recordings of spikes, which will store up to
were impaired relative to the ApoE3 mice in their ability to 2 hours of wideband neural data on a flash memory on-board
distinguish between old and new objects and this was asso- the animal. This unique device will weigh <6 gr, including
ciated with decrease exploration. Control experiments battery, and will be the first of its kind in the world.
revealed that the velocity and locomotion of ApoE4 was
similar to those of ApoE3 mice. Fear conditioning experi- Effects of picture repetition on oscillatory MEG gamma
ments which were performed on the same mice used in the band activity in patients with schizophrenia
object recognition test revealed a decrease in the freezing Sauer A* 1,2, Castellanos NP 3, Singer W 1,2, Uhlhaas PJ 1,4
1
time of the ApoE4 mice relative to the ApoE3 mice. This Dept. of Neurophysiology, Max Planck Institute for Brain
effect however was not statistically significant. Lastly, the Research, Frankfurt am Main, Germany 2Ernst Strüngmann
ability of the mice to nest was assessed. This revealed that at Institute (ESI) for Neuroscience in Cooperation with Max
the age of 4 months, both ApoE3 and ApoE4 build nests but Planck Society, Frankfurt am Main, Germany 3Laboratory
the ApoE4 mice do so less efficiently.This effect was age of Cognitive and Computational Neuroscience, Centre for
dependent and was much more pronounced in 1 year old Biomedical Technology, Universidad Politécnica de
ApoE4 mice. Madrid, Spain 4Institute of Neuroscience and Psychology,
Conclusions: The results show that male ApoE4 mice are University of Glasgow, Scotland
cognitive impaired at the age of 4 months. The extent to which
these cognitive deficits are related to the neuropathological Background: Cognitive dysfunctions represent a core feature
effects will be discussed. of schizophrenia and a predictor for disability and long-term
S106 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
outcome. Impaired learning due to reduced cortical plasticity brain-derived neurotrophic factor (BDNF), and stress-
may constitute one possible mechanism for the cognitive mediating factors in dams as well as nulliparous (NP) mice.
deficits. In the current study, we aimed to explore whether The impact of CB1R deficiency upon maternal care was
experience-dependent modifications of cortical networks are assessed by time to retrieve pups, as well as the pups'
disturbed in patients with schizophrenia. ultrasonic vocalization and body weight.
Methods: To address this issue, we employed magnetoence- On postpartum day 8, wild type (WT) dams displayed
phalography (MEG) during a repetition priming paradigm in a elevated levels of CB1R and OXTR in the hippocampus
sample of chronic patients with schizophrenia, and in a group compared to NP mice. In contrast, CB1R KO dams showed
of healthy controls. Repetition priming refers to the change in no such elevation of OXTR expressionin comparison to NP
speed and accuracy in processing a stimulus following prior mice. Furthermore, CB1R KO dams exhibited lower hippo-
exposure to the same stimulus and is thought to be a form of campal OXTR and higher corticotropin-releasing hormone
implicit learning. Recent neuroimaging studies have shown (CRH) mRNA levels when compared to NP mice. These
that behavioral priming is typically associated with a decrease effects were not seen among WT dams in comparison to NP
of neural activity (repetition suppression) which has been mice. Serum oxytocin levels in NP CB1R KO were higher
related to the sharpening of the underlying neural network. than in NP WT, but no difference was found between CB1R
In the experiment, pictures of everyday objects were presented and WT dams. Hippocampal BDNF mRNA levels of CB1R
three times and repeated either consecutively or with 5-15 KO mice were lower than those of WT mice, among both
different intervening stimuli. The participants' task was to dams and NP animals.
decide whether the object was natural or man-made. MEG Thus, it appears that the blocking of endocannabinoid
signals were analyzed for spectral changes in oscillatory ac- signaling by CB1R deletion alters expression of genes involved
tivity in the frequency range of 25-200 Hz. in hippocampal regulation of the stress response, leading to
Results: Compared to healthy controls, schizophrenia patients deleterious effects upon maternal behavior.
showed a reduced behavioral priming effect and significantly
reduced repetition suppression of gamma-band activity over Cell-targeted holographic retinal photo-stimulation
parieto-occipital sensors. These effects were more pronounced in vivo
for repetitions that were temporally separated. Schejter A* 1, Tsur L 1, Farah N 1, Reutsky-Gefen I 1,2,
Conclusions: These results suggest that schizophrenia is Shoham S 1
1
associated with aberrant learning-dependent modifications Faculty of Biomedical Engineering, Technion IIT, Haifa
2
of neural oscillations which could be involved in cognitive Dept. of Medical Engineering, Ruppin Academic Center,
dysfunctions of the disorder. Emek Hefer
CB1 receptor deficiency affects maternal behavior Background: Degenerative diseases of the outer retina lead
and alters the dam's hippocampal oxytocin receptor to photoreceptor loss and eventually cause blindness. How-
and BDNF expression ever, the retinal ganglion cells (RGCs) are relatively pre-
Schechter M 1,2,3, Weller A 4, Pittel Z 1, Zimmer A 5, served. Artificial photo-stimulation of these functional cells
Pinhasov A* 1 could be the key to developing retinal neuroprosthetic devi-
1
Dept. of Molecular Biology, Ariel University Center of ces, which will restore patients' vision. A successful retinal
Samaria, Ariel, Israel 2Faculty of Life Sciences, Bar Ilan prosthesis should induce activity patterns which will enable
University, Ramat-Gan, Israel 3Gonda Brain Research Cen- downstream circuits to correctly interpret the artificially
ter, Bar Ilan University, Ramat-Gan, Israel 4Dept. of Psy- generated stimulus as the intended image. In previous work,
chology and Gonda Brain Research Center, Bar Ilan we demonstrated patterned photo-stimulation of RGCs in-
University, Ramat-Gan, Israel 5Institute of Molecular Psy- vitro, using optogenetic and photo-thermal mechanisms.
chiatry, University of Bonn, Bonn, Germany Methods: The research presented here constitutes a first step
in advancing towards in-vivo retinal stimulation. We have
Maternal care is the newborns' first experience of social constructed a system which integrates precise spatiotemporal
interaction, which affects their development and social com- holographic photo-stimulation with high resolution fundus
petence throughout life. For the first time, we investigated imaging. This system allows one to target the projected pattern
the involvement of the endocannabinoid system (ECS) in at specific locations in order to excite desired RGCs.
mother-infant interaction in mice. We recently found that Results: The system was utilized to acquire both brightfield and
postpartum blocking of the CB1R endocannabinoid receptor fluorescence fundus images of mice and rats in-vivo. In addition,
impaired maternal behavior. In this study, we examined the holographic patterns were projected onto the rodents’ retinas
impact of complete deletion of the CB1R (CB1R KO) on and imaged. The optical parameters of the holographic
hippocampal expression of oxytocin receptor (OXTR), photo-stimulation system have been characterized. The
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S107
system’s imaging resolution allows one to identify sin- associated with depression such as EEG activity and
gle RGCs for stimulation. The stimulation spot diameter neurocognitive measures, have been examined for the
is sufficient for cellular targeting using patterned photo- impact of polymorphic variation in genes such as brain
stimulation in-vivo. derived neurotrophic factor (BDNF).
Conclusions: Our system enables single-cell resolved Conclusions: Our understanding of the genetic contributors
patterned holographic photo-stimulation of RGCs. In addi- to the mood disorders is still developing, with no genes of
tion, it could prove to be a basic tool for non-invasive in-vivo major effect having been identified. However, using com-
small animal retinal imaging in a wide array of vision appli- plementary approaches, progress has been made in identify-
cations, including the tracking of fluorescently tagged cells ing a number of genes which contribute to the risk of
and the expression of gene-therapy and optogenetic vectors. developing depression or bipolar disorder.
Furthermore, functional calcium imaging may be performed National Health and Medical Research Council, Australia;
using this system in order to translate the aforementioned Australian Research Council.
research to an in vivo setup.
We gratefully acknowledge the financial support of the Harnessing immune cells to the benefit of the central
European Research Council (grant #211055). nervous system: no longer 'if' but 'how'
Schwartz M
Genetic approaches to understanding the etiology Neurobiology, The Weizmann Institute, Rehovot
of mood disorders
Schofield PR* 1,2, Fullerton JM 1,2, Gatt JM 3,4, Williams Introduction: The central nervous system (CNS) tissues,
LM 3,4, Mitchell PB 5,6 including the brain, the eye and the spinal cord, are
1
Neuroscience Research Australia, Sydney, Australia immune-privileged, secluded from the circulation by a com-
2
School of Medical Sciences, University of New South plex of barriers and equipped with their own myeloid cell
Wales, Sydney, Australia 3The Brain Dynamics Centre, population, the resident microglia. Based on the classical
Westmead Millennium Institute, Sydney, Australia 4Psycho- perspective of immune-brain interactions and on the contri-
logical Medicine, Western Clinical School, University of bution of such interactions to the progression of Multiple
Sydney, Australia 5School of Psychiatry, University of New Sclerosis, an autoimmune inflammatory disease of the CNS,
South Wales, Sydney, Australia 6Black Dog Institute, Sydney, circulating immune cells were traditionally viewed as an
Australia enemy of the nervous system. However, over the past two
decades, we demonstrated the pivotal role of monocyte-
Background: Within the mood disorders, depression is derived macrophages and adaptive immune cells in CNS
moderately heritable whereas bipolar disorder is highly her- repair and functional plasticity including neurogenesis, cog-
itable. This suggests that differing approaches may be of use nition, and coping with mental stress. The biggest eniga has
in attempting to identify genetic contributors to these con- been how the immmune cells get excess to the traumatized
ditions. Genetic linkage analysis and fine mapping associa- CNS, given its unique structure, and where is the site of their
tion studies of bipolar disorder has led to the identification activity in the healthy CNS.
of several potential candidate loci and susceptibility genes, Results: We have identifies the unique routes through
while genome wide association studies have also led to the which immune cells infiltrate to the traumatized CNS
identification of several potential susceptible genes. A sec- that does not necessitate break down of barriers but
ond approach, used more frequently in studies of depres- rather activation of a physiological route of entry the
sion, is to examine the effect of polymorphic variation in choroid plexus epithelium that we identified as a site
previously implicated candidate genes on biomarkers asso- that orchestrates the fate of the infiltrating cells to drive
ciated with illness. a risk-free benefit for their repairing effect. In the
Results: Linkage studies of bipolar disorder have implicated healthy CNS we identified how the same site, the cho-
a locus on chromosome 15q25-26 and fine mapping associ- roid plexus epithelium, as a site whereby adaptive im-
ation studies have identified the sialyltransferase gene munity controls in a remote way CNS plasticity, and
ST8SIA2 as a putative bipolar susceptibility gene. Rese- how such immunity from essential becomes detrimental
quencing analysis of the sialyltransferase gene and one of with aging.
its targets, NCAM1, have given insights into the genetic Conclusions: Taken together, these recent advances re-
variation that may underpin susceptibility for bipolar veal a dramatic therapeutic opportunity for controlled
disorder. International collaborative genome wide asso- harnessing immune cells for repair of the damaged
ciation studies have have led to the characterisation of CNS following acute insults, and for modulating the
candidates such as neurocan (NCAN), calcium channels aging, distressed and neurodegenerative conditions, and
(CACNA1C) and ODZ. Finally, biomarker traits in psychiatric disorders.
S108 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
The role of sexually dimorphic hypothalamic neurons Results: We found that participants with ADHD resolved
in regulation of maternal responses conflicts between meanings slower than controls. The differ-
Scott N*, Kimchi T ence between the groups became more pronounced as a func-
Dept. of Neurobiology, Weizmann Institute of Science, Rehovot tion of the conflict complexity. We also found a significant
76100, Israel correlation between the executive attention score (measured
by a location-direction Strooplike task) and the efficiency of
The hypothalamus plays a critical role in coordinating the conflict resolution in a metaphorical processing task.
expression of reproductive behaviors and physiological Conclusions: The study suggests that attentional functions
responses with environmental cues. Its close anatomical modulate high level language processing, though partici-
and physiological relationship with the pituitary gland pants with ADHD may show intact structural language but
provides an effective means for coordinating diverse inefficient processing of figurative language. The study
homeostatic processes through neuroendocrine regulation emphasizes the connections between the attentional networks
of hormone secretion. The hypothalamus contains sexual and language processing, and offers to use sensitive and
dimorphic areas which are different in morphology, den- specific language evaluation tools, to assess abilities and
sity, gene expression and neuronal projections. One of difficulties of participants with attention disorders.
the sexually dimorphic neuronal populations in the hy- The first author is funded by a President’s Excellence PhD
pothalamus is tyrosine hydroxylase expressing (TH-ir) fellowship, Hebrew University
neurons whose number is greater in female than in male
mice. The role of the sexual dimorphism of these TH-ir A BBB disrupter is also a potent alpha-Synuclein
neurons is still unknown. In this work we used 6- aggregation Inhibitor: a novel dual mechanism
hydroxydopamine (6-OHDA) to "masculinize" the num- of mannitol for the treatment of Parkinson's disease
ber of a specific TH-ir neuronal population in the hy- Segal D* 1, Shaltiel-Karyo R 1, Frenkel-Pinter M 1, Rockenstein
pothalamus of adult female mice. 6-OHDA is a E 2, Patrick C 2, Levy-Sakin M 1, Egoz-Matia N 1, Masliah E 2,
neurotoxin known to selectively ablate dopaminergic Gazit E 1
1
and noradrenergic neurons. Our results indicate that Dept.of Molecular Microbiology & Biotechnology, Tel Aviv
TH-ir lesioned females exhibit lower maternal behavior. University 2Dept of Neurosciences, UCSD, San Diego, CA
This suggests that the sexually dimorphic TH-ir neuro-
nal population in adult mice is involved in regulation of Misfolding and aggregation of α-synuclein (α-syn) is the
sexually dimorphic parental behavior. hallmark of Parkinson's disease (PD). No disease modifying
treatment is available for PD. Osmolytes, such as polyols,
The role of attention in the resolution of verbal conflicts are small molecules which accumulate under stress condi-
while processing metaphorical language among adults tions and stabilize protein structure, acting as 'chemical
with ADHD and without it chaperones'. Thus, they may reduce protein misfolding and
Segal D* 1, Mashal N 2, Shalev Mevorach L 3 aggregation in neurodegenerative diseases. The polyol Man-
1
The Hebrew University 2Bar-Ilan University 3Tel-Aviv nitol is one such compound. It is a non-metablolized FDA-
University approved osmotic diuretic agent that also has BBB disrupt-
ing properties. We examined the ability of Mannitol to
Background: Conventional metaphors are expressions that interfere with the aggregation of α-syn in vitro and in vivo.
lost their metaphoricity due to repeated use. In order to under- Low concentrations of Mannitol (450 and 225 mM)
stand conventional metaphors like 'time is money' people must inhibited the in vitro formation of α-syn fibrils. High con-
make an appropriate abstraction of the vehicle ("money") and centrations (900 mM) significantly decreased formation of
inhibit its literal meaning. Therefore, we assume that in early tetramers and high molecular weight oligomers, and shifted
stage of processing, there is a competition between the literal the secondary structure from a-helical to a different struc-
and the metaphorical meanings. Thus, we offer to refer to this ture, suggesting alternative potential pathways for aggrega-
competition as a conflict resolution task. Attention deficit/hy- tion. Feeding α-syn expressing Drosophila, which serve as
peractivity disorder (ADHD) is a chronic disorder of childhood an established model for PD, with 75 mM Mannitol dramat-
onset that persists into adolescence and adulthood. Individuals ically corrected their behavioral defects and reduced the
with ADHD often demonstrate difficulty with 'executive atten- amount of a-syn aggregates in their brains. Daily injection
tion' that is manifested in a difficulty to resolve conflicts be- (IP) of 1 g/kg Mannitol to mThy1-human α-syn transgenic
tween stimuli and/or responses. In the current study we mice caused a significant decrease of α-syn accumulation in
addressed the question whether adults with ADHD are less several brain regions, suggesting that Mannitol promotes α-
efficient in processing conventional metaphors and resolving syn clearance from the cell bodies. Mannitol appears to have
conflicts between their literal and metaphoric meaning. a general neuroprotective effect in the transgenic treated
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S109
mice, which includes the dopaminergic system. No adverse Elevation of Nrf2 in Astrocyte mediates neuroprotection
effects were observed in control Mannitol-treated flies or in stroke in an IL-10-dependent manner
mice. We therefore suggest Mannitol as a basis for a dual Segev Amzaleg N 1, Trudler D* 2,1, Frenkel D 2,1
mechanism therapeutic agent for the treatment of PD – a 1
Dept. of Neurobiology, George S. Wise Faculty of Life
BBB disruptor that will also serve by itself as a chemical Sciences, Tel Aviv University, Tel Aviv, Israel 2Sagol School
chaperone correcting the pathogenic misfolding of α-syn. of Neuroscience, Tel Aviv University, Tel Aviv, Israel
Parkinson' Disease Foundation
Background: Oxidative stress plays an important role in the
Cannabinoid and glucocorticoid receptors in the amygdala pathogenesis of different brain insults such as stroke. Astroglia
modulate the stress- induced impairment of LTP are the main glial cells that play a fundamental role in main-
in the hippocampal-accumbens pathway taining the homeostasis of the CNS and are important for
Segev A, Akirav I* protection, and aid the brain in the functional recovery from
Dept. of Psychology, University of Haifa injuries. It was shown that the brain can be prepared to with-
stand an oxidative stress insult by a process known as precon-
Background: Exposure to acute stress results in release ditioning. We investigated whether preconditioning to mild
of glucocorticoids which are potent modulators of both oxidative stress and glucose deprivation (OSGD) of astroglia
learning and plasticity, and these effects are presumably can lead to better cell survival and to neuroprotective features.
mediated by the basolateral amygdala (BLA). Since high Results: We discovered in our work selective changes in
densities of cannabinoid CB1 receptors are expressed in astroglia activity when preconditioned to mild vs. severe
the BLA, and our previous data suggest that cannabinoid oxidative stress. Interestingly, we discovered significant in-
receptor agonists in the BLA can prevent the effects of crease in levels of the anti-inflammatory cytokine IL-10 vs.
stress on learning and memory, the present experiment pro-inflammatory cytokine IL-1β, in mild vs. severe oxidative
investigated whether cannabinoid receptor activation and stress, respectively. We discovered that preconditioning astro-
glucocorticoid receptor (GR) blockade in the BLA can glia to mild OSGD increases survival to second insult through
alleviate the effects of acute stress on plasticity in the activation of Nrf-2 pathway. Furthermore, we discovered that
ventral subiculum (vSub)-nucleus accumbens shell preconditioned astroglia are neuroprotective in an IL-10-
(NAcS) pathway. dependent manner. By using tert-Butylhydroquinone
Results: We examined: (a) whether intra- BLA microinjec- (tBHQ), a known specific activator of Nrf-2, we suggest that
tions of Ru-486 (RU), a GR antagonist, or WIN55,212-2 Nrf-2 can enhance IL-10 expression.
(WIN), a CB1/2 receptor agonist, can reverse the effects of Conclusion: We demonstrated that preconditioning astro-
acute stress on plasticity in the vSub-NAcS pathway, and (b) glia to mild oxidative stress increase cell survival through
whether RU and WIN can normalize the stress-induced elevation of Nrf2 and increase neuroprotection through se-
alterations in the levels of phosphorylated cAMP response cretion of IL-10. Further studies of Nrf-2 mediated cellular
element-binding protein (pCREB) in the NAcS. Both bilat- pathways in astroglia through IL-10 may provide useful
eral and contralateral BLA administration of RU or WIN insights into the development of therapeutic intervention
reversed the impairing effects of stress on vSub-NAcS LTP. following oxidative stress insults, such as ischemic stroke
Administering RU or WIN bilaterally into the BLA with no and other neurological insults.
stress exposure also impaired LTP. Further, exposure to
stress or WIN-only significantly reduced pCREB levels in Giving the brain a helping hand: manipulating empathy
the NAcS compared with the vehicle group and this effect through motor action
was normalized in rats exposed to both stress and intra-BLA Shaham G* 1, Perry A 2, Aviezer H 1, Bentin S 1,3
1
WIN. Dept. of Psychology, Hebrew University of Jerusalem,
Conclusions: The results suggest that the preventing Jerusalem, Israel 2Dept. of Psychology, University of
effects of intra-BLA WIN and RU on vSub- NAcS Haifa, Haifa, Israel 3Interdisciplinary Center for Neural
plasticity are not necessarily mediated through a direct Computation, Hebrew University of Jerusalem, Jerusalem,
pathway from the BLA to the NAc, and that CREB Israel
activation in the NAcS is involved in the preventing
effects of WIN. RU and WIN reverse the effects of stress Background: Viewing motor actions performed by another
on plasticity and hence could represent a therapeutic person causes automatic activation of motor brain circuits
target for the treatment of stress-induced cognitive involved in producing the same actions. Different theories
impairments. suggest that empathy relies on this kind of motor resonance
This research is supported by The Israel Science Founda- between self and other. However, support for these theories
tion (grant no. 222/08 to I.A.) is usually limited to correlational data, not allowing to infer
S110 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
causality. If one could experimentally manipulate motor res- pathology occurs in multiple regions, involves multiple
onance, it would be possible to test its causal connection to interneuron types and impacts GABA receptor levels. Inter-
empathy. Continuous muscle contraction elicits far reaching neurons require growth factors for their differentiation and
cognitive effects that can last up to several minutes after the survival and we find promoter-specific reductions in cortical
motor manipulation. These effects are attributed to the spread- BDNF in people with schizophrenia and an unexpected
ing of Mu-rhythm desynchronization over central and frontal increase in the truncated BDNF receptor, trkB, changes
brain areas. Interestingly, during action observation, motor which are strongly correlated with interneuron demise. We
resonance is thought to be indexed by similar Mu rhythm have evidence that interneurons are displaced and found in
desynchronization. It is possible then, that the muscle contrac- the white matter [previously termed interstitial white matter
tion paradigm can also affect motor resonance. neurons (IWMNs)]. Our observation challenges the long-
Hypothesizing that such modulation can indeed occur, we held interpretation that these IWMNs are subplate neurons
explored the possibility of affecting empathic ability by and suggests instead that they are derived from the ventral
activating the motor system. Participants rated the valence telencephalon. This is important as the ventral telencephalon
and arousal of their reaction to emotional facial expressions produces neurons capable of migration to areas of cortical
and completed a test of emotion recognition after continu- injury in adulthood and we have evidence that cortical
ously squeezing a ball or after rest. injury and neuroimmune activation occurs in a subset of
Results: Preliminary data suggests that contracting both people with schizophrenia (~40 %). We suggest that in-
hands or only the left hand results in enhanced emotion creased IWMN density found in people with schizophrenia
recognition compared to rest, with both-hands contraction may represent new neurons being recruited to the damaged
yielding the larger effect. cortex in an attempt to rebuild. Our working model is that
Conclusions: These data are a first step in establishing a para- people with schizophrenia will have altered interneuron
digm that can manipulate motor resonance. This has the potential development due to multiple factors that reflect the hetero-
of providing an easy, yet powerful technique to investigate the geneous nature of the illness, such as genetic variation in
long hypothesized causal role of motor resonance in empathy. interneuron growth factors or variations in hormone respon-
siveness. For example, some patients carry risk variants in
Incubation of craving and fear: behavioral and neuronal the schizophrenia susceptibility gene neuregulin (NRG1)
mechanisms which changes expression levels of NRG1 and alters the
Shaham Y* 1,2 development and maturation of cortical interneurons, while
1
Intramural Research Program 2NIDA-NIH others exhibit worse symptoms when estrogen signalling is
low and low estrogen is known to impair neuronal matura-
Using a rat model of drug relapse and craving, we previous- tion and survival. We have begun to test the extent to which
ly found time-dependent increases in cue-induced cocaine stimulation of estrogen receptor alpha (ERa) can bring about
seeking after withdrawal from the drug, suggesting that clinical improvement.
cocaine craving incubates over time (Grimm et al. Nature
2001). In this lecture, I will summarize results from studies The modulatory effect of Munc13-1 and PKC on neuronal
on the generality of this incubation phenomenon to other network activity
drug and non-drug rewards and to fear conditioning in a rat Lavi A* 1,2, Shapira R 1, Ashery U 1,2
1
model of delayed-onset PTSD. I will then summarize results Dept. of Neurobiology, the George S. Wise Faculty of Life
from a series of studies on the neuronal mechanisms of sciences, Tel Aviv University, Tel Aviv.2Sagol School of
incubation of drug craving. These include recent studies Neuroscience, Tel Aviv University, Tel Aviv
on the role of Toll-like receptor 4 (an innate immune system
pattern recognition receptor) in incubation of heroin crav- Background: Neuronal neurotransmitter release is a tight-
ing, and the role of orbitofrontal cortex neuronal ensembles ly regulated process controlled by complex protein ma-
in this incubation. Supported by NIDA chinery at the synapse. Munc13-1 is an active zone
protein regulating the priming process of synaptic
Neurobiology of Schizophrenia vesicles into a fusion competent state. Diacylglycerol
Shannon Weickert C* 1,2,3 (DAG) and phorbol esters potently potentiate synaptic
1
Neuroscience Research Australia, Sydney, Australia 2Uni- transmitter release by activating protein kinase C (PKC)
versity of New South Wales, Sydney, Australia 3Schizophrenia and Munc13 in parallel pathways. Here, we used micro-
Research Institute, Sydney, Australia electrode arrays (MEAs) to elucidate the effect of
Munc13-1 overexpression on the activity of cortical neu-
There is widespread agreement that cortical interneurons are ronal networks and its relative role in the phorbol ester
pathological in schizophrenia. We have shown that this potentiation of cortical transmission.
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S111
Results: In networks grown on MEA plates the activity load was manipulated by road curvature: (1) curve road
converges into a synchronized mode of spiking activity (complicated) produced high perceptual load, (2) straight road
(network burst) separated by periods of reduced acti- produced low perceptual load. Single (BT or CDT) and dual
vity. Cortical networks overexpressing Munc13-1 tasks (both tasks simultaneously) were used. Response times
showed enhanced network activity with increased net- (RTs) to LV and accuracy rates to color changing billboards
work burst rate and reduced inter-burst interval. The recurring were compared according to the perceptual load (curve vs.
bursting activity reduced the network synchronization and led straight). As expected, accuracy for CDT deteriorated under
to a significant decrease in the number of spikes in each burst. high perceptual load. Hence, the interference effect by the IS
While phorbol-ester 12,13-dibutyrate (PDBu) dramatically task was undermined under high perceptual load, whereas
increased the network firing rate and disrupted the network under low perceptual load it was practically unimpaired. The
synchronization, the PKC blocker Gö6983 only partially data suggest that high perceptual load may assist drivers to
reduced the potentiation. As Munc13-1 overexpression ignore IS task to the driving primary task, thus drivers may
caused similar effects as PDBu after PKC inhibition by focus more attention on RS (e.g., hazards).
Gö6983, it is reasonable to assume that the remaining effects A final course project: Introduction to Traffic Safety, Prof.
of PDBu are attributed to the activation of Munc13-1 by D. Shinar and Mrs. I. Oppenheim
PDBu.
Conclusions: This work demonstrates how manipulation of From a visual to a symbolic object in algebra and geometry:
Munc13-1 expression levels in the cellular level affects the ERP study with mathematically excelling male adolescents
neuronal network activity. Although Munc13-1 supports Shaul S 1,2, Waisman I 1, Leikin M 1, Leikin R 1
1
increased transmitter release in the cellular level it alters University of Haifa 2Edmond J. Safra Brain Research
neuronal network activity by inducing smaller bursts at a Center for the Study of Learning Disabilities
higher frequency; possibly as a result of insufficient vesicle
replenishment. Our data suggest a role for both PKC and Background: In this study we performed a comparative
Munc13-1 in PDBu potentiation of cortical network activity. analysis of brain activity associated with transition from
visual objects to symbolic objects in algebra and geometry.
The role of perceptual load in driving: eliminating Algebraic tasks required translation from graphical to sym-
interference of irrelevant task during driving bolic representation of a function whereas tasks in geometry
Shaposhnik H required transition from a geometrical object to symbolic
Dept. of Brain and Cognitive Science, Ben Gurion University representation of its property. We focused on brain activa-
of the Negev tion associated with solving advanced mathematical tasks
by adolescents excelling in mathematics who differ in their
Drivers' attention can be modulated by relevant and general giftedness level.
irrelevant stimuli (RS, IS) presented inside and outside Results: Geometry and Algebra Tests were designed of
the vehicle. Those IS (e.g., Smartphones, billboards) batteries of short choice-reaction tasks. 32 right-handed
tend to impose costs such as high information load on male-students who excel in mathematics were chosen for
drivers, interrupting the primary purpose of safe driving, comparative data analysis. We found that non gifted (NG)
the detection and/or recognition of critical events. Per- participants had higher brain activity than their gifted (G)
ceptual load theory (Lavie, 1995) describes the process- counterparts. This difference was significant in the first
ing of IS, suggesting that the extent to which IS can be stage of the task, 300-400 ms post stimulus at parieto-
ignored depends on how the processing of RS is affect- middle areas of the cortex. Moreover, higher brain activity
ed by perceptual load. Thus, under high attentional load was found during the geometry test as compared to the
perceptual resources are fully occupied so there is no algebra test. In addition laterality differences for found
capacity left for processing IS, and the effect of IS can between the different types of tests.
be eliminated. The current study examined whether Conclusions: The finding are consistent with the neural
drivers are capable of ignoring visual irrelevant tasks efficiency hypothesis of intelligence, stating that brighter
under conditions of high perceptual load. The author individuals display lower (more efficient) brain activation
used driving simulation video scenarios in which, while while performing cognitive tasks (for review see Neubauer
following a lead vehicle (LV), participants responded to & Fink, 2009). These differences seem to stem from the
the LV's braking lights, and detected color changing different visual-spatial strategies of processing in the intro-
billboards. Participants had to ignore the color changing duction stage. ). In addition, we can argue that geometric
billboards, defined as low prioritized change detection task tasks increase the participants' working memory load by
(CDT; irrelevant task) to the main driving task, and to assign keeping the visual geometric object in working memory
high priority to the braking task (BT; relevant task). Perceptual until the problem is solved.
S112 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
Depressive disorders and cognitive impairment PSD95 from the cytosol to the membrane and its commu-
may share similar molecular mechanisms nication with sub-synaptic molecules. Impaired expression
Sheinin A 1,2, Nesher E 3, Gross M 3, Borovok N 1, of Dlgap members was reported in fragile X syndrome and
Pinhasov A 3, Michaelevski I* 1,2 in mental disorders. We have shown abnormal Dlgap2 ex-
1
Dept. of Biochemistry and Molecular Biology, Tel-Aviv Uni- pression associated with maladaptation to trauma in PTSD-
versity 2Sagol School of Neuroscience, Tel-Aviv University like rats. The aim of this study was to identify a role for
3
Dept. of Molecular Biology, Ariel University Center, Ariel Dlgap2 in PSD zone and in synaptogenesis by its silencing
in Sprague-Dawley rat hippocampal primary culture. Time-
Background: Age-related cognitive impairment is a devastat- dependent morphological changes of cultures, which includ-
ing disorder of unclear etiology developing over a period of ed increased neurits length and number, with no change in
years. Memory deficit is one of the strongest manifestations of cell size, were associated with bell a shape-like change in
this disorder. Depression and apathy are common comorbidities mRNA and protein levels of Dlgap2. Additional members
presenting with cognitive impairments. We developed animals of PSD, such as PSD95, Neuroligin (NLG) 1 and 2 and
with strong dominant and submissive phenotypes, of which NMDA receptor subunits NR2A and NR2B showed parallel
submissiveness is an essential element of depressive condi- changes in their mRNA levels, which were highly correlated
tions, and antidepressant drugs from different classes and gen- with those of Dlgap2. Silencing of Dlgap2 using shRNA
erations tend to reduce submissive behavior. In this study we technique, which resulted in 73 % reduction in Dlgap2
attempt to find functional substrates common to the develop- mRNA and 62 % of its protein levels was associated with
ment of cognitive impairments related to submissive behavior, a significant reduction in PSD95 mRNA levels (35 %). A
an important element of depressive conditions, and to aging. tendency towards significant reduction was also observed in
Results: Use of the Morris water maze and new object recog- two additional PSD zone proteins CAMK2 and NR2B, while
nition paradigms showed that although young (3 months) not in NLG1, NLG2 and NR2A. Concomitantly, synapto-
submissive animals' performance was similar to dominant genesis, measured by co-localization of synapsin1 and
and wt mice, it markedly declined with advanced age PSD95, pre and post-synaptic markers, respectively, was re-
(9 months), in comparison to their dominant and wt counter- duced by 42 % in Dlgap2 silenced cultures. The data suggest a
parts. Despite the absence of cognitive dissimilarity at the role for Dlgap2 in synaptogenesis and in the modulation of
early stage of life, electrophysiological study revealed signif- mRNAs of the PSD members. The latter may be through the
icant differences in short- and long-term synaptic plasticity interaction of Dlgap2 as well as other members of the PSD
between dominant and submissive animals: acute hippocam- with the mRNA binding protein FMRP. We believe that if
pal slices taken from submissive mice failed to develop paired verified such a mechanism may be of relevance to impaired
pulse facilitation in the CA1 region upon stimulation of postsynaptic function in mental disorders.
Shaffer collaterals, in contrast to dominant counterparts.
Moreover, upon application of primed burst (PB) stimulation The compositional representation of trajectory in the motor
paradigm, we observed strong sustained LTP in submis- cortex: An fMRI study
sive mice, which declined within an hour among slices Shmuelof L*, Kodl J, Flash T
from dominant mice. In addition, qPCR analysis Dept. of Computer science and applied Mathematics, Weizmann
revealed that IGF-1 (deficit of which is associated with Institute of Science, Israel
cognitive impairment and dementia) mRNA levels were
significantly lower among submissive animals in com- Human actions are highly stereotypical despite the large
parison to dominant and wt mice. number of degrees of freedom available at the anatomical,
Conclusions: This study further demonstrates that depressive- kinematic, and neural control levels. These redundancies
like state may accelerate cognitive impairments. may be simplified by the construction of elementary control
building blocks (primitives). Despite the appeal of this the-
The role of Dlgap2 (SAPAP2) in PSD zone; possible ory, the neural substrates of primitives are still unknown. Of
implication to synapse formation a particular interest are the primitives underlying curved
Shertser K, Chertkow-Deutsher Y, Ben-Shachar D trajectories: while could be composed of a superposition of
Laboratory of Psychobiology, Dept. of Psychiatry, B. straight strokes, curved trajectories have recently shown to
Rappaport Faculty of Medicine, Technion IIT and Rambam be composed of parabolic elements (Polyakov et al., 2009).
Medical Center Haifa, Israel. We used a task developed by Hocherman and Wise (1991),
where subjects are required to reach 3 targets employing
Disks Large-Associated Protein (Dlgap) family is one of the curved and straight trajectories. Using classification meth-
less studied components of the PSD zone. It was proposed ods of fMRI signals, we examined the neural substrates of
to mediate the translocation of the scaffolding protein primitives by searching for cortical areas that show
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S113
sensitivity to trajectory shape irrespectively of its position in to cognitive decline, the present study shows that aging-
space (e.g. generalization). The differential representation of related changes in non-reactive microglia are brain-region
straight and curved trajectories was examined within regions dependent and closely correlate with behavior. Ladostigil
of interest and across the whole brain. Classification analy- prevents these changes keeping the relation to cognition
sis showed generalization of trajectory shape across space in similar to that of adult rats.
premotor dorsal (PMD) and caudal parietal cortex. While in
primary motor cortex (M1) classification rates for trajecto- Lost in translation: failure of the NMDA antagonists
ries were higher than chance, generalization was not found. clinical trials in TBI and stroke
This result suggests that movement shape is represented in Shohami E* 1, Biegon A 2
1
PMD and its specification in space is represented in M1. Dept. of Pharmacology, Institute for Drug Research, The
Whole brain comparison between straight and curved tra- Hebrew University, Jerusalem, Israel 2Medical Dept.,
jectories revealed increased activation for curved trajectories Brookhaven National Lab, Upton, NY, USA
in motor and visual cortices. Yet, classification analysis in
M1 and PMD showed higher classification rates for the For more than two decades the intensive research effort on
straight trajectories. These results suggest that the neural the role of NMDA receptors (NMDAR) in traumatic brain
representation of curved trajectories may correspond to the injury (TBI) and cerebral ischemia (stroke) was led by
superposition of multiple elements. Our results provide observations from in-vitro and in-vivo studies that overstim-
insights into the dynamic compositional organization of ulation of these receptors plays a major role in brain pathol-
movements along the cortical motor hierarchy. ogies. NMDA-mediated glutamate toxicity is considered
responsible, at least in part, for the devastating neurological
Ladostigil prevents aging-related changes in microglia: and psychiatric sequelae of head trauma and stroke.
brain region-dependence and correlation with cognition In view of this concept studies in animal models have dem-
Shoham S*, Weinstock M onstrated that indeed, NMDAR antagonists improve outcome
Hebrew University, Institute for Drug Research after TBI and stroke. These findings led to some large scale
placebo-controlled clinical trials with NMDAR antagonists.
Background: We have shown that ladostigil, a drug that However, all these trials have demonstrated either no benefit
inhibits cholinesterase and monoamine oxidase, prevents or even deleterious effects suggesting that NMDAR inhibition
aging-related cognitive decline. Although ladostigil attenu- is either irrelevant or even harmful for TBI and stroke out-
ates reactive microgliosis in some brain regions the correla- come. Critical review of the reports on these clinical trials
tion with cognitive performance is not consistent. In the suggest that in the translational phase not enough attention
present study we correlate morphological changes in non- was paid to the pre-clinical findings that NMDAR antagonists
reactive (ramified) microglia with cognitive performance. lose efficacy if administered more than 30–60 min post-injury.
Methods: Wistar rats were randomized to receive ladostigil The discrepancy between the animal and human studies in
1 mg/kg or 8.5 mg/kg from 16 months of age for 6 months. the treatment protocol on one hand, and on the final out-
There were non-treated age-matched and adult control rats. come on the other, prompted us to investigate the temporal
Tests of cognition: spatial - Morris water maze and object changes of the NMDAR after brain insult in animal models
location; non-spatial: object recognition. Immunohistochemical of TBI and stroke, using 3H-MK-801 autoradiography. We
tests included complement 3 receptor (C3R) using OX42 clone found desensitization and loss of functional NMDAR,
and a polyclonal antibody to ionized calcium-binding adapter which persists for weeks. After showing the long lasting
molecule 1 (Iba1). hypo-functional state of NMDAR we propose a paradigm
Results: Microglial process ramification: In hippocampal shift towards targeting stimulation, rather than inhibition of
CA1 region, Iba-1 demonstrated aging-related de- NMDAR as a therapeutic substrate for TBI and stroke, and
ramification of microglia that was prevented by ladostigil believe that the road is now cleared for clinical trials based
and correlated with spatial cognition but not with object on this approach.
recognition. In peri-rhinal cortex, ramification correlated with Supported by grants: BSF# 2005-021-01; NIH 1R01NS050285,
object recognition but not with spatial cognition. In parietal and in part Israeli Ministry of Defense
cortex, microglial process ramification was increased by aging
and by ladostigil but did not correlate with cognition. How- The perceptual consequences of action: preferential
ever, in the parietal cortex, aging-related increase in C3R- binding with vision
positive bulbous tips was prevented by ladostigil and corre- Shore DI* 1, Vallet GT 2
1
lated with spatial- but not with non-spatial cognition. Psychology, Neuroscience & Behaviour, McMaster Unive-
Conclusions: Although it is widely assumed that aging- sity, 2Attaché Temporaire d'Enseignement et de Recherche
related microglial activation in all brain regions contributes (A.T.E.R.), Laboratoire EMC, Université Lyon 2
S114 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
Acting on the environment creates perceptual consequences—- neuronal markers supporting the need for further exploration
moving an object changes its visual appearance, and potentially of the effect of this early life event not only at adulthood but
creates an auditory event. In order to examine the relative impact also earlier in development in both sexes.
on auditory and visual events, we had observers make a voluntary
action to initiate each trial, and subsequently make an audiovisual Location-specific adaptation of auditory responses
temporal order judgment. The first stimulus could appear imme- in the human EEG
diately after the action, or be delayed by 500 ms. The visual event Shrem T* 1, Deouell LY 1,2
1
was perceived sooner (i.e., the auditory event had to be presented Dept. of Psychology, The Hebrew University of Jerusalem
2
sooner to achieve a point of subjective simultaneity) when the Edmond & Lily Safra Center for Brain Sciences, The
action immediately preceded the first stimulus. Manipulations of Hebrew University of Jerusalem
relative spatial arrangement had no effect on this shift in perceived
onset of the visual event. There is some indication that Background: To probe the representation of sound location in
the action must be voluntary to produce this effect. the human brain it is essential to find a neural index of spatial
Results are discussed in terms of the impact of action sensitivity. Early studies have found attenuation of the N1-P2
on perception. vertex response following repetition of sounds from the same
Funded by: Natural Science & Engineering Council of Canada location. However, these studies reported the peak to peak N1-
P2 amplitude, but not each component's amplitude separately.
Prenatal stress differentially disrupts the normal course In recent years the question of whether N1 and P2 reflect the
of development of hippocampal neuronal markers same or different processes has become subject to debate.
in the male and female rat offspring Furthermore, previous studies were conducted in very unnatu-
Shoshani Y, Shoham S, Weinstock M* ral conditions, some manipulating sound source difference by
The Institute for Drug Research, Dept. of Pharmacology, changing Inter-aural Intensity Differences (IID), and mainly
Hebrew University of Jerusalem using pure tones, which are relatively hard to localize. Here
we presented pairs of complex tones from 3 speakers in free
Background: Stress during pregnancy increases the preva- field and measured the N1 and P2 responses. We compared the
lence of anxiety, learning deficits and depression in humans degree of attenuation to the second stimulus when preceded by
and experimental animals, which may be sex-specific. There a sound in the same location, 30° apart, or 60° apart.
are hardly any studies that examined the effect of prenatal Results: In line with previous studies we found overall atten-
stress on brain histology that can underlie these behavioural uation of the N1 and P2 responses to the second stimulus
changes and none has examined whether these differ accord- compared to the first in all conditions. In addition, we found
ing to the age and sex of the offspring. In the present study, that the amplitude of the second sound P2, but not N1, was
we analysed the developmental course of hippocampal neu- positively correlated with the distance between the locations of
ronal markers which were correlated with learning and the first and second sounds.
memory, in control and prenatally-stressed male and female Conclusions: These findings indicate that P2 reflects
rats at pre-puberty and adulthood. activity based on spatially selective neurons, with a
Results: Pre-pubertal control females had a higher intensity of resolution of at least 30° within hemispace. Further-
staining of GluR1 and nNOS markers and a higher count of more, the discrepancies between our findings and previ-
activated neurons (measured by c-Fos) in the hippocampus, ous research support the notion that N1 and P2
but lower staining intensity of DCX (a marker of neurogene- represent different processes, which might be affected
sis) in the hippocampal sub-granular zone than their male differently by complexity of stimuli and by different
siblings. Prenatal stress selectively reduced the intensity of manipulations of sound source perception.
GluR1 and nNOS in females, but not in males. An increase in
the number of c-Fos+ neurons was seen in both sexes but to a Synapsin IIa function is regulated by an ATP binding
much higher degree in males. A reduction in DCX intensity site
was only seen in males. At adulthood, most of the sex differ- Shulman Y Gitler D
ences in these neuronal markers (except for c-Fos+ neuronal Dept. of Physiology and Cell Biology, Faculty of Health
count) were no longer evident. Prenatal stress increased the Sciences, Zlotowski Center for Neuroscience, Ben-Gurion
number of GluR1 and nNOS positive neurons in both sexes in University of the Negev, Beer-Sheva 84105
contrast to what was seen at pre-puberty. An enduring reduc-
tion in DCX intensity in adult males and an increase in c-Fos+ The synapsins are neuron-specific proteins mostly known
cell counts in both sexes were also evident at adulthood. for their capability to cluster synaptic vesicles and to control
Conclusions: The present data provide evidence for sex and vesicle movement between adjacent en-passant synapses.
age specific effects of prenatal stress on hippocampal Early studies revealed various sites that were suggested to
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S115
regulate the activity of synapsin I, the first synapsin to be in C57B WT mice that were exposed to EE and in mice model
described. Although synapsin IIa was recently shown to be of AD as compared to their control mice. We found several
the dominant member of this family, at least in small gluta- important microRNAs which were substantially upregulated
matergic synapses, its regulation has not been studied in any in 3xTgAD mice compared to their age-matched WT C57B
detail to date. All members of the synapsin family bind ATP control group. These microRNAs were highly concentrated in
at a well-conserved site in their central "C" domain. Intrigu- the synaptic fraction of the brain, and are predicted to down-
ingly, ATP binding is differentially regulated by calcium regulate essential synaptic proteins. MicroRNAs that were
ions, suggesting a physiological function. Nevertheless, the inversely-regulated in mice model of AD or following EE
significance of ATP binding has not been investigated in the affected not only synaptic proteins and modulators, but also
context of neurotransmission. To study this question, we molecular factors that are associated with AD pathology and
measured the rescue of synaptic depression in autaptic neu- may contribute to the rescue effect of EE on AD pathology.
rons lacking all synapsins by the over expression of either Conclusions: By modulation of the expression levels of
exogenous wild type synapsin IIa or synapsin IIa carrying a microRNAs, EE can enhance the expression of proteins that
mutation (K270A) which prevents ATP binding. We found mitigate AD pathology as well as many key-players in the
that K270A-synapsin IIa only partially rescues synaptic synaptic transmission machinery. Moreover, EE also influ-
depression. All results support a role for ATP in regulating ences survival factors and neurofactors that are essential for
synapsin activity in synapses in-vivo. neuronal viability, thus preventing the neuronal loss attrib-
uted to AD pathology.
Elucidating the role of environmental enrichment
in mitigating Alzheimer's disease pathology Bilateral and multisensory integration in striatal
through microRNAs regulation microcircuits
Shvarts Serebro I 1, Barak B 1,2, Modai S 3, Gilam A 3, Silberberg G*, Reig R
Okun E 4,5, Belinson H 1, Michaelson DM 1, Mattson M 6, Dept. of Neuroscience, Karolinska Institute, Stockholm
Shomron N 3,2, Ashery U* 1,2 17177, Sweden
1
Dept. of Neurobiology, Life Sciences faculty, Tel Aviv Uni-
versity, Tel Aviv 69978, Israel 2Sagol School for Neurosci- The basal ganglia are involved in various motor and reward-
ence, Tel Aviv University, Tel Aviv 69978, Israel 3Dept. of related functions, however, their role in sensory processing
Cell and Developmental Biology, Sackler Faculty of Medi- remains unclear. The striatum is the input layer of basal
cine, Tel Aviv University, Tel Aviv 69978, Israel. 4The Mina ganglia, receiving excitatory inputs from most cortical areas
and Everard Goodman Faculty of life sciences, Bar Ilan and from both hemispheres. In this study we aimed to
University, Ramat-Gan, 52900, Israel 5 The Gonda answer how striatal neurons integrate bilateral and multisen-
(Goldschmidt) Multidisciplinary Brain Research Center, sory sensory input. To answer this question we obtained in
Bar Ilan University, Ramat-Gan, 52900, Israel 6Laboratory vivowhole-cell patch-clamp recordings from neurons in the
of Neurosciences, National Institute on Aging Intramural dorsolateral striatum and in cortical layer V of the barrel
Research Program, NIH, Baltimore, MD 21224, USA field (BF) in anesthetized mice. We recorded the evoked
responses to ipsi- and contralateral whisker stimulation us-
Introduction: Exposure to enriched environment (EE) has ing air-puff, and responses to simultaneous whisker and
been shown to have protective effect in mice as well as in visual stimulus (delivered as light flashes in front of the
human subjects, by slowing disease progression and reduc- contralateral eye). Recorded neurons were stained with neu-
ing AD-like cognitive impairment. We were interested in robiotin and the different types of striatal neurons were
studying the molecular consequences of the exposure of WT identified by their morphological and electrophysiological
C57B mice to EE on the one hand, and of AD pathology in properties. Our results show that all recorded striatal neu-
3xTgAD mice model on the other hand. rons respond to bilateral whisker stimulation, responding
Results: Measuring the proteins levels in the hippocampi of faster to contra- than ipsilateral stimulation. Around 35 %
WT C57B mice that were exposed to EE, we have found that of neurons respond to visual stimulation too, showing that
EE increases the level of expression of proteins that are neurons in the dorsolateral striatum integrate inputs from
positively involved in synaptic transmission like synaptophy- different sensory modalities. Striatal MSNs have slower
sin and reduces the level of negative regulatory proteins such onset slopes compared with those in cortical neurons. Fur-
as tomosyn. As opposed to EE, old 3xTgAD mice showed thermore, slopes were significantly slower for D2 than D1
significantly higher expression levels of Tomosyn in all of the MSNs. D1 MSNs responded with larger amplitudes and lon-
hippocampal sub-areas compared to control mice. To study ger delays between ipsi- and contralateral responses. These
the molecular regulators responsible for the changes in syn- results suggest different functional roles in bilateral sensory
aptic proteins we studied the expression levels of microRNAs integration by the direct and the indirect pathways. Our results
S116 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
show that individual striatal neurons perform bilateral and whether a single acute stress, which manifests long lasting
multimodal sensory integration of cortical inputs. changes in behavior, affects the interaction of Mdm2 with p53,
ERC starting grant to G.S. b2AR, and b Arrestin-1 in the dorsal and ventral hippocampal
CA1. Adult rats were subject to underwater trauma, a brief
Measuring the intricacy of a stimulus forceful submersion under water. A month later, behav-
Snitz K*, Jacobson M, Weisler K, Yablonka A ioral tests were conducted and immediately followed by
Weizmann Institute of Science biochemical analysis. Elevated plus maze tests con-
firmed that a month after trauma the animals present
Intuitively we can distinguish an intricate image or sound heightened levels of anxiety. An examination of the
from simple ones. However, characterizing intricacy of CA1 hippocampal areas of the same rats showed that
stimuli in a measurable manner remains a challenge. underwater trauma caused a significant increase in the
We propose that perceptual variance can be taken as a association of Mdm2 with b2AR, b Arrestin-1, and p53
measure of stimulus intricacy. The more variance - the more in the ventral but not dorsal CA1. Our results provide
intricate the stimulus. For this property to be a property of support for the idea that stress-related events may result in
the stimulus it needs to be consistent regardless of the biochemical changes restricted to the ventral 'emotion-related'
question asked. Thus, we set out to test the initial hypothesis parts of the hippocampus.
that perceptual variance is stimulus-specific. We obtained 3
different data sets of odor ratings applied by ~50 subjects to ~20 Mismatched microRNA/acetylcholinesterase interaction
odorants, containing ~250 different perceptual questions in total. as a diagnostic predictor of anxiety disorders
We found that the relative amount of variance associated with a Hanin G 1, Shenhar-Tsarfaty S 1, Greenberg D 1, Sklan E 2,
given odor is highly consistent, regardless of the descriptors Hoe Y 3, Rao D 4, Rankinen T 5, Bouchard C5, Geifman-
applied. When we simulated the mean variances for two sets of Shochat S 3, Soreq H* 1
1
20 randomly selected descriptors we got spearman correlations Silberman Inst. of Life Sciences & Safra Center for Brain
greater than r00.8 across the two sets. When we used sets of 30 Sciences, The Hebrew Univ. of erusalem 2Clinical Microbi-
descriptors we got spearman correlations greater than r00.86 ology and Immunology, Sackler School of Medicine, Tel
across the two sets, indicating the highly consistent ordering of Aviv University 3School of Biological Sciences, Nanyang
the variance of the stimuli. Thus we conclude that a property of Technological University, Singapore 4Division of Biostatis-
intrinsic perceptual variability can be reliably assigned to a stim- tics, School of Medicine, Washington University in St. Louis,
ulus, and we propose to take this as a measure of stimulus St. Louis, Mo. 5Human Genomics Laboratory, Pennington
intricacy. Lastly we propose this measure as a tool to directly Biomedical Research Center, Baton Rouge, LA
investigate logical aspects of processing of stimuli.
MicroRNAs (miRs) may modulate entire pathway(s) by
Selective increase in the association of the beta2 simultaneously interacting with conserved sequence motifs
adrenergic receptor, beta Arrestin-1 and p53 with Mdm2 in multiple mRNA targets. Therefore, single-base mis-
in the ventral hippocampus four weeks after underwater matches preventing the miR-based repression of one mRNA
trauma target might lead to elevated levels of this target while
Sood R 1 , Ritov G 2,3 , Richter-Levin G 2,4,3 , Barki- exacerbating silencing of its other targets, resulting in bidi-
Harrington L* 1 rectional modulations affecting the entire pathway. Here, we
1
Dept. of Human Biology, Faculty of Natural Sciences, report a primate-specific miR which impairs cholinergic
University of Haifa 2The Sagol Dept. of Neurobiology, Fac- signaling by interacting with the 3'-untranslated region of
ulty of Natural Sciences, University of Haifa 3The Institute acetylcholinesterase (AChE) mRNA, increasing the risk of
for the Study of Affective Neuroscience (ISAN), University of chronic and acquired anxiety-related diseases. We further
Haifa 4Dept. of Psychology, Faculty of Social Sciences, provide surface plasmon resonance (SPR) evidence that a
University of Haifa single nucleotide mismatch in the AChE target site for this
miR weakens its AChE interaction by 15-fold. Also, in
Although activation of the sympathetic nervous system is a transfected cells, this mismatch led to greater miR-
critical stress response aimed at maintaining homeostasis, its mediated suppression of another of its targets, the anxiety
prolonged activity is harmful in the long run. A recent study regulator Rho GTPase CDC42. Furthermore, 76/372 healthy
showed that chronic infusion of mice with a b2 adrenergic young carriers of this SNP in the HERITAGE cohort (average
receptor (b2AR) analogue causes long-term DNA damage in a age: 34 years) showed higher trait anxiety, systolic and
pathway which involves b Arresin-1-mediated activation of diastolic blood pressure and inflammation (p<0.001). Our
Mdm2 and subsequent degradation of the tumor suppressor findings present a multi-leveled approach for studying the
protein p53. The objective of the present study was to test physiological impact of specific miR-target interactions. At
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S117
the translational level prognostic SNP genotyping for eval- Radiocarbon analysis of neurogenesis in the adult
uating the risk of anxiety-related diseases in mismatch human brain
carriers is important because these specific risks may be Spalding Kl* 1, Bergmann O 1, Alkass K 1, Buchholz B 2,
minimized by changes in life style and prophylactic Salehpour M 3, Possnert G 3, Liebl J 4, Steier P4, Kutschera
treatment. W 4, Bernard S 5, Druid H 1, Frisen J 1
1
Karolinska Institute 2Lawrence Livermore National Labora-
Compartmentalization of voltage-gated Ca2+ channels tories 3Uppsala University 4University of Vienna 5University
in the membrane of rat anterior pituitary cells of Lyon
Sosial E 1, Tzour A 1, Meir T 2, Canello T 3, Naveh-Many T
2
, Gabizon R 3, Nussinovitch I* 1 Background: Much of the impetus in regenerative medicine is
1
Dept. of Medical Neurobiology, Institute for Medical fuelled by the prospect of promoting cell replacement, or block-
Research-Israel-Canada, Hebrew University Faculty of ing unwanted cell production. Without knowing, however, if a
Medicine, Jerusalem, Israel 2Minerva Center for Calcium specific cell type is renewed in the healthy or pathological
and Bone Metabolism, Hadassah University Hospital, situation, it remains uncertain whether it may be realistic and
Jerusalem, Israel 3Dept. of Neurology, The Agnes Ginges rational to modulate this process. Despite the importance of this
Center for Human Neurogenetics, Hadassah University information, remarkably little is known about the age of cells in
Hospital, Jerusalem. Israel many regions of the adult human brain and body, particularly
neuronal replacement in the brain. This is largely due to diffi-
Introduction: Voltage-gated Ca2+ influx (VGCI) through Ca2+ culties in studying this process in humans.
channels plays a key role in the secretion of pituitary hormones. Methods: Using recently established methodology, which inte-
It is well established that L-type Ca2+ channels are involved in grates biomedical approaches with recent developments in
this VGCI. Whether non-L-type Ca2 channels contribute to this nuclear physics, it is possible to establish the turnover of cells
VGCI is unknown. In this study we examined: 1. whether non- in human tissues. By measuring 14C derived from nuclear
L-type Ca2+ channels exist in the membrane of pituitary cells. 2. bomb tests in DNA it is possible to retrospectively establish
Whether Ca2+ channels are segregated among different mem- the birth date of cells. This principle can be applied to neurons
brane compartments in the membrane of pituitary cells. isolated from the adult human brain and neurogenesis in health
Results: Whole-cell recordings and the use of specific Ca2+ and pathology in humans assessed.
channel toxin blockers revealed a fraction of non-L-type Results: Previously we reported no evidence for the long term
VGCI that might reach ~46 %. Western blotting identified stable integration of newborn neurons in the adult human cortex.
immunblots for; α1C, α1D, α1A, α1B and α1E subunits, More recently we show that contrary to expectation, 14C con-
corresponding to Cav1.2, Cav1.3, Cav2.1, Cav2.2, and centrations in olfactory bulb neurons correspond to atmospheric
Cav2.3 channels. Additionally, RT-PCR identified tran- levels at the time of birth of the individuals, establishing that
scripts for α1C, α1D, α1A and α1B subunits. Transcripts for there is very limited, if any, postnatal neurogenesis. Thus iden-
α1E were non-specific and transcripts for α1S were not tifying a fundamental difference in the plasticity of the human
detected at all. Taken together these results clearly demon- brain compared to other mammals. Unpublished work on adult
strate the co-existence of L-type (Cav1.2 and Cav1.3) and human hippocampal neurogenesis will also be discussed.
non L-type (Cav2.1, Cav2.2 and Cav2.3) Ca2+ channels in
the membrane of anterior pituitary cells. Whether these Neuropsychological subtypes among adults
channels are segregated among different membrane com- with and without ADHD
partments was further investigated in flotation assays, dem- Spanier AB* 1, Kolodny T* 2, Geva AB 3, Shalev L 4
1
onstrating that Cav1.2 and Cav2.1 channels were mostly The Selim and Rachel Benin School of Engineering, the
localized in light Nycodenz gradients fractions, i.e., in lipid Hebrew University, Jerusalem 2Dept. of Cognitive Sciences,
raft domains. Cav1.3 channels were distributed among both the Hebrew University, Jerusalem 3Electrical and Computer
light and heavy gradient fractions, i.e., among raft and non- Engineering Dept., Ben-Gurion University, Beer-Sheva
4
raft domains whereas Cav2.2 and Cav2.3 channels mostly School of Education and the Sagol School of Neuroscience,
among nonraft domains. Tel Aviv University
Summary: We demonstrate here multiple pathways for *Contributed equally
VGCI through L-type and non-L-type Ca2+ channels in the
membrane of native anterior pituitary cells. Compartmental- Background: Attention deficit hyperactivity disorder
izations of these channels among raft and nonraft membrane (ADHD) is a prevalent developmental disorder, defined by
domains suggest differential regulation by signaling path- behavioral symptoms of inattention, and/or hyperactivity and
ways of VGCI in pituitary cells. Supported by the Israel impulsivity which affects approximately 10 % of children and
Science Foundation (ISF) Grant no. 1325/08 to I.N. 4 % of the adult population. ADHD has lately been
S118 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
conceptualized as a heterogeneous syndrome with multiple by the incubation of neurons expressing mutant-human-tau in
underlying cognitive mechanisms. In a recent study, Fair and 5 nM paclitaxel. Higher paclitaxel concentrations (100nM) do
colleagues (2012) applied a community detection algorithm to not prevent the unfolding of the pathology. Our results dem-
identify neuropsychological subtypes among children with onstrate that MT-stabilizing (antimitotic) reagents may serve
ADHD and typically developing children. In the present to slow down or prevent the development of tauopathies.
study, we follow the four functions of attention model (Tsal The C. Smith and Prof. J. Elkes laboratory for collaborative
et al., 2005) as a framework for ADHD, and by using graph research in psychobiology
theory and community detection, we explored whether data-
driven attentional subtypes could improve discrimination of A cognitive trap: chemistry defines the biology of amyloid
adults with/without ADHD. proteins, not human language
Methods: 151 adult ADHD participants and 123 controls Steinman L
performed four visual attention tasks assessing performance Stanford University, CA, USA
of the sustained, selective, orienting and executive func-
tions. Four summarizing measures from these four tasks Amyloid proteins, whether tau, Abeta, PrPSc, huntingtin
were used as an input to the Newman's community structure (>35Q), alpha-synuclein are considered to play a pathogenic
in networks algorithm. role in a swathe of neurodegenerative conditions. "When
Results: Five subgroups were identified by Newman's al- Bad is Good" is the title of an editorial accompanying a
gorithm. Each subgroup consisted of a similar number of recent publication showing that we could reverse paralysis
ADHD and controls. In each of those subgroups an SVM and inhibit inflammation in a model in mice of multiple
classification algorithm was utilized which classified a nov- sclerosis, termed experimental autoimmune encephalomy-
el participant as either ADHD or control, with an average of elitis (EAE). Our previous experiments established that
66 % accuracy, 76 % sensitivity and 58 % specificity. amyloidogenic peptides from the small heat shock protein,
Interestingly, different levels of correct classification were HspB5, and from Amyloid β fibrils, characteristic of Alz-
obtained in each of the clusters, ranging from 52 % to 82 %. heimer's disease, were therapeutic in EAE, which models
Conclusions: Multiple attentional profiles exist among aspects of neuroinflammation in multiple sclerosis. To under-
adults with and without ADHD. This research demonstrated stand the molecular basis for the therapeutic effect, a set of
(a) how a graph theory approach can enrich the theoretical amyloidogenic hexameric peptides, including those from the
framework of ADHD by revealing the nature of the relations major prion protein, tau, Amyloid β, HspB5, amylin, serum
between the four functions of attention (b) how discrimina- amyloid P and insulin Β chain, were shown to be anti-
tion of ADHD and control participants can benefit from an inflammatory, capable of reducing serological levels of IL-6,
identifying profile category. and of attenuating paralysis in EAE. Loss of function experi-
ments emphasize the protective role of amyloids: Remarkably,
Rescue of neurons from undergoing hallmark the clinical signs and inflammation of EAE are exacerbated in
tau-induced Alzheimer’s disease cell-pathologies knockout mice for various amyloid proteins including HspB5,
by the antimitotic drug paclitaxel amyloid-β A4, the major prion protein, serum amyloid P, and
Spira M*, Shemesh O, Erez H tau compared to wild type animals. Genetic deletion of mole-
The Life sciences Institute, The Hebrew University of cules that bind amyloid including Apolipoprotein E is known
Jerusalem also to exacerbate EAE. We need to reconsider whether amy-
loid molecules are good or bad. Daniel Kahneman, 2002 Nobel
Through the use of live confocal imaging and electron- Laureate, wrote "A reliable way of making people believe in
microscopy, we documented that mutant-human-tau (mt-hu- falsehoods is frequent repetition, because familiarity is not
man-tau) induces hallmark Alzheimer's disease (AD) cell easily distinguished from truth." (Kahneman Thinking, Fast
pathologies in cultured Aplysia neurons. These included: and Slow). We need to question whether amyloid proteins and
swelling of axonal segments, translocation of tau and micro- hexameric derivatives are not just always 'bad', ie pathological,
tubules (MT) to submembrane domains, reduction in the but might also be protective and physiological. We need to
number of MTs along the axon, the reversal of the MT polar think about this in terms of chemistry not language.
orientation, impaired organelle transport, accumulation of
macro-autophagosomes and lysosomes, compromised neurite Properties of cultured neuronal networks taken
morphology and degeneration. When expressed presynapti- from down syndrome mice
cally these structural changes are associated with reduced Stern S* 1, Segal M 2, Moses E 1
1
EPSP amplitude, faster homosynaptic habituation and the Physics of Complex Systems, Weizmann Institute of
reduced ability to undergo 5HT induced facilitation. The Science, Rehovot 2Neurobiology, Weizmann Institute of
development of these neuronal cell pathologies are rescued Science, Rehovot
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S119
Down Syndrome (DS) is a chromosomal condition in Atomique, Division of Life Sciences, Institute of Bioimaging,
humans characterized by cognitive impairment. Two murine Neurospin, Gif sur Yvette, 91191 France 8Université Paris
models for DS exist: Ts65Dn with an extra small chromo- 11, Orsay, France 9The Edmond and Lily Safra Center for
some including about 50 % of the ortholog genes of DS, and Brain Sciences (ELSC), The Hebrew University of Jerusalem,
TC1 which has an extra human 21 chromosome and about Jerusalem 91220, Israel10The Cognitive Science Program,
92 % of the DS genes. We have used patterned neuronal The Hebrew University of Jerusalem, Jerusalem 91220
cultures from WT and DS littermates to determine the differ-
ences in properties of normal and DS neurons. Using one- Using a visual-to-auditory sensory substitution algo-
dimensional cultures we measured the speed of propagation rithm, congenitally fully-blind adults were taught to read
of the network activity. This is sensitive to both synaptic and recognize complex images using "soundscapes"-
strength and the number of connections per neuron. Our sounds topographically representing images. fMRI was
results indicate that the velocities of WT were 50 % higher used to examine key questions regarding the Visual
than Ts65Dn cultures (Ts65Dn: 105±10 mm/sec, 5 cultures, Word Form Area (VWFA): its selectivity for letters over
119 network bursts, control: 153±6 mm/sec, 14 cultures, other visual categories without visual experience, its
315 network bursts) and 25 % higher than TC1 cultures feature-tolerance for reading in a novel sensory modality
(TC1 132±3 mm/sec, 19 cultures, 890 network bursts, con- and its plasticity for scripts learned in adulthood. The
trol: 166±5 mm/sec, 13 cultures, 428 network bursts). Im- blind activated the VWFA specifically and selectively
aging of [Ca2+]i variations in populations of cultured during the processing of letters soundscapes relative to
neurons provides a reliable measure of network activity. of both textures and visually-complex object categories,
We imaged [Ca2+]i in populations of neurons, and observed and relative to mental-imagery and semantic-content
that WT was higher by about 50 % than DS (Ts65Dn 0.59± controls. Further, VWFA recruitment for reading sound-
0.02, TC1 0.52±0.02, WT 1±0.03 (normalized intensity: scapes emerged following two hours of training in a
absolute amplitude divided by baseline)) This result was blind adult on a novel script. Therefore, the VWFA
reproduced in two-dimensional cultures. Higher resolution shows category-selectivity regardless of input sensory
measurements showed that in both DS and WT almost all modality, visual experience and long-term familiarity or
neurons fire in each synchronization burst, and therefore it expertise with the script. The VWFA may perform a
may be that different fluorescence level indicates that DS flexible task-specific rather than sensory-specific com-
neurons fire fewer action potentials in a burst. We also found putation, possibly linking letter shapes to phonology.
a significant change in spike afterhyperpolarization (AHP):
at 5 ms after a spike, AHP amplitude was: TS65Dn -2v± Sweet neurobiology: new insights into the importance
0.6v (8 cells), WT -9.4v±2.5v (11 cells). This difference of glycosylation in Alzheimer’s disease
may underlie the difference in bursting properties between Tal S 1, Frenkel-Pinter M 1, Waldman Y 2, Stempler S 2,
the control and DS cultures. We conclude that neurons in DS Alyagor I 1, Solovey L 1, Rupin E 2, Gazit E. 1, Segal D* 1
1
generate networks with different properties than controls.. Dept. of Molecular Microbiology & Biotechnology, The
These results encourage a continuation of the exploration of Sagol Interdisciplanary School of Neurosciences, George
differences between WT and DS, which may contribute to S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-
the understanding of the disease process. Aviv 69978, Israel.2The Blavatnik School of Computer Sci-
ence, Raymond and Baverly Sackler Faculty of Exact Sci-
Reading with sounds: sensory substitution selectively ences, Tel-Aviv University, Tel-Aviv 69978, Israel
activates the visual word form area in the blind
Striem-Amit E* 1, Cohen L 2,3,4, Dehaene S 5,6,7,8, Amedi Neurodegenerative diseases are associated with patho-
A 1,9,10 genic oligomers of misfolded proteins that aggregate
1
Dept. of Medical Neurobiology, The Institute for Medical and cause loss of neurons in the brain. One process
Research Israel-Canada, Faculty of Medicine, The Hebrew which can be affected in neurodegenerative disorders
University of Jerusalem, Jerusalem 91220, Israel 2Univer- is post-translational protein modification, known to be
sité Pierre et Marie Curie-Paris 6, Faculté de Médecine derailed during aging. Protein modifications e.g. phos-
Pitié-Salpêtrière, IFR 70, Paris, France 3INSERM, ICM phorylation, acetylation, glycosylation and oxidation are
Research Center, UMRS 975, Paris, France 4 AP-HP, critical to normal function of many proteins. We focus
Groupe Hospitalier Pitié-Salpêtrière, Dept. of Neurology, on protein glycosylation. The majority of proteins syn-
Paris, France 5Collège de France, 11 Place Marcelin Ber- thesized in the rough ER undergo glycosylation, an
thelot, 75005 Paris, France 6Institut National de la Santé et enzyme-directed site-specific process. Protein glycosyla-
de la Recherche Médicale, Cognitive Neuroimaging Unit, tion also occurs in the cytoplasm and nucleus as an O-
Gif sur Yvette, 91191 France 7Commissariat à l’Energie GlcNAc modification, which, interestingly, competes
S120 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
with phosphorylation of the same amino acids. We Results: Our results in the open field test indicate that DISC1
explore the role of glycosylaition in Alzheimer's disease mice showed lower locomotor activity accompanied by in-
(AD). The hallmarks of AD are Aβ plaques and neuro- creased anxiety. In the novel object recognition test DISC1
fibrillary tangles of hyper-phosphorylated tau protein. mice revealed a lower cognitive score, and in social preference
Several reports indicated vast alterations in protein gly- test impaired sociability compared to wild type mice. Biochem-
cosylation in the brain of AD patients, while others ical analysis of prefrontal cortex and hippocampus reveaedl a
demonstrated changes in glycosylation of specific pro- significant decrease in BDNF in the DISC mice compared to
teins related to AD pathology in the disease state, such controls. Surprisingly, DISC1 mice showed higher levels of
as tau and APP, the Aβ precursor. GAD 67 and pERK. In addition we found a marked decrease in
Using an in silico approach we found that many the expression of canabinoid-1 CB1 receptors in DISC-1frontal
glycosylation-related enzymes exhibit different expression cortex of females and hippocampus of males.
profile in brains of AD patients as compared with healthy Conclusions: DISC1 mice show disrupted behavioral pat-
subjects. We next studied the effect of enhancing or reduc- tern associated with increased anxiety and impaired cogni-
ing expression of the glycosylation-related genes in trans- tive and social behavior. These modifications paralleled a
genic Drosophila over-expressing human tau, which serve decrease in brain BDNF and alterations in pERK and CB1
as an established AD model. We identified key glyco- brain expression. Our .results show for the first time a
sylation enzymes, both augementing and ameliorating possible link between DISC1 and the cannabinoid system.
tauopathy symptoms using the Drosophila eye neuro-
degeneration as a model. For example, over-expression Sparse decoding and blind extraction of representational
of CG6370, the Drosophila homologe of human RPN2, structure from human spike trains
partially ameliorated the defective eye phenotype caused Tankus A* 1,2, Fried I 2,3,4, Shoham S 1
1
by tau over-expression. As expected, silencing CG6370 Faculty of Biomedical Engineering, Technion-Israel Insti-
increased neurodegeneration. The effct of leading tute of Technology, Haifa 32000, Israel.2Dept. of Neurosur-
enzymes on tau pathology will be further evluated be- gery, University of California, Los Angeles, CA 90095,
haviorally and biochmically. USA. 3Functional Neurosurgery Unit, Tel-Aviv Medical
Center, Tel-Aviv 64239, Israel. 4Sackler School of Medicine,
Evidence for impaired social behavior associated Tel-Aviv University, Tel-Aviv 69978, Israel
with decreased BDNF in DISC1 muted mice, a genetic
model for Schizophrenia Background: Brain–machine interfaces (BMIs) rely on
Taler M 1, Kaminitz 1, Barzilay R 2, Segal H 2, Offen D 2, decoding the activity of neuronal populations from multiple
Weizman A 1,3, Gil-Ad I 1 electrodes. The implantation procedures, however, guarantee
1
Lab of Biological Psychiatry, FMRC and Sackler Faculty an anatomical distance between recording sites rather than a
of Medicine, Tel Aviv University, Israel 2Neurosciences lab, physiological task-relevance of recorded neurons. Therefore,
FMRC and Sackler Faculty of Medicine, Tel Aviv University, selection of task-relevant neurons is critical to decoder perfor-
Israel 3Research Unit, Geha Mental Health Center, Israel mance. Nevertheless, it is typically performed heuristically.
Results: We describe two new methods for analyzing neural
Background: Schizophrenia (SCZ) is a prevalent psychiat- spike trains. The first algorithm decodes/classifies volitional
ric disease affecting approximately 1 % of the population. actions from multiple spike trains, by automatically selecting
Evidence indicates that polygenic factors combined with a relevant neurons. The method uses a sparseness constraint
variety of environmental insults influence neurodevelop- during the classification to simultaneously optimize neuronal
ment that enhances the vulnerability to develop SCZ. Dis- weights and select the relevant neuronal features. The new
rupted in Schizophrenia 1 (DISC1) is considered the most method was tested against a range of existing methods using
prominent candidate gene for SCZ. The disease is associated simulations and recordings of the activity of 1592 neurons in
with complex of neurotransmitter 23 neurosurgical patients who performed motor or speech
disregulation, predominantly increased dopamine, de- tasks. The parameter estimation algorithm is orders of magni-
creased GABA and glutamate resulting in low glutamate– tude faster than existing methods and achieves significantly
decarboxylase 67 (GAD67) and altered availability of brain higher accuracies for both simulations and human data.
neurotrophic factors mainly BDNF. We have used male and As a second step, we employ the classifier and its error
female transgenic mice expressing a mutant DISC1 gene structure (confusion matrices) to deduce the natural organiza-
(acting as a dominant negative DISC1 mutant). Mice (wild tion of features represented in the population-level neural
type compared to DISC1) were tested in several behavioral code. The method was employed to extract the representation
procedures. Behavior was videotaped and analyzed using of vowels in the neuronal population code. Using activity of
the Noldus system and software. 716 neurons from 11 neurosurgical patients, our method has
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S121
shown that the neuronal representation of vowels matches that This research was supported by a grant from the Israeli
of the international phonetic alphabet (IPA) chart, representing Science Foundation (ISF, 384/10) to GA.
the highest point of the tongue during articulation.
Conclusions: The highly effective performance of sparse Ongoing excitation and inhibition are not balanced
decoders and the ability to discover hidden structures in the across brain states
representation of population-level neural firing patterns Taub A*, Katz Y, Lampl I
could contribute to both BMI systems and basic neurosci- Dept. of Neurobiology, The Weizmann Institute of Science,
ence research. Rehovot
We thank ERC (STG 211055),NINDS,Dana Foundation,Lady
Davis,L&L Richmond for funding. The prominent feedback connections between excitatory and
inhibitory neurons in the mammalian cortex suggest that the
Impaired holistic processing in congenital prosopagnosia cortex operates at a balanced state in which inhibition modu-
and its possible amelioration lates the magnitude of excitation. We recorded intracellularly
Tanzer M, Weinbach N, Freud E, Ganel T, Henik A, the ongoing excitatory and inhibitory inputs onto cortical neu-
Avidan G* rons across distinct brain states, induced by altering the depth of
Dept. of Psychology , Ben-Gurion University of the Negev, anesthesia. While the magnitude of inhibition increased under
Beer Sheva, Israel the deeper-state, the magnitude of excitation was not state-
dependent. Importantly, these results were recapitulated using
Background: Congenital prosopagnosia (CP) is a face pro- different anesthetics, indicating that state-dependent changes in
cessing deficit that is often accompanied by impaired holis- the balance between excitation and inhibition are mediated
tic processing even for non-face stimuli that was suggested upstream to the cortex. That excitation was indifferent to the
to account for the difficulty in face perception. Here we state-dependent changes in inhibition, suggests that ongoing
further investigate this intriguing observation by examining cortical activity is not at a balanced state but rather operates as
8 CP individuals and their controls on two tasks involving expected from feedforward mechanisms.
holistic processing of non-face stimuli.
Results: We first, applied a classic Garner interference task in Motor coding in the human supplemental motor area
which participants were asked to judge the width of visually Taubman H 1, Tankus A 2,3, Fried Y 4,5, Vaadia E 6,7,8, Paz R
9
presented rectangles while ignoring their task irrelevant , Chechik G* 1
1
height. As expected, controls were affected by changes in Gonda Multidisciplinary Brain Research Center, Bar-Ilan
the irrelevant dimension hence exhibiting Garner interference. University, Ramat-Gan, Israel 2Neurosurgery, David Geffen
In contrast, the CP group demonstrated no interference, attest- School of Medicine, University of California, Los Angeles,
ing to their impaired holistic processing. We then used a California 3Technion-Israel Institute of Technology 4Neuro-
variation of the Navon task in which participants were presented surgery and Institute for Neuroscience and Human Behav-
with a large arrow made of small arrows. The small and large ior, School of Medicine, UCLA, California 5Functional
arrows could either point to the same (congruent) or different Neurosurgery Unit, TelAviv Medical Center & School of
directions (incongruent). Participants were asked to attend to the Medicine, TelAviv University Israel 6Medical Neurobiology,
global or local shape in separate blocks. The critical modifi- Faculty of Medicine, Hebrew University, Jerusalem, Israel
7
cation was the addition of an auditory, warning cue, The Interdisciplinary Center for Neural Computation, He-
which preceded the arrow in half of the trials and was brew University, Jerusalem 91904, Israel 8The Edmond and
shown to enhance global processing in normal partici- Lily Safra Center for Brain Sciences, Hebrew University,
pants (Weinbach & Henik, 2011; 2012). As expected, Jerusalem 91904, Israel 9Dept. of Neurobiology, Weizmann
the CP group differed from controls in the no-warning Institute of Science, Rehovot, Israel 76100
trials and showed a local processing bias. However,
similarly to controls, they benefited from the warning Background: The neural code in the motor system was
cue such that during the local task, global interference intensively studied using animal models, in which
was greater in warning compared to no-warning trials. recordings are made after a long training period. It is
Conclusions: Together, the results highlight the holistic largely unknown how these studies reflect the naive
impairment in CP and underlie it as a possible mecha- coding in the human motor system, where such a
nism for the impairment in face perception. The en- prolonged training is not present. Using deep electro-
hancement in global processing obtained in these des, we study the activity characteristics of human
individuals, following the warning cue, could serve as neurons in the supplemental motor area (SMA), a brain
a potential rehabilitation mechanism which may amelio- region known to participate in movement planning and
rate, at least to some extent, the face processing deficit. execution.
S122 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
Results: Many human neurons exhibit very narrow sensitivity Conclusions: We conclude that social investigation behavior
to movement direction, as compared to parallel neurons in the evokes synchronized neuronal activity in a dispersed neuronal
SMA and primary motor area (M1) of rhesus monkeys. These network known to be modulated by neurohypophysial hor-
narrow direction tuning curves yield significantly lower signal mones, the magnitude of which is proportional to the novelty
correlations between pairs of cells with close preferred direc- of the social stimulus.
tions. When the full activity profile of human SMA neurons is
used to infer movement direction from spike counts, the decod- Stimulus asynchronicity during pair associate learning
ing accuracy is inferior to that obtained with the similar full modulates ERP correlates of episodic cued recall
activity of monkey neurons. This difference is largely due to a Tibon R, Peer A, Ben-Zvi S, Levy DA*
sharp decline in decoding accuracy after movement onset, The School of Psychology,The Interdisciplinary Center,
which was not observed in monkey SMA or M1. Herzliya
Conclusions: Coding of movement direction in SMA neu-
rons in naive human subjects differs significantly from the The time course and distribution of brain processes support-
parallel coding in monkeys: in humans, the tuning curves are ing associative retrieval have yet to be well characterized.
narrower, the signal correlations are weaker, and the decoding We investigated one important aspect of associative memo-
accuracy is lower. These differences could be due to effect of ry: the ability to remember connections between stimuli
training, or due to inter species differences. Also, human SMA experienced asynchronously. We hypothesized that varia-
neurons operated in a "launch and forget" mode when coding tions in the temporal structure of stimulus presentation
movement direction, and may be rapidly switching to code would affect the nature of the associative binding of the
other aspects of movement such as movement speed. stimuli, in turn affecting processes required for retrieval.
Young adult participants studied pairs of object pictures
Synchronized rhythmic neuronal activity encodes which were presented either simultaneously or sequentially,
the novelty value of a stimulus during social recognition by making semantic judgments about the relationships be-
Tendler A* 1, Wagner S 1,2 tween the depicted objects. At retrieval, one pair member
1
Dept. of Neurobiology and Ethology, University of Haifa, was presented, and participants were asked to recall the pair-
Haifa, Israel. 2Center for Gene Manipulation in the Brain, associated item. EEG was recorded while subjects per-
University of Haifa, Haifa, Israel formed the recall task, allowing us to track the temporal
dynamics of the retrieval processes. The results indi-
Background: The ability of an animal to recognize familiar cated that there are two activation patterns associated
individuals is critical for mammalian social behavior. Most with retrieval success. An early retrieval success effect
mammals rely primarily on olfactory cues for social recog- was observed in both tasks, maximal in frontal chan-
nition. A meeting between two unfamiliar rats or mice nels at ~350 msec post cue presentation. A later re-
usually starts with a period of intensive olfactory investiga- trieval success effect was maximal in posterior
tion, which precedes further social interactions. We used the channels at ~800 msec, but was only apparent in the
social recognition paradigm, which is known to depend on asynchronous condition. This indicates that episodic
brain activity of both oxytocin and vasopressin, to explore retrieval of asynchronous association involves addi-
the electrophysiological changes in the brain of behaving tional processes beyond those needed for retrieval of
rats during the acquisition of social memory. By combining synchronous events.
video recordings with wireless data acquisition, we could
monitor neuronal activity in several brain areas, including Acute stress effect on perception and the involvement
the main and accessory olfactory bulbs, the medial amyg- of attentional load. A behavioral- EEG study
dala and the lateral septum, in behaving rats. Tiferet C 1,2,3, Hensel M 4, Tzelgov J 1,2, Friedman A* 1,3
1
Results: A power-spectrum analysis of the recorded LFP The program for Brain and Cognitive Sciences, Zlotwoski
signals revealed a peak around 8 Hz (theta rhythm) which Center for Neuroscience, Ben-Gurion University of the
was most prominent during investigation of a novel animal Negev, Beer-Sheva, 2Dept. of Psychology, Ben-Gurion Uni-
and gradually declined during repeated investigations of the versity of the Negev, Beer-Sheva, 3Dept. of Physiology and
same stimulus. Accordingly, the strength of the theta rhythm in Cell Biology and The Dept. of Biomedical Engineering,
these brain areas correlates with the time of investigation, Ben-Gurion University of the Negev, Beer-Sheva,. 4Dept.
which serves as a measure for the social recognition memory. of Psychology, Trier University, Dresden, Germany
These changes in neuronal activity are social stimulus-specific
and do not occur during object recognition. Moreover, they are Background: For optimal performance in a stimuli saturat-
not limited to episodes of actual investigation hence seem to ed world it is essential to have attentional selectivity to
represent an internal state of the animal during social behavior. relevant information. Perceptual load (PL) is created by
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S123
processing relevant information while ignoring irrelevant invasive alternative diagnostic method for various diseases.
stimuli. Under low PL attentional resources are available The objective of this research is to identify VOC patterns in
allowing irrelevant information to be processed and inter- the exhaled breath of patients using nanomaterial-based-
fere; however, under high PL this interference is eliminated. sensors and to assess whether there are specific breath-
Factors such as stress modulate attentional selectivity. It is prints to AD and PD that could be utilized to identify the
suggested that acute stress and PL consume the same atten- diseases.
tional resources and together enhance attentional selectivity Results: Alveolar breath was collected from 57 volun-
under optimal conditions. We aimed to test the interactions teers (AD and PD patients and healthy controls) and
between acute stress and attentional load using the emotion- analyzed using sensors based on organically functional-
al cognitive load paradigm and electroencephalography ized carbon nanotubes or gold nanoparticles. Discrimi-
(EEG) measurements. nant factor analysis was applied to detect statistically
Results: 29 healthy students were recruited of which 11 significant differences between study groups and classi-
performed the Trier social stress test (TSST) before the fication success was estimated using cross-validation.
task. During the task a target letter was presented along The sensors could clearly distinguish both AD and PD
with 1 (low load) or 5 (high load) distracting letters, in from healthy states, as well as AD from PD (classifica-
the absence or presence of a picture. Subjects were asked tion accuracy: 85 %, 78 % and 84 %, respectively). The
to respond to the target letter by pressing a computer chemical composition of the breath samples was studied
keyboard and their response time (RT) was measured. In using gas chromatography/mass spectrometry; the analysis
the control group, heightened PL or the presence of a showed statistically significant differences in the average
picture increased RTs. However, in the stress group only abundance of several VOCs in the breath of AD, PD and
under low PL, RTs increased due to picture presence. healthy subjects, thus supporting the breath-prints observed
EEG results were consistent with the behavioral results with the sensors.
and revealed virtually no significant differences in elec- Conclusions: The results of this pilot study point to
trical brain activity in the absence or presence of a specific breath-prints of AD and PD that could have
picture, under high PL conditions. In the control group, future potential to aid diagnosis, especially in non-
high load condition evoked increased activity in both specialist settings. Further studies to evaluate the use-
hemispheres in the Cuneus, middle temporal gyrus, infe- fulness of these breath-prints in clinical practice are
rior parietal lobule, and posterior cingulate while stress underway.
evoked increased activity in additional areas.
Conclusions: Stress enhance attentional selectivity but only Synchronization between grid cells in the medial
when attentional resources are limited. We suggest that high entorhinal cortex
PL and stress consume the same attentional resources and Tocker G 1,2, Derdikman D* 1
the same neurophysiological processes. 1
Rappaport Faculty of medicine, Technion – Israel Institute
of Technology, Bat Galim, Haifa, 2The Gonda Multidisci-
The breath-prints of Alzheimer’s and Parkinson’s plinary Brain Res.Center, Bar-Ilan Univ., Ramat-Gan
diseases: a pilot study
Tisch U 1, Schlesinger I 2, Ionescu R 1, Nassar M 2, Axelrod Grid cells are an exclusive category of excitatory neurons of
N 1, Robertman D 1, Tessler Y 1, Azar F 1, Marmur A 1, the medial etorhinal cortex (MEC). These cells are thought
Aharon-Peretz J 3, Haick H* 1 to participate in formation of a cognitive map underlying
1
Dept. of Chemical Engineering, Technion – Israel Institute spatial navigation. Grid cells fire with a spatially reproduc-
of Technology, Haifa 2Dept. of Neurology, Rambam Health ible hexagonal pattern, when the animal is foraging in an
Care Campus, Haifa, 3Cognitive Neurology Unit, Rambam open field. The hexagonal pattern of each cell can be char-
Health Care Campus, Haifa acterized by a typical spatial frequency, orientation and
spatial phase. Previous studies have shown that the relative
Background: The prevalence of neurodegenerative diseases spatial phase between two grid cells in the MEC is preserved
such as Alzheimer's disease (AD) and Parkinson's disease between environments. One explanation for this phenome-
(PD) is expected to increase as the population ages. To date, non is that the connectivity between cells affects the spatial
the ante-mortem diagnosis of AD and PD still relies mostly phase between pairs of grid cells. Indeed, many models
on clinical symptoms and is thus associated with highly share the tenet that grid cells closer in phase are also more
variable sensitivity and specificity, depending on the profi- strongly interconnected. In order to check this assumption,
ciency of the treating physician. Breath testing based on the we analyzed a database of grid cells available publically
analysis of volatile organic compounds (VOCs) is currently (Sargolini, Fyhn et al. 2006). We compared pairs of grid
attracting much research interest as a possible fast and non- cells, and classified those cells, which have a similar spatial
S124 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
frequency, as belonging to the same module. We then mea- Mouse model of empathy reveals differences in neural
sured the spatial phase difference between pairs of grid cells activity underlying recollection of ‘witnessed’ vs.
belonging to the same module. In addition, we compared the ‘experienced’ trauma
temporal cross-correlations at short windows between the Tsoory MM 1, Furman O 2, Chen A* 2
1
same pairs of grid cells. We found that pairs of neurons Phenotyping Unit - Dept. of Veterinary Resources Weiz-
which are similar in spatial phase have a tendency to be mann Institute of Science, Rehovot, Israel 2Dept. of Neuro-
temporally correlated to each other. Moreover, there was biology, Weizmann Institute of Science, Rehovot, Israel
a functional relation, such that the smaller the spatial
phase difference was, the larger was the temporal cor- The DSM IV criteria for diagnosing post traumatic
relation. All in all, our results demonstrate that spatial stress disorder (PTSD) include both personal experience
relations between grid cell fields may be explained by and witnessing a traumatic event. However, physiologi-
synchronization between highly interconnected cells in cal differences between recalling 'experienced' and 'wit-
this network. nessed' trauma are not well understood, and their
investigation using animal models is a challenge. Recent
Dysfunction in DJ-1 protein linked to Parkinson’s observational fear learning protocols indicate that mice
disease accelerates microglia neurotoxicity exhibit freezing following witnessing other mice receiv-
Trudler D 1,2, Segev Amzaleg N 1, Frenkel D* 1,2 ing foot shocks, and that freezing duration is related to
1
Dept. of Neurobiology, Faculty of Life Sciences, Tel familiarity between these mice. Still, the neural sub-
Aviv University, 2Sagol School of Neuroscience, Tel Aviv strates of long term representations of 'witnessed' trauma
University, Tel Aviv, in rodents remain obscure. The current study compared
behavioral and neural responses in three groups of mice:
Background: Parkinson's disease (PD) is a progressive neu- mice subjected to foot shocks (Shocked); mice that
rodegenerative disorder affecting more than 1 % of individu- observed a cage-mate being shocked (Observer); and
als over 55-year-old and more than 3 % of those over age 75. cage-mate pairs that were not shocked (Naive). In a
Activation of glial cells in the CNS is the first defense mech- context test two weeks after the manipulation, a gradient
anism against pathological abnormalities that occur in neuro- in freezing duration was evident; Observer mice freeze signif-
degenerative diseases. Recently, we and others have icantly longer than Naive mice but significantly shorter than
discovered that microglia dysfunction may lead to stress con- Shocked mice. Furthermore, when compared with Naive
ditions resulting in neuronal death. DJ-1, an oxidative stress mice, Observer mice spend significantly more time
sensor that localizes to the mitochondria when the cell is directing their attention to their Shocked cage-mates.
exposed to oxidative stress, was linked to PD. We postulate Neural activity during the context test, assessed by
that DJ-1 dysfunction may affect microglia cell activity in PD. immediate early genes expression, differed between the
Methods: DJ-1 mutations are loss of function mutations. groups in the lateral septum, bed nucleus of the stria
In order to address the role of DJ-1 in microglia activity terminalis, basolateral/central amygdala and paraventric-
we down-regulated the DJ-1 expression using shRNA ular nucleus of the hypothalamus but not in the hippo-
approach. Microglial cell line was transfected with campus, medial amygdala or prefrontal cortex.
shRNA against DJ-1 or with non target shRNA used The findings suggest that the although the behavioral
as control, and cell activity was evaluated by gene manifestation of recalling 'experienced' and 'witnessed'
expression, protein levels, reactive oxygen species pro- trauma may appear similar, they may be mediated by
duction and neurotoxicity. activity in discrete neuronal circuits. Characterizing
Results and conclusions: We found that down-regulation of these neural differences may provide opportunities for
the DJ-1 gene increases microglial pro-inflammatory cyto- better targeted interventions in PTSD patients.
kines IL-1β and IL-6 levels, as measured by ELISA. Fur-
thermore, DJ-1 impairment results in increased microglia A New multispectral combinatoric tracing technique
production of reactive oxygen species (ROS) levels and enables mass neuronal mapping and reveals two level
accelerated microglia neurotoxicity in rotenone models of circuit rearrangement during development
PD. We suggest that dysfunction in DJ-1 protein in micro- Tsuriel S 1,2, Leibovich H 1, Lichtman JW 2, Binshtok AM* 1
1
glia may accelerate neuronal death in PD. Further studies of Dept. of Medical Neurobiology, Institute for Medical
DJ-1-mediated cellular pathways in microglia may provide Research Israel Canada and Center for Research on
useful insights into the development of PD providing future Pain, The Hebrew University Medical School, Jerusa-
avenues for therapeutic intervention. lem, Israel 2Center for Brain Science and Dept. of Molec-
This research was supported by grants from the Alzheimer's ular and Cellular Biology, Harvard University, Cambridge,
association, HFSP and ISF MA, USA
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S125
The fundamental aspect of neural organization is that each astrocytes and in PCs, monitored optically with the Ca2+
neuron's axon projects specifically to particular regions but indicator Fluo-4. This effect was seen also in presence of
not to others. Due to the remoteness of neuronal somata from blockers of excitability or of fast synaptic transmission. The
their targets and the convolution of the projections of neighbor- evoked increase in Cai was due, at least in astrocytes, to Ca2
ing neurons, it has been difficult to map the projections of many + release from the endoplasmic reticulum (ER), as it was
different nearby neurons in the same preparation. Therefore, we abolished by ER depletion. Intriguingly, elimination of
have developed a novel strategy allowing us to map the precise astrocytes, by preincubation of slices with the gliotoxin L-
projections of neuronal cells to their targets. We injected the AA, prevented the ADPβS-induced Cai elevations in PCs.
tracer Wheat Germ Agglutinin (WGA) conjugated to 4 spec- However, L-AA application did not prevent Cai elevation in
trally distinct colors in 4 proximate points in the neurons target PCs induced by caffeine or mGluR activation. The ADPβS-
area. The concentrated dyes diffusely dispersed from the injec- induced Cai elevation in PCs, but not in astrocytes, was
tion points and created an area in which each small region blocked by MCPG, a mGluR antagonist. We conclude that
contains different combinations of the 4 colors, determined by extracellular ATP mediates the spread of intracellular Ca2+
the distance of this region form each injection point. Neurons waves from astrocytes to PCs by activating astrocytic P2Y1
innervating this area took up the WGA with the unique color receptors, causing Ca2+ release from astrocytic ER. This, in
combination and transported it to the cell body in vesicles. turn, causes the release of astrocytic glutamate, which activates
Thus, many neuronal somata distanced from the injec- mGluRs in PCs, causing Ca2+ release from its ER. This cascade
tion point contain a distinct combination of colors may participate in astrocytic-neuronal signaling in a variety of
which can be matched to the original injection site. This physiological and pathophysiological processes. Supported by
enables us to reconstruct the axonal arbor distribution in ERC (AB), ISF (YY), and the Henri J. and Erna D. Leir Chair
the target area of that neuron. We named this technique for Research in Neurodegenerative Diseases (YY).
Neuronal Positioning System (NPS) due to the ability to
detect a neuron's position by its distance from known Representation of three-dimensional space
reference points. Using this approach we were able to in the hippocampus of freely flying bats
map projections of dorsal root ganglion (DRG) neurons Ulanovsky N*, Yartsev M, Dept Neurobiology, Weizmann
to the skin preparation of a rodent hind paw and map Institute
projections of the submandibular (SM) ganglion cells to
their large peripheral end organ, the SM gland. More- Place cells are neurons in the mammalian hippocampus which
over, application of NPS in a Brainbow mouse demon- are active in a restricted region of the environment; this activity
strated that neurons in the SM ganglion, which are region is termed the 'place field'. Place cells are considered
innervated by the same axon, occupy proximate areas pivotal elements in the brain circuitry underlying spatial mem-
in the gland. Thus, this approach enables us, for the ory and navigation, and are typically studied in one-dimensional
first time, to show the relation between the develop- (1D) or two-dimensional (2D) environments. Little is known,
ments of two levels in the same neuronal circuit. however, on how these neurons encode three-dimensional (3D)
Human Frontiers Science Program, NIH, ERC space. This question is important, because most animals, on air,
water or land, navigate in 3D environments. Here, we used a
Astrocytic P2Y1 receptors induce the spread of calcium tetrode-based microdrive and a custom, lightweight multi-
waves from astrocytes to neurons channel neural telemetry system, and conducted the first elec-
Tzour A, Binshtok A, Yaari Y trophysiological recordings from the hippocampus of a freely
Dept. of Medical Neurobiology; Institute for Medical Re- flying mammal, the Egyptian fruit bat. Experiments were con-
search Israel Canada, The Hebrew University-Hadassah ducted in two different 3D enclosures, a 6×5×3 meters rectan-
School of Medicine gular cuboid enclosure and a 3×3×3 meters cube, and revealed
that the 3D firing fields of single hippocampal neurons were
ATP released by astrocytes mediates the spread of Ca2+ strongly tuned to all three dimensions of the environment. In
waves through the astrocytic network. It was shown in the both experimental setups, the 3D firing fields represented each
hippocampus that ATP affects also the excitability of CA1 dimension with the same precision (same size of place field in
pyramidal cells (PCs) by activating P2Y1 receptors. How- the x, y and z-dimensions), and were isotropically tuned in all
ever, recent evidence suggests that PCs do not express P2Y1 directions. Individual place-fields from different neurons oc-
receptors. We therefore hypothesized that the PCs respond curred in different locations in the room, and the firing locations
to astrocytic P2Y1 receptor activation via other signaling across the neuronal population spanned the flight-room, repre-
pathways. Application of the P2Y1 receptor selective ago- senting uniformly the entire available environment. The firing
nist ADPβS to rat hippocampal slices led to a significant fields of individual neurons were stable throughout the record-
increase in cytosolic Ca2+ concentration (Cai) both in ing session, thus providing accurate and reliable representation
S126 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
of the bat's position in 3D space during flight – including altitude Duke University, Durham, NC, USA 3Institute for Genome
(z-height). Finally, the neural activity of almost all hippocampal Sciences and Policy, Duke University, Durham, NC, USA
4
place-cells did not show theta modulation during flight, which Neurobiology, Hebrew University, Jerusalem, Israel, 5 De-
argues against a temporal phase-code for 3D position. Taken partment of Psychology, University of Haifa, Haifa 31905,
together, these results suggest that the mammalian hippocampus Israel 6 Hadassah Medical Organization, Department of
represents 3D space by a uniform and isotropic rate-code. Labor and Delivery, Jerusalem, Israel 7Psychology Depart-
ment, National University of Singapore, Singapore
Brain angiotensin receptor type 2 mediates
nueroprotection after traumatic brain injury Increasing evidence point to a role of dopaminergic path-
Umschweif G* 1, Alexandrovich A 2, Trembovler V 2, ways in modulating social behavior. Specifically, a poly-
Horowitz M 3, Shohami E 2 morphic region in the third exon of the Dopamine D4
1
Institute for Drug Research the Hebrew University of Jer- receptor (DRD4) has been associated with a host of social
usalem 2Institute for Drug Research Hebrew University of behaviors in an environment sensitive manner. Empathy is
Jerusalem 3Dept. of Physiology, Faculty of Medicine, The thought to be an important motivator of prosocial behaviors
Hebrew University of Jerusalem, Jerusalem, Israel and is multi-faceted, combining cognitive empathy (CE) and
emotional empathy (EE). In the current study we analyzed
Background: HA is a preconditioning model achieved by the association between DRD4 and the two empathy facets,
long term exposure to mild heat (34±1C°) for a period of and it's contingency on gender as a meaningful predictor of
4 weeks. This model has been found to suggest cross tolerance empathy. A large sample of adult participants (477 partic-
against various novel stressors including traumatic brain inju- ipants) was inventoried for general empathy, CE and EE and
ry (TBI). In efforts to characterize the mechanisms underlying genotyped for the DRD4 exon 3 polymorphism. Women
HA mediated nueroprotection, we have previously found up scored higher than men on all empathy measures and no
regulation of hypoxia inducible factor 1α (HIF-1α), brain main effect of genotype was observed. Importantly, a sig-
derived neurotrophic factor (BDNF) alongside with reduced nificant interaction between genotype and gender emerged
apoptosis. However upstream signals or receptors responsible specifically for CE, with women carriers of the 7R-allele
to described alternations are currently unknown. One candi- scoring higher than non-carriers, whereas in men 7R-carriers
date receptor that is capable to trigger such effects was also scored lower than -7R. Notably, these findings were replicat-
found to mediate nueroprotection in brain ischemia. is angio- ed in an independently recruited sample (121 participants).
tensin receptor type 2 (ATR2). Aims: In the current study we The current report shows that the DRD4 exon3 polymorphism
have used ATR2 antagonist to explore ATR2 role in HA is associated with cognitive empathy and the direction of the
phenotype establishment. Other perspective of this study association is gender sensitive.
was to evaluate the implication of ATR2 pharmacological
activation in control (normothermic) mice. Non-invasive detection of brain microvascular
Results: We have found that ATR2 blockage did not affect dysfunction by near infrared spectroscopy
post injury recovery or cognitive function of the control Vayman V, Martsiano S, Weinstein M, Nachum-Biala Y,
group, however HA benefits were abolished after the treat- Troen A*
ment. Moreover, ATR2 activation in control mice dramati- Institute of Biochemistry and Nutrition; Faculty of Agricul-
cally improved functional recovery and cognitive memory ture; Hebrew University of Jerusalem.
in a dose-response manner.
Conclusions: We conclude that ATR2 has a role in adapting Structural and functional disturbances of the brain's microcir-
HA neuroprotective phenotype and most importantly, may culation are common in aging. However their contribution to
be a novel drug target to treat TBI victims. cognitive impairment is uncertain. We have developed an
The Hoffman Leadership and Responsibility Program , the innovative non-invasive near infrared spectroscopy (NIRS)
Hebrew University of Jerusalem system to address this question, allowing us to obtain quanti-
tative, absolute measurements of oxygen-bound [HbO],
The dopamine D4 receptor gene shows a gender sensitive oxygen-free [Hb] and total brain hemoglobin concentration
association with cognitive empathy: Evidence from two [HbT], hemoglobin oxygen saturation (StO2%), blood vol-
independent samples ume and vascular reactivity at rest and in response to transient
Uzefovsky F.1, Shalev I.2,3, Israel S.2,3, Edelman S.4, Raz physiological challenges in rat models of Vascular Cognitive
Y.4, Perach-Barzilay N.5, Mankuta D.6, Shamay-Tsoory Impairment (VCI). NIRS measurements in the Spontaneous
SG.5, Knafo A.1, Ebstein RP.7 Hypertensive Rat model of VCI reveal significant decrease of
1
Psychology Department, Hebrew University, Jerusalem, cortical [HbT] without change in StO2% and a tendency for
91501, Israel 2Department of Psychology and Neuroscience, attenuated response to hypercapnia challenge compared to
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S127
normotensive controls. In folate-deficiency (FD) induced indicate that repetitive TMS (rTMS) at low frequency (1 Hz) is
VCI, Hallacoglu et al. observed decreased hemoglobin con- more efficient in increasing BBB permeability compared to
centration [HbT] and cerebral blood volume, decreased stimulation at 10Hz, and that this increase lasts for about an
StO2%, and impaired vascular reactivity. Our goal is to vali- hour after the stimulation. We also similarly measured rTMS
date the hypothesis that FD causes brain vascular rarefaction induced BBB permeability to various seizure-inducing factors
and concurrent reduction in CBV and StO2% and determine (e.g. Penicillin) and chemotherapeutics. These findings suggest
whether Methionine supplementation, an essential amino acid that rTMS may be used as a new, non-invasive approach to
whose metabolic salvage is a product of folate-dependent produce controlled and transient BBB opening for the
metabolism, would ameliorate FD effect on NIRS. We have more efficient delivery of drugs into the brain.
found that [HbT], [HbO] and StO2% were reduced by *This work is done with partial support of Brainsway
FD diet but were not restored by Methionine. [Hb] was Ltd.
unaffected by FD and by Methionine. There was a
significantly more profound cerebrovascular reactivity MRI multiparametric hemodynamic characterization
in the control group as oppose to FD. This was restored of the normal brain
by Methionine to control levels. Together, these findings Vitinshtein F 1, Artzi M 1,2, Aizenstein O 1, Abramovitch R
3
are consistent with the hypothesis that reduced [HbT] , Ben Bashat D* 1
1
reflects capillary rarefaction and reduced brain perfu- The Wohl Institute for Advanced Imaging, Tel Aviv Soura-
sion. Ultimately, this will advance the validation of sky Medical Center 2Sackler Faculty of Medicine, Tel Aviv
absolute NIRS for non-invasive monitoring of cerebral University 3The Goldyne Savad Institute for Gene Therapy,
microvascular health in humans. Hadassah Hebrew University Medical Center
Transcranial magnetic stimulation enhances blood-brain Introduction: Blood oxygenation level dependent (BOLD)
barrier permeability imaging under either hypercapnia or hyperoxia, and dynam-
Vazana U 1, Prager O 2,3, Chassidim Y 2,3, Kamintsky L 1, ic susceptibility contrast (DSC) imaging have been used to
Friedman A* 2,3 study vascular properties in healthy subjects and in patients.
1
Dept. of Biomedical Engineering 2Dept. of Physiology and These techniques enable a comprehensive characterization
Neurobiology 3Zlotowski Center for NeuroscienceBen- of the structure and function of the brain’s vascular system.
Gurion University of the Negev,Beer-Sheva, The aim of this study is to characterize brain tissue vascu-
larity and regional differences in healthy subjects using
Transcranial magnetic stimulation (TMS) is a non-invasive multiparametric hemodynamic MRI methods.
method that uses electromagnetic field generation to induce Methods: 21 healthy subjects were included in this. MRI
low –level electric currents in the cerebral cortex. This protocol was performed on a 3 T MRI scanner and included:
induction is produced by passing high-level electric currents DSC, BOLD hypercapnia and hyperoxia challenges. Signal
through an electromagnetic coil placed adjacent to the scalp. recovery, maximum signal change, cerebral blood volume and
The blood-brain barrier (BBB) is a complex structure flow maps were calculated from the DSC images and areas
designed to maintain a stable extracellular environment by under curve maps were calculated from the DSC and BOLD
limiting the penetration of intravascular hydrophilic mole- images. Unsupervised k-mean classification was performed
cules into the brain. While an intact BBB is essential for based on these three methods. The obtained clusters were later
proper brain functions, it also limits the delivery of chemo- identified as dura&blood vessels, gray matter and white mat-
therapeutics and the effective treatment of primary and ter. Hemodynamic values were measured in the identified
metastatic brain tumors. Thus, a strategy to increase the brain tissues; vascular territories; arteries and veins.
efficiency of drug delivery to the brain should induce a Results: Significant differences emerged between all tissue
transient, preferably local increase in BBB permeability to types for most hemodynamic parameters, supporting the grad-
allow better administration of chemotherapy in the chosen ing vascularity of the tissues (BVD>GM>WM). Significant
time and place. Using a novel approach for analyzing BBB differences between vascular territories were detected only for
permeability in-vivo, we present here that the application of the DSC parameters, with delayed start time and prolonged
TMS can result in increased BBB permeability in anesthe- transfer time in the posterior cerebral artery compared to other
tized rats. Before, following and post stimulation the rat is territories. The DSC start time of the vein was significantly
injected intravenously with a BBB-impermeable fluorescent delayed by 1.3 sec relative to that of the arteries.
tracer, (e.g. sodium-fluorescein, MW0376 Da), and cortical Conclusions: Multimodal vascular characterization of several
surface images are acquired at 5/s simultaneously. Offline brain areas was performed; reference values were obtained
image analysis is performed using home-made MATLAB from the healthy brain; and differences between vascular terri-
algorithms in order to quantify BBB permeability. Our results tories and between veins and arteries were detected. Findings
S128 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
from this study may have clinical importance in patients with this disease is the primary death of oligodendrocytes. To
cerebrovascular diseases such as stroke and carotid stenosis. specifically test such oligodendrocyte death as a trigger for
Grant support: This work was supported by the James S. anti-CNS immunity, we inducibly killed oligodendrocytes
McDonnell Foundation number 220020176 in an in vivo mouse model. Strong microglia-macrophage
activation followed oligodendrocyte death, and myelin com-
Stereo-fusion acquisition and preservation: effects ponents in draining lymph nodes made CNS antigens avail-
of peripheral fusion locks able to lymphocytes. However, even conditions favoring
Wagner M 1, Berliner E 1, Schwalb N 1, Shapiro I J* 2 autoimmunity—bystander activation, removal of regulatory
1
Ariel University Center, Ariel, Israel 2Hadassah Academic T cells, presence of myelin-reactive T cells and application of
College Jerusalem demyelinating antibodies—did not result in the development
of CNS inflammation after oligodendrocyte death. In addition,
We studied the efficiency and stability of the oculomotor mech- this lack of reactivity was not mediated by enhanced myelin-
anism to create stereo fusion undertaken with, or without zero- specific tolerance. Thus, in contrast with previously reported
disparity fusion locks. We were motivated by optometric expe- impairments of oligodendrocyte physiology, diffuse oligoden-
rience showing that peripheral locking devices improve the drocyte death alone or in conjunction with immune activation
stability of binocular vision. Eight normal-sighted participants does not trigger anti-CNS immunity.
were trained to elicit free-fusion stereo images embedded in
RDS stereo pairs. Stimuli were static Landolt-C rings or"E" General ability vs. expertise in mathematics: An ERP
targets (2 deg diameter), displayed in one of four directions. In study with school students who answer geometry
phase 1 we tested stimuli with crossed or uncrossed horizontal questions
disparity of 1 Pixel (1.7 arc-minutes). In a second phase the Waisman I 1, Leikin M 1, Shaul S 1,2, Leikin R 1
1
same participants were presented with identical stimuli, but University of Haifa 2Edmond J. Safra Brain Research
horizontal disparities of 3 5or7Pixels (5.2,8.6, and 12 arc- Center for the Study of Learning Disabilities.
minutes). The peripheral locks were white rectangular frames,
symmetrically superimposed on target area Small Frame:17.5× Background: Research has been conducted on (а) neural
9 deg. Large Frame: 25.5×13 deg. We measured reaction-times foundation of mathematical cognition (e.g. Dehaene et al.,
for Landolt-C gap or letter E direction detection. Binocular eye- 2003), (б) Human intelligence including individual differ-
movements were recorded (EyeLink1000 system) during trials ences in general intelligence (e.g. Deary et al., 2010), and
and ITI's. With 1-Pixel horizontal disparity displays (Phase1), (c) Mathematical giftedness (e.g., Grabner et al., 2009).
presence of both peripheral locks significantly enhanced stereo- However, differences between giftedness and expertise have
fusion efficiency. In all experimental conditions the task of not been addressed in brain research. We integrated 4 groups
uncrossed fusion was more difficult than crossed fusion. Fusion of adolescents (43 participants), divided according to gen-
locks significantly improved performance with uncrossed fu- eral giftedness (G) and mathematical expertise (E). The
sion targets, which was found extremely difficult without fu- study uses ERP methodology to shed light on the temporal
sion locks. Contrary to Phase1 with 3,5or7-Pixels horizontal characteristics of geometric reasoning.
disparity in Phase2 the effect of peripheral locks was reversed Results: There were no main effects of G and E factor on
and interfered with the stereo fusion process. In both phases, the accuracy measure. There was significant main effect of
detection with crossed fusion was more efficient and easier than E factor on the RT measure: RT(E)<RT(NE). The mean
uncrossed fusion. We also observed4 of the participants to have activity in these time frames was significantly lower in S1
reversed fusion directions: targets they perceived recessed were than in S2. This finding suggests that the introduction stage
perceived by the others as in front. Our results support the role demanded fewer cognitive resources than the verification
of remote peripheral zero-disparity images as trigger of a sus- stage. Electrophysiological data revealed also that both G
tained Vergence fusion-lock mechanism during stereopsis. and E factors caused different patterns of brain activity in
later time epochs (starting from 300 ms after stimuli presen-
Primary oligodendrocyte death does not elicit anti-CNS tation) of the process of geometric problem solving. The
immunity findings demonstrated that both in anterior and posterior
Waisman A 1,2 parts of the brain, differences between two subsequent
1
University Medical Center Mainz 2Institute for Molecular stages of problem-solving are significantly less prominent
Medicine in the G-E group. The more significant difference was found
between the G-E and NG-NE groups.
Anti-myelin immunity is commonly thought to drive multi- Conclusion: G factor does not influence problem solving
ple sclerosis, yet the initial trigger of this autoreactivity performance. E factors reflects participants expertise which
remains elusive. One of the proposed factors for initiating is mainly expressed in RT. We hypothesise that G factor and E
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S129
factor are of different neuro-cognitive nature. We hypothesize (1 mg/kg) or vehicle were systemically administered for
that G-E students start solving the task at S1 while for NG-NE 6 months to aged rats (20 month-old). Behavioral and cognitive
students main activity starts only at S2. tests were performed 4 weeks before the end of treatments.
Results: M30 and VAR treated-aged mice and rats, respective-
The Interaction between Alertness and Executive ly, exerted significant neuroprotective effects on neuropsychia-
Control try functions and cognitive age-related impairments,
Weinbach N*, Henik A accompanied by a marked decrease in cerebral amyloid precursor
Dept. of Psychology and the Zlotowski Center for Neurosci- protein and beta amyloid deposition. Both compounds increased
ence, Ben-Gurion University of the Negev, Beer-Sheva, Israel the levels of hippocampal brain-derived neurotrophic factor and
its upstream regulator cAMP responsive element binding protein
Background: There is growing interest in how attentional in aged mice and rats. Additionally, M30 and VAR caused a
networks interact in order to achieve adaptive behavior. An significant selective inhibition of brain MAO-A and -B activities,
example is the interaction between executive control—a system and markedly regulated cerebral iron accumulation and iron
that deals with goal achievement—and alertness—a homeostatic-related genes in aged-treated animals.
subcortical-based mechanism that modulates the level of arous- Conclusions: Our results demonstrated that our novel com-
al. Specifically, studies have revealed an increased cognitive pounds, M30 and VAR, prevented memory impairments and
conflict (i.e., congruency) following presentation of alerting beta amyloid deposition, and thus may provide a potential
cues. This interaction reflects a modulation of higher brain therapeutic strategy for age-related neurodegenerative dis-
regions (i.e., prefrontal cortex) by a lower subcortical system. ease, such as AD.
However, the mechanisms underlying this effect are unclear.
Results: Inaseriesofstudieswefoundthatincreasedcongruency, Cannabinoids modulation of the effects of trauma
following alerting signals, was limited to conflict tasks in which and situational reminders on behavior and synaptic
spatial attention was required. When no spatial distractors were plasticity in a rat model of PTSD
present, the effects of alerting and congruency were additive. Weinshtok N, Akirav I*
Conclusion: We suggest that alerting does not actively inhibit Dept. of Psychology, University of Haifa
executive control as was previously suggested, but rather disrupts
conflict resolution by allocating attention to irrelevant competing Background: The formation of a fear memory following
stimuli in the periphery. a traumatic event is an important mechanism for the
subsequent development of anxiety disorders, such as
Attenuation of Alzheimer associated cerebral and behavioral post-traumatic stress disorder (PTSD). The consequences
deficits by novel multi-target iron chelating compounds of exposure to trauma are affected not only by aspects of
in animal model of aging the event itself, but also by the frequency and severity of
Weinreb O*, Kupershmidt L, Bar-Am O, Danovitch L, Amit trauma reminders. There is a growing body of data
T, Youdim MB pointing to a therapeutic potential of cannabinoids for
Eve Topf Center for Neurodegenerative Diseases Research, treatment of PTSD. Here we aimed to test the hypothesis
Faculty of Medicine, Rappaport Institute, Technion-Israel that exposure to a single traumatic event followed by
Institute of Technology, Haifa, Israel discrete reminders of the event would have a profound
impact on the neuronal networks implicated in emotional
Background: Aging of the brain appears to be the main risk disorders in rats, and to explore whether early interven-
factor for Alzheimer's disease (AD) and thus, investigating tion using cannabinoid activation would prevent the
the pathological brain changes occurring in aging is of effects of exposure to trauma and reminders on behavior
crucial importance to treat cognitive diseases. Recently, we and plasticity.
have synthesized multi-target non-toxic, brain permeable Results: Rats were exposed to a single shock (1.5 mA,
iron-chelators, M30 and its stable derivative VAR, possess- 10 sec) followed by exposure to two contextual 1-minute
ing the N-propargyl moiety of the anti-Parkinsonian drug/ reminders of the shock on days 3 and 5 after the trauma.
monoamine oxidase (MAO)-B inhibitor, rasagiline and the WIN55,212-2 (0.5 mg/kg) or vehicle were injected i.p.
antioxidant-iron chelator moiety of 8-hydroxyquinoline de- 2 hrs after trauma exposure. One week after the initial
rivative, VK28, as drug candidates for age-related neurode- trauma, we examined the rats' ability to extinguish the
generative diseases. The main objectives of this study were initial trauma using an avoidance procedure and mea-
to investigate the neuroprotective effects of the novel mul- sured plasticity in the hippocampal-accumbens pathway.
tifunctional compounds, M30 and VAR in aged rodents. We found that shock exposure resulted in the blockade of
M30 (1 and 5 mg/kg) or vehicle were systemically admin- extinction, hence rats demonstrated persistent avoidance
istered for 6 months to aged mice (15 month-old), and VAR from the trauma context. The agonist WIN prevented this
S130 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
effect. Shocked rats exposed to reminders also demon- Psycho-semantics of odor space
strated impaired LTP in the hippocampal-accumbens Weissler K 1,2, Snitz K* 1, Frumin I 1, Sobel N 1
1
pathway and this impairment was prevented by the can- Neurobiology, Weizmann Institute of Science 2Psychology,
nabinoid agonist WIN55,212-2. Tel-Aviv University
Conclusions: These results strongly support the notion that
cannabinoid activation in proximity to trauma can prevent Several standard references describe the space of odors
the subsequent development of anxiety disorders and PTSD according to different sets of descriptors. We propose our
in particular. own set of descriptors based on a quantitative semantic anal-
ysis of 20 subject's free descriptions of 11 odors. The subjects
Stimulating the brain through the nose generated 7800 responses, which were merged and catego-
Weiss T 1, Weissbrod A* 1, Secundo L 1, Shushan S 1,2, rized, resulting in a compact set of 109 relevant descriptors.
Shoffel H 1, Sobel N 1 We compared our set of descriptors to the commonly used set
1
Dept. of Neurobiology, Weizmann Institute of Science, described by Dravnieks [Atlas of odor character profiles] in
Rehovot, Israel 2Dept. of Otolaryngology-Head and Neck terms of their predictive power reliability and information
Surgery, Edith Wolfson Medical Center, Tel-Aviv University content. We found that our semantically selected set of
Sackler School of Medicine, Holon, Israel descriptors outperformed Dravnieks in every measure: The
Cronbach's Alpha of the new questionnaire is 0.895 against
In animals, electrical stimulation of the olfactory epithelium 0.683 of the Dravnieks questionnaire, and the correlation of
induces responses at the olfactory bulb. Whether these the new Questionnaire with the Euclidean distances between
responses reflect an olfactory percept remains unclear. Elec- every 2 odors is 0.670 against correlation of 0.416 of Drav-
trical stimulation of the human olfactory epithelium has nieks questionnaire. Furthermore, as opposed to Dravnieks'
generated mixed results, ranging from diverse olfactory descriptors, the descriptors arrived at through our selection
sensations (Uziel et al., 1973), to no sensation at all (Stras- process were relatively free of comparisons to familiar objects.
chill et al, 1983, Ishimaru et al, 1997). We set out to test the I.e. the selected descriptors tended to be of attributes (e.g.,
hypothesis that modern methods would allow us to generate "warm"; "heavy") rather than comparisons (e.g., "like an
odor perception by electrical stimulation. We used endo- orange; "like a banana"). This result supports a theory of
scopic guidance to place a pure silver stimulating-electrode perception where features are decided before identification is
on the ventral surface of the middle turbinate. Stimulation made. A similar theory is well established in Vision, and we
was generated using a battery-powered electronic stimula- suggest a similar process in olfaction.
tor, driven by an electro-optically isolated function genera-
tor. Different electrical stimulus parameters were tested. At Specific morphological features of a synaptic spine
high currents, those stimuli generated tactile sensations, predict its life-time in vivo
pain, and visual phosphenes, but failed to generate olfactory Yanover U 1, Loewenstein Y* 2, Rumpel S 3
1
percepts. The Hebrew University, Jerusalem, Israel 2Dept. of Neuro-
Whether or not an odor percept is generated, electrical biology, The Alexander Silberman Institute of Life Sciences,
stimulation of the olfactory mucosa may nevertheless The Interdisciplinary Center for Neural Computation,
induce brain activation. To test for this, we repeated Edmond and Lily Safra Center for Brain Sciences, The
the stimulation procedure concurrent with EEG. The Hebrew University, Jerusalem, Israel 3IMP - Research In-
EEG signals were recorded continuously by using a stitute of Molecular Pathology, Dr. Bohr-Gasse 7, Vienna,
Biosemi Active II system with 64 Ag-AgCl pin-type 1030, Austria
active electrodes mounted on an elastic cap according
to the extended 10–20 system, and from two additional The persistence of synapses, manifested as the stability of
reference electrodes placed at the right and left mas- spines, is believed to underlie our ability to store memories
toids. Recordings were sampled at 256 Hz. To date, we for long periods of time. Therefore, to understand how
have failed to identify an EEG response to stimulation. memories are maintained, it is important to study spine
This result may reflect either a failure to activate the turnover in the living brain. In recent years, chronic spine
brain, or a brain activation pattern that does not influ- imaging in living mice has opened the door to studying
ence EEG. To address this, we will present data of a many individual spines over extended periods of time. Pre-
repeat of this method, concurrent with fMRI. If we can vious studies have demonstrated that the persistence of a
successfully drive brain activation through electrical spine is positively correlated with both its age and its size:
stimulation in the nose, this may provide a novel means the larger and the older a spine is, the longer it will survive.
of treatment for a host of neurological diseases treated However, because spine age and spine size are positively
through brain stimulation. correlated, it has been unclear whether spine turnover
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S131
depends on the age of the spine, its size or both. The goal of control of PS responses. We identified several regimes of
this study is to quantitatively characterize the dependence of PS generation and, through analytical treatment of an
spine turnover on spine age, spine size and two additional analogous mean-field model, demarcated the regions in
morphological characteristics of the spine. For this purpose, parameter space that allow SSA. Our results compare
we chronically imaged of more than 1,800 spines in the with experimental data and provide predictions that will
auditory cortex of mice in vivo. We demonstrate substantial be tested by electrophysiological recordings in rats.
turnover that is correlated with (1) spine size and (2) spine
age. Moreover, we observe that spine size is correlated Using next generation sequencing to elucidate the role
with spine age, in line with previous studies. To study of hypocretin neuronal networks
the relative contribution of the two factors to the turn- Yelin-Bekerman L 1,2 , Elbaz I 1,2 , Gibbs-Bar L 3 ,
over, we use logistic regression and show that the life- Appelbaum L* 1,2
1
time of a spine independently depends on both its size The Mina and Everard Goodman Faculty of Life Sciences,
and its age. We extend the model to incorporate the Bar-Ilan University,Israel 2The Leslie and Susan Gonda
contribution of additional morphological features, the Multidisciplinary Brain Research Center, Bar-Ilan Univer-
ellipticity of the spine and its distance from the dendrite sity,Israel 3Dept. of Biological Regulation, The Weizmann
to spine turnover. We show that spine turnover also Institute of Science, Rehovot 76100, Israel
depends on ellipticity such that the more elongated a
spine is the less stable it is. By contrast, we found no The mechanism that regulates sleep and metabolism is
dependence of life-time on the distance of the spine's conserved in all vertebrates. The hypothalamic hypocre-
center of mass from the dendrite. In conclusion, these tin/orexin (HCRT) neurons, integrate internal and external
results demonstrate that the survival of spines in vivo inputs to regulate feeding and sleep behavior and loss of
depend both on their age, their size and on specific HCRT neurons cause the sleep and metabolism disorder
morphological characteristics. narcolepsy. However, the molecular identity of HCRT
neurons and the mechanism of narcolepsy are poorly
Stimulus-specific adaptation in a model of primary understood. In zebrafish, the HCRT neurons encompass
auditory cortex only ~16 cells and their brain location and function are
Yarden TS 1,2,3, Nelken I* 1,2,3 conserved in mammals. Furthermore, genetic ablation of
1
Dept. of Neurobiology, Silberman Institute of Life Sciences HCRT neurons altered sleep and locomotor response to
2
Edmond and Lily Safra Center for Brain Sciences external stimuli in zebrafish larvae. To identify the genes
3
Interdisciplinary Center for Neural Computation, Hebrew that co-localized in HCRT neurons and potentially in-
University of Jerusalem, Jerusalem, Israel volved in regulation of sleep and metabolism, we have
developed a novel protocol to specifically isolate mRNA
In the primary auditory cortex (A1) of cats and rats, neurons from only 300 EGFP-labeled HCRT neurons and to
decrease their responses to frequently-presented stimuli but sequence the whole transcriptome. A transgenic hcrt:
not to rare stimuli. This phenomenon, called stimulus- EGFP line was used for FAC sorting and isolation of
specific adaptation (SSA), originates in the cortex and may the whole population of HCRT neurons.. In order to
underlie short-term sensory memory and deviance detection. prepare the library for next generation sequencing
To investigate possible mechanisms of SSA, we employed a (RNA-seq), we used a unique method, which enables
neural network previously used to reproduce several other cDNA synthesis and amplification from ultra low
A1 response properties, including frequency tuning, forward amounts of RNA. We have further sequenced the entire
masking, lateral inhibition, and hyper-sensitive locking sup- transcriptome of the neurons and used bioinformatics and
pression (Loebel et al. 2007). This network has synaptic in vivo techniques to determine the list of putative can-
depression, which gives rise to population spikes (PSs). didate genes, which may be involved in sleep and me-
Our model exhibits SSA: rare stimuli elicit a PS but frequent tabolism regulation, and narcolepsy. Zebrafish is a unique
stimuli do not. In contrast to a model based on adaptation of model empowering to specifically isolate the entire
excitation in narrow frequency bands (analyzed in Taaseh HCRT neuron population. Using the advantages of zebra-
et al. 2011), our model shows clear preference to devi- fish as genetic transparent model organism, this transcrip-
ance, i.e. a contrast with regularity of the background as tome will be tested in live animal and the mechanism of
opposed to rarity in an irrgeular background – in line narcolepsy may be clarified. It will also open the oppor-
with previous experimental results (Taaseh et al. 2011). tunity to untie the complex neuronal networks that regu-
SSA in our model strongly depends on stimulus and late sleep and metabolism.
network parameters (input amplitude, inter-stimulus inter- Legacy Heritage biomedical program of the Israel Science
val, time-constants of synapse recovery etc.) through their Foundation
S132 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
Novel new multi target anti Alzheimer drugs during CFS, but the role of primary visual cortex (V1) is still
with neuroprotective and neurorestorative activities controversial.In this study, we resolve this dispute and also begin
Youdim MB characterizing the computational processes underlying CFS.
Technion-Eve Topf Center of Excellence, Haifa Results: Early visual cortical activity was measured with func-
tional magnetic resonance imaging while human subjects
The role of iron and oxidative stress in Alzheimer's Disease viewed stimuli composed of target and mask, presented to the
(AD) lead us to develop non-toxic, lipophilic propargyl- same or different eyes. Stimulus-evoked responses in early
amine, brain permeable multifunctional compounds with visual cortex were smaller when target and mask were in differ-
iron chelation, cholinesterase (ChE) and monoamine oxi- ent eyes compared to the same eye, not only for the lowest
dase (MAO) inhibitory moieties properties for AD. We contrast target rendered invisible by CFS, but also for higher
investigated the neuroprotective and neurorestorative effects contrast targets which were visible even when presented to the
of M30, HLA20 and M30P in transgenic APP/PS1 (Tg) eye opposite the mask.
mice model of AD. These studies include regulation of Ab Conclusions: We infer that CFS works by modulating the gain
aggregation and plaque areas, holo-APP expression levels of neural responses, akin to reducing target contrast.
and APP-processing mechanisms and cognitive abilities, SYG supported by EU Marie Curie fellowship and Weizmann
since the 5' untranslated region of APP mRNA has a func- Institution Advancing Women in Science award
tional iron-responsive element. Comprehensive behavioral
batteries determined at 10 month of age revealed that trans- Zebrafish as a model for monocarboxyl transporter
genic APPswe/PS1 mice given M30 during that period 8-deficiency
were protected from cognitive impairments in a verity Zada D 1,2, Vatine G 1,2, Lerer T 1,2, Tovin A 1,2, Appelbaum
of tasks of spatial learning and memory retention, work- L* 1,2
1
ing memory, learning abilities, anxiety level, and mem- The Mina & Everard Goodman Faculty of Life Sciences,
ory for the novel food and nesting behavior. Non Bar-Ilan University, Ramat-Gan, 52900, Israel 2The Leslie
treated transgenic mice remained impaired in all of and Susan Gonda Multidisciplinary Brain Research Center,
these cognitive tasks/domains. M30 markedly reduced Bar-Ilan University, Ramat-Gan, 52900, Israel
the levels of holo- APP and β-CTF in the frontal
cortex, hippocampus and parietal cortex of APP/PS1 Allan Herndon Dudley syndrome (AHDS) is a severe psycho-
treated mice compared to non-treated animals. Coordi- motor retardation characterized by neurological impairments
nately, the levels of cerebral amyloidogenic Aβ peptide and abnormal thyroid hormone (TH) levels. Mutations in the
in soluble and insoluble fractions and the number of Aβ TH transporter, monocarboxylate transporter 8 (MCT8), are
plaques and dimeric Aβ contents in the frontal cortex, associated with AHDS. MCT8-knockout mice exhibit impaired
hippocampus and parietal cortex were decreased in TH levels; however, they lack neurological defects. Here, the
M30-Tg mice as compared to non-treated animals. Regarding zebrafish mct8 (Slc16a2) gene and promoter were isolated, and
aspects of cell signaling pathways associated with Alzheimer's a Tg(mct8:EGFP) transgenic line was used to show that, similar
disease (AD) pathology, M30 activated HIF, induce cell cycle to humans, mct8 is primarily expressed in the nervous and
arrest at G0/G1, enhanced the levels of BDNF, GDNF VEGF, vascular systems. Knockdown and rescue experiments showed
phospho-AKT and phospho- glycogen synthase kinase that MCT8 is a crucial regulator during embryonic develop-
(GSK)-3b and attenuated Tau phosphorylation. Our findings ment. This study establishes the first vertebrate model for
provide support for long-term M30 therapy as primary strat- MCT8-deficiency that exhibits a neurological phenotype.
egy for treatment of AD. This work was supported by the Sherman foundation inc.,
Australia
Continuous flash suppression modulates cortical activity
in early visual cortex Prereproductive stress in female rats affects CRF type 1
Yuval-Greenberg S* 1,2, Heeger DJ 1 receptor expression in brain and oocytes, and alters
1
New York University 2The Hebrew University of Jerusalem behavior in offspring
Zaidan H, Golumbic Y, Leshem M, Gaisler-Salomon I
Background: A salient visual stimulus can be rendered invis- Dept. of Psychology, University of Haifa, Israel
ible by presenting it to one eye while flashing a mask to the other
eye. This compelling phenomenon, called continuous flash We have previously shown in rats that stress to the dam well
suppression (CFS), has been proposed as an ideal way of before she becomes pregnant (preconceptual stress, PRS)
studying awareness as it can make a stimulus imperceptible impacts her future offspring's behavior. The offspring's emo-
for extended periods of time. Previous studies have reported tional and social behavior is altered in complex ways that
robust suppression of cortical activity in higher visual areas differ in males and females, and persist into their adulthood.
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S133
Here we investigate whether the transgenerational stress- trials, respectively. Comparing these results with previous
induced changes is mediated by alterations in mRNA expres- passive and active touch VTSDs reveals remarkable and
sion of CRF type 1 receptor 1 (CRF1) in brain and oocytes. moderate improvements, respectively. Our results also indi-
Stress is well known to affect the expression of CRF1 in brain cate better performance in speed and accuracy of an active-
in cortical regions, hippocampus, amygdala, brainstem and touch VTSD when compared with a VHSD (vOICe). We
cerebellum. In the ovary, CRF1 expression is dependent upon analyzed sensor (hand) movement and its interactions with
the ovulatory stage and is believed to contribute to reproduc- the object as well as participants' reports and behavior. We
tive success. We examined CRF1 expression in several brain recognize three major factors that may account for the
regions of PRS and control female rats and their adult off- observed improved performance: (i) Capturing ~25 % of
spring. In addition, we examined CRF1 expression in oocytes the object size in each snapshot, (ii) attaining externalization of
of PRS and control rats, and in the brains of their offspring at the sensed data, and (iii) developing an ability to identify local
birth. We found an increase in CRF1 in PRS females, as well features (e.g., orientations, curvatures, vertex, corners). We con-
as in the brain of their female offspring at birth and in off- clude that using motion-dependent tactile sensation and having
spring exposed to psychological stress in adulthood. In addi- motion and sensation on the same organ can improve perception
tion, we found a 20-fold increase in CRF1 mRNA in the via a VTSD significantly, and that this improvement depends
oocytes of female PRS rats, which did not correlate with litter critically on the participant's active strategy.
size or birth weight. These findings indicate that (1) CRF1
expression changes both centrally and peripherally in Enhancement of addictive behaviors and neurochemical
response to unpredictable stress; (2) both behavioral markers associated with drug addiction in two distinct
alterations and CRF1 expression changes are transmitted animal models of depression
across generations; (3) CRF1 expression in the oocyte Zilkha N* 1,2, Zangen A* 2
1
may play a role unrelated to reproductive success, and Dept. of Neurobiology, Weizmann Institute of Science,
may mediate the offspring's response to stressful situa- Rehovot 2Dept. of Life Sciences, Ben-Gurion University of
tions. While the exact molecular mechanism of this the Negev, Beer-Sheva
finding remains to be clarified, this may suggest an
epigenetic mode of inheritance whereby stress effects Major depressive disorder (MDD) is one of the world's
are transmitted across generations. greatest health problems, and it is often accompanied by a
Acknowledgements Supported by an Israel Science Founda- comorbid substance abuse disorder (SUD). A few mecha-
tion (ISF) grant to IGS. nisms have been suggested for this phenomenon, however
the full set of features, especially whether or not there is a
Vision to touch substitution in the real world causal basis for this comorbidity, are not completely under-
Zilbershtain-Kra Y* 1,2, Ahissar E 2, Arieli A 2 stood. In the following study, we have investigated the
1
Gonda Interdisciplinary Brain Research Center, Bar Ilan effects of depressive-inducing manipulations on different
University 2Dept. of Neurobiology, Weizmann Institute of features of drug addiction. For this purpose, we employed
Science two distinct animal models representing either environmental
or genetically induced depression: the commonly used chronic
Sensory substitution is an approach that uses one sense (e.g., mild stress (CMS) model; and a genetic model developed in
touch) for gathering environmental information usually gathered our lab based on selective breeding for a depressive-like
by another sense (e.g., vision). In most vision to touch/hearing phenotype. Our results indicate that induction of a depression
substitution devices (VTSD/VHSD) the sensor and stimulator like state using either CMS or selective breeding strengthened
are attached to different body organs, and light intensity is a preference of heroin over a natural reward in a conditioned
translated to tactile/acoustic vibrations. Here we examined the place preference paradigm. Moreover, CMS increased rates of
efficiency of a VTSD attached only to the hand and which relapse to cocaine seeking behavior in the self administration
translates light intensity to tactile pressure directly. Therefore, a (SA) paradigm, while genetically depressed-like animals from
stationary stimulus creates a constant pressure and sensory our selective breeding model displayed higher rates of lever
adaptation. To activate mechanoreceptors of the fingers, thus, presses during acquisition and maintenance of cocaine self
the subject must move the hand much like during natural touch. administration, and tended to display higher relapse rates than
Six blindfolded participants were asked to recognize a 2D control animals. The results in both environmental and genetic
black shape in the first stage (1.5 hours) and a 3D colored models for depression clearly indicate that induction of a
object in the second stage (1.5 hours). In each trial they were depressive-like state in rats enhances different behavioral
presented with 5 objects of ~15*15 cm size from a distance features of drug addiction.
of ~1 meter. The participants succeeded in recognizing 2D In addition, we found that CMS followed by heroin CPP of
and 3D shapes in less than 30s in 86 % and 95 % of the cocaine SA caused several alterations in the protein levels of
S134 J Mol Neurosci (2013) 51 (Suppl 1):S1–S135
Brain-Derived Neurotrophic Factor (BDNF) and of the alpha- Rationale: An increasing number of pregnant women with
amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) depression are being treated with antidepressant drugs but it is
receptor subunit GluA1 in reward related brain regions. These not clear whether any benefits of treatment outweigh the
changes might shed light on the mechanism by which potential adverse effects on the offspring.
depression-like states enhanced addictive behaviors. Objectives: To compare the early and long-term effects of
prenatal citalopram in prenatally-stressed (PS) and control
The neural mechanisms of selective attention at a ‘cocktail rats of both sexes.
party’ Methods: Pregnant rats were administered citalopram
Zion Golumbic E* 1, Poeppel D 2, Schroeder CE 1 (10 mg/kg/day) in their drinking fluid from day 7 of gesta-
1
Columbia University Medical Center, New York, NY 2New tion until after their pups were weaned. Half of them were
York University, NY subjected to once-daily varied stress from day 14-21 of
gestation. Offspring behaviour and gene expression of the
Background: The ability to focus on and understand one CRH family in the amygdala was evaluated in adulthood.
talker in a noisy social environment is a critical social- Results: PS rats showed anxiety in the elevated plus maze,
cognitive capacity, whose underlying neuronal mechanisms depressive-like behaviour in the forced swim test, and sex
are unclear. We investigated the manner in which speech dependent alterations in CRH signalling in amygdala. Cit-
streams are represented in brain activity and that way that alopram prevented anxiety of stressed mothers and in their
selective attention governs the brain's representation of female offspring, but not the depressive-like behaviour in
speech using a 'Cocktail Party' Paradigm, using direct elec- both sexes. Citalopram had little effect on CRH signalling in
trocorticography recordings (ECoG) from the cortical sur- PS males but reduced the expression of CRH, and its bind-
face in surgical epilepsy patients. Participants attended to ing protein, CRHR1 and CRHR2 in PS females. Citalopram
long segments of natural speech while ignoring other con- treatment of control mothers induced depressive-like behav-
currently presented speech by another speaker. iour in the offspring of both sexes.
Results: We find that brain activity dynamically tracks Conclusion: Although citalopram can prevent anxiety in
speech streams using both low frequency phase and high stressed rat mothers it does not normalize behaviour of their
frequency amplitude fluctuations, and that optimal speech offspring. Blockade of the 5HT transporter by citalopram
encoding likely combines the two. In and near low level during development could lead to reduced activation of post-
auditory cortices, attention 'modulates' the representation synaptic 5HT receptors resulting in changes in CRH signalling
by enhancing cortical tracking of attended speech streams, in the amygdala and depressive-like behaviour in adulthood.
but ignored speech remains represented. In higher order
regions involved in speech processing and attentional con- Noise and the perceptual filling-in effect
trol, such as inferior frontal cortex inferior partial lobule, the Zomet A 1,2, Polat U* 1, Levi D 2
1
representation appears to become more 'selective,' in that that Goldschleger Eye Research Institute, Faculty of Medicine,
there is detectable tracking only of attended by not of ignored Tel-Aviv University, Israel 2 School of Optometry, UC
speech. This selectivity itself seems to sharpen as a sentence Berkeley, Berkeley, CA, USA
unfolds.
Conclusions: Our results provide an empirical basis for the Background: It was shown that collinear flankers increased the
idea that selective attention in a 'Cocktail Party' setting relies reports of a target present (false alarms, FA), an effect that is
on an interplay between bottom-up sensory responses and attributed to filling-in of the target location due to increased
top-down control, resulting in a dynamic and selective neural activity induced by the flankers. A filling-in effect is character-
representation of attended speech, particularly in higher- ized by high FA and a high percent correct, leading to low
order regions. This pattern of results provide a compelling decision criterion, which indicates high reports of a target pres-
example of 'Active Sensing', a process in which the brain ent. However, according to the standard notion, FA is attributed
dynamically shapes its internal representation of stimuli, and to noise in the system. We hypothesized that if the reports for FA
particularly those of natural and continuous stimuli, accord- are due to noise, then different levels of external noise imple-
ing to environmental and contextual demands. mented in the filling-in task should modulate the filling-in effect.
Method: Here we investigated the effect of manipulation on the
Maternal administration of citalopram induces sex- filling-in effect by external noise that was added to the Gabor
dependent changes in behaviour, CRH-mRNA and that target, presented between two collinear Gabor flankers in differ-
of its receptors in prenatally stressed and control rats ing target-flanker separations. The target was masked by white
Zohar I, Weinstock M* noise with differing levels of contrast.
Dept. of Pharmacology, Institute of Drug Research, Hebrew Results: The results show that raising the levels of the noise
University modulate the filling-in effect; increasing FA at low noise levels,
J Mol Neurosci (2013) 51 (Suppl 1):S1–S135 S135
but decreasing the filling-in effect for higher noise levels. The thermal transients with a well-defined and highly-
visual sensitivity (d') decreases with increasing noise, indicating localized dynamics which was visualized using temper-
a masking effect of the noise on the target alone. ature sensitive dyes, and matched theoretical predictions.
Conclusions: The results indicate that the filling-in effect is Using calcium sensitive dye imaging, we observed that
not due to noise induced by flankers on the target location, the thermal transients repeatedly excited neurons in the
rather, it can be inferred to stem from real lateral excitation close vicinity of the absorbers, when pulse power/energy
on the target by the lateral flankers. exceeded a certain threshold. The threshold activation energy
decreased as a strong function of pulse duration (from a couple
Characteristics of photo-absorber induced of micro joules to ~hundred nano joules) and the threshold
neuro-thermal stimulation (PAINTS) behavior for short pulses was found to be highly dependent on
Zoubi A, Farah N, Matar S, Brosh I, Shoham S* laser properties. The overall behavior matched a quantitative
Biomedical Engineering I.I.T model's prediction.
Conclusion: Photo-absorber induced neural-thermal stimu-
Background: Low power IR pulses can directly stimulate lation (PAINTS) introduced here resulted in high spatiotem-
neurons using thermal transients resulting from the laser's poral activation of neurons. The observed differences
energy absorption. Here we present the characteristics of a between CW and pulsed lasers suggest that the observed
novel physical method for optical neural stimulation which phenomenon potentially combines both photothermal and
relies on the absorption of focused laser beams by exogenous photo-mechanical effects. PAINTS can be combined with
micron-scale photo-absorbers introduced in the vicinity of advanced microdisplay systems to achieve parallel control
target cells. To induce highly localized thermal transients, a of a large number of neurons and thus lead the way to the
CW laser or a femtosecond IR laser were focused onto the development of new minimally intrusive optically based
particles and pulsed for periods ranging from 50 μs to 5 msec. neuro- prosthetics.
Results: Focused laser pulses absorbed by carbon-based The authors gratefully acknowledge the financial support of
photo-absorbers, led to rapid (milliseconds timescale) the European Research Council