Yang Dan 2012 (Neuromodulation of Brain States)

Neuron
Review
Neuromodulation of Brain States

Seung-Hee Lee1 and Yang Dan1,*
1Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, Howard Hughes Medical Institute,
University of California, Berkeley, Berkeley, CA 94720, USA

*Correspondence: ydan@berkeley.edu
http://dx.doi.org/10.1016/j.neuron.2012.09.012
Switches between different behavioral states of the animal are associated with prominent changes in global
brain activity, between sleep and wakefulness or from inattentive to vigilant states. What mechanisms control
brain states, and what are the functions of the different states? Here we summarize current understanding of
the key neural circuits involved in regulating brain states, with a particular emphasis on the subcortical neuro-
modulatory systems. At the functional level, arousal and attention can greatly enhance sensory processing,
whereas sleep and quiet wakefulness may facilitate learning and memory. Several new techniques developed
over the past decade promise great advances in our understanding of the neural control and function of
different brain states.
Introduction lated with the network activity (Crochet and Petersen, 2006;
In our complex and changing environment, animals constantly Li et al., 2009; Okun et al., 2010; Poulet and Petersen, 2008;
switch between different behavioral states. The most conspic- Steriade et al., 1993b) (Figure 1). For example, during NREM
uous changes occur at the sleep-wake transitions, and effective sleep and under certain anesthesia, the EEG and LFP show
neural control of these transitions is critical for the fitness and pronounced slow oscillations (<1 Hz). In individual cells, these
survival of the animal (Mahowald and Schenck, 2005). Sleep oscillations manifest as alternating UP and DOWN states of the
can be further divided into two distinct types: rapid eye move- membrane potential (Steriade et al., 2001), with the UP state
ment (REM) sleep with vivid dreams and non-REM (NREM) sleep characterized by a barrage of excitatory and inhibitory synaptic
with dull or lack of sensation (Hobson, 2005). During wakeful- inputs, and the DOWN state with deep hyperpolarization and
ness, animals must also dynamically adjust their behavioral little synaptic activity (Figure 1C).
states, switching rapidly from quiet, inattentive to aroused, vigi- There are two fundamental questions concerning brain states:
lant states upon task demand. what mechanisms control brain states and what is the function of
These switches of behavioral states are accompanied by each state. Lesion studies have identified multiple brain regions
obvious changes in the global pattern of neural activity in many important for regulating brain states, including those in the brain-
brain areas, which can be measured electrophysiologically stem, hypothalamus, and the basal forebrain/preoptic area, but
(Gervasoni et al., 2004). In 1924, the German psychiatrist Hans the specific role of each region and the underlying synaptic
Berger first measured the voltage difference between two elec- circuits are not yet well understood. The striking state-depen-
trodes placed on the scalp of a human subject (Berger, 1929), dent changes of ensemble neuronal activity observed in many
which later became known as the electroencephalogram brain areas suggest that different brain states are associated
(EEG). He found that the pattern of EEG changes dramatically with distinct functions, but definitive evidence for some of these
with the behavioral state of the subject. When the subject is functions is still lacking. In this Review, we summarize our
awake, the EEG is fast and low voltage, and as the subject falls current understanding of these issues and propose future
asleep, the EEG changes progressively into high-voltage slow studies using newly developed techniques.
patterns. We now know that the high-amplitude slow EEG
activity reflects the synchronous alternation between firing and Neural Control of Wakefulness and Sleep
inactivity of a large population of neurons (Steriade et al., Wakefulness and sleep can be well distinguished by measuring
1993a), thus the corresponding brain states are referred to as both EEG and electromyogram (EMG). During wakefulness, the
‘‘synchronized states.’’ The desynchronized states (with low- EEG is generally desynchronized, and the EMG indicates high
voltage fast EEG) are often referred to as the ‘‘activated states’’ muscle tone. During NREM sleep, the skeletal muscle EMG
because of their association with behavioral activation. activity is reduced, and the EEG is dominated by slow (<1 Hz)
Another commonly used measure of population neural activity and delta (1–4 Hz) oscillations. Interestingly, during REM sleep,
is the local field potential (LFP), the low-frequency (<200 Hz) the EEG shows a desynchronized pattern that is similar to the
voltage fluctuations recorded by inserting the electrodes into awake state. However, the EMG indicates an almost complete
brain tissues. The LFP mainly reflects the excitatory and inhibi- loss of muscle tone, thus allowing a clear-cut distinction from
tory synaptic processes, and compared to EEG it measures the awake state.
activity from a more local brain area (Kajikawa and Schroeder, Identification of the brain areas controlling sleep and wakeful-
2011; Katzner et al., 2009; Xing et al., 2009). Network activity ness began with the work of Constantin von Economo, a Roma-
can also be inferred from intracellular recordings, since mem- nian neurologist who studied patients with encephalitis. He
brane potential fluctuations in individual cells are strongly corre- found that lesions in the brainstem and posterior hypothalamus
Neuron 76, October 4, 2012 ª2012 Elsevier Inc. 209

Neuron
Review
Figure 1. Different Methods for Monitoring
Brain States
(A) Schematic showing the recording configura-
tion for simultaneous measurement of EEG, LFP,
and single-cell membrane potential in the S1
barrel cortex. A pyramidal neuron in layer 2/3 was
reconstructed.
(B) EEG, LFP, and whole-cell recordings show
large-amplitude, low-frequency activity during
quiet wakefulness and synchronous state change
during whisking (figures adapted and reproduced
with permission from Poulet and Petersen, 2008).
(C) Synchronized (left) and desynchronized (right)
brain states observed with simultaneous whole-
cell patch-clamp recording from a visual cortical
neuron and LFP recording 2 mm from the patch
electrode. Figures reproduced from Li et al. (2009).
2009). Optogenetic stimulation of the

noradrenergic neurons can cause an
immediate transition from sleep to wake-
fulness (Carter et al., 2010). Although
earlier studies suggested that the effect
of LC stimulation on cortical activation is
indirect (Dringenberg and Vanderwolf,
1998), probably through its projection to
the basal forebrain cholinergic circuit, a
recent study showed that pharmacolog-
cause excessive sleepiness (Von Economo’s sleepy sickness), ical blockage of noradrenergic signaling within the cortex
whereas lesions of the anterior hypothalamus and basal fore- prevents the desynchronization when the animal is awake (Con-
brain cause the opposite symptom of insomnia (Von Economo, stantinople and Bruno, 2011), indicating that the intracortical
1930). Subsequent work by Moruzzi and Magoun showed that release of noradrenaline is important for the desynchronization.
the ascending reticular activating system originating in the brain- The histaminergic neurons located in the TMN in the posterior
stem is crucial for wakefulness and arousal (Moruzzi and hypothalamus show similar projection patterns (Thakkar,
Magoun, 1949). More recent studies have further identified the 2011). Antihistamine drugs promote sleep, and lesion of the
various cell groups in the brainstem, hypothalamus, and basal histamine neurons or blockade of histamine synthesis induces
forebrain that contribute to sleep-wake regulation (Figure 2). hypersomnia (Monti, 1993). The serotonergic neurons in the
Brainstem and Posterior Hypothalamus DRN also project widely to the cortex and subcortical areas.
The brainstem is a key region that regulates both the brain state Application of agonists to a variety of 5-HT receptors enhances
and muscle tone. In humans and other animals, large damage in wakefulness, whereas antagonist application increases sleep
the brainstem can cause coma, a prolonged state of uncon- (Dugovic et al., 1989; Monti and Jantos, 2008). Genetic knockout
sciousness and unresponsiveness. From the brainstem, two of the 5-HT1B receptors also changes the ratio between REM
pathways are critical for maintaining wakefulness: the ascending and NREM sleep (Boutrel et al., 1999). Interestingly, all of these
reticular activating system projecting to the thalamus, hypothal- monoaminergic neurons fire at high rates during wakefulness,
amus, basal forebrain, and neocortex is important for cortical low rates during NREM sleep, and they virtually stop firing during
activation, and the descending pathway to the spinal cord is REM sleep (Aston-Jones and Bloom, 1981; Jacobs and Fornal,
important for maintaining muscle tone (Holstege and Kuypers, 1991; Kocsis et al., 2006; Steininger et al., 1999; Takahashi
1987; Jones and Yang, 1985). Activity of the two pathways et al., 2006, 2010). Thus, these neurons appear to serve similar
must be coordinated to ensure that voluntary movement is functions in promoting cortical desynchronization and behav-
enabled when (and only when) the brain is awake. ioral arousal (Jones, 2003).
The ascending activating system consists of several nuclei in The cholinergic neurons in the brainstem are clustered in the
the brainstem and posterior hypothalamus. They contain essen- pedunculopontine tegmental (PPT) and lateral dorsal tegmental
tial neuromodulators, including acetylcholine (ACh) and several (LDT) nuclei, and they project extensively to the thalamus, hypo-
monoamines—norepinephrine (or noradrenaline) from the locus thalamus, and basal forebrain (Hallanger et al., 1987; Jones and
coeruleus (LC), serotonin (5-HT) mostly from the dorsal raphe Cuello, 1989; Steriade et al., 1988). These neurons fire at high
nucleus (DRN), and histamine from the tuberomammillary rates during wakefulness. However, unlike the monoaminergic
nucleus (TMN) (Figure 2). The LC consists of a very small number neurons, which cease firing during REM sleep, the cholinergic
of noradrenergic neurons (1,500 in rat), but it projects widely to neurons are also highly active during REM sleep (Maloney
almost the entire central nervous system (Berridge, 2008; Sara, et al., 1999; McCarley and Hobson, 1975; Steriade et al.,
210 Neuron 76, October 4, 2012 ª2012 Elsevier Inc.

Neuron
Review
Figure 2. Schematic Diagram Showing the
Key Circuits Involved in Regulating Brain
States
Sagittal view of mouse brain. Arrows indicate major
pathways connecting the brain areas. Red arrows,
pathway inducing cortical desynchronization;
blue arrows, pathway inducing cortical synchroni-
zation; black arrows, pathway that mediates both
synchronization and desynchronization; light red
arrows, possible pathway for desynchronization;
light blue arrow, possible pathway for synchroni-
zation. Each cell type was schematically illustrated
by colored dots in each brain area.
(Adamantidis et al., 2007), whereas loss

of orexin, orexin receptors, or orexin
neurons causes narcolepsy, a sleep dis-
order characterized by excessive sleepi-
1990). Since both wakefulness and REM sleep are associated ness and sudden sleep attacks (Chemelli et al., 1999; Hara
with desynchronized EEG, activity of these cholinergic neurons et al., 2001; Lin et al., 1999; Peyron et al., 2000). Orexin neurons
appears to be linked to cortical activation but not necessarily innervate the cortex, basal forebrain, and brainstem, where they
behavioral arousal. Lesion of the cholinergic neurons in the provide a strong excitatory input to the ascending arousal
PPT nucleus significantly reduces REM sleep (Shouse and Sie- system (Sutcliffe and de Lecea, 2002). Glutamatergic neurons
gel, 1992), suggesting their causal role in promoting REM sleep. within the hypothalamus are also known to be activated by
While the studies summarized above indicate that both the orexin, and they in turn activate the orexin neurons to orchestrate
cholinergic and monoaminergic systems are important for the the hypothalamic arousal system (Li et al., 2002).
overall brain activation, their specific impacts on each target In the basal forebrain, one of the main cell types is cholinergic
area may differ substantially (Edeline, 2012; Hirata et al., 2006). (Zaborszky et al., 1999) (Figure 2). In fact, the basal forebrain is
Much remains to be learned about how each neuromodulator the primary source of cholinergic input to the cortex. Similar to
affects circuit functions by activating its multiple receptors that the cholinergic neurons in the brainstem, these basal forebrain
are differentially expressed among neuronal subtypes (Bacci neurons are also active during both waking and REM sleep but
et al., 2005; Lee et al., 2010). Furthermore, although the functions not during NREM sleep (Lee et al., 2005a). Lesion of the basal
of the cholinergic and monoaminergic neurons have been forebrain can cause a dramatic increase of EEG delta waves
studied extensively by manipulating their outputs, the inputs during wakefulness (Berntson et al., 2002; Buzsáki et al., 1988;
controlling the activity of these neurons remain poorly under- Fuller et al., 2011), and combined cholinergic and serotonergic
stood. For example, in the PPT and LDT nuclei, there are blockade completely prevents cortical desynchronization
GABAergic and glutamatergic neurons intermingled with the (Vanderwolf and Pappas, 1980). Conversely, stimulation of the
cholinergic neurons (Ford et al., 1995) (Figure 2). These cell types basal forebrain induces cortical desynchronization, which can
exhibit complex activity patterns during different brain states be observed from both the reduced EEG/LFP power at low
(Boucetta and Jones, 2009), but whether and how they modulate frequencies (Metherate et al., 1992) and the decrease in corre-
the activity of cholinergic neurons is unclear. Microinjection of lated spiking among cortical neurons (Goard and Dan, 2009)
GABA receptor agonist in the PPT increases REM sleep and (Figure 3). At the cellular level, the desynchronization is known
decreases wakefulness (Pal and Mallick, 2009; Torterolo et al., to depend on the muscarinic ACh receptors (mAChRs) in the
2002), but which neurons mediate these effects is unknown. In cortex, and a modeling study (Bazhenov et al., 2002) suggests
addition to the local synaptic interactions, each nucleus also that this may be mediated by both the suppression of excitatory
receives long-range inputs from numerous brain regions. Delin- intracortical connections (Gil et al., 1997; Hsieh et al., 2000; Ki-
eating both the local and long-range synaptic inputs to the mura et al., 1999) and the depolarization of cortical pyramidal
modulatory neurons will be essential for understanding the neurons (McCormick and Prince, 1985; Nishikawa et al., 1994).
neural control of sleep and wake states. Intermingled with the cholinergic neurons are a large number
Lateral Hypothalamus and Basal Forebrain/ of GABAergic neurons (up to 60% of all neurons in the basal fore-
Preoptic Area brain/preoptic area). These neurons are likely to play diverse
Several forebrain regions are also important for regulating brain roles in brain state regulation, as some of them are active during
states: the lateral hypothalamus containing orexin/hypocretin wakefulness, while others are active during sleep (Manns et al.,
neurons and the basal forebrain containing cholinergic neurons. 2000; Szymusiak and McGinty, 1989). Several studies have iden-
These areas also contain many local and long-range projecting tified groups of GABAergic neurons in the ventrolateral preoptic
GABAergic, glutamatergic, and neuropeptidergic neurons. area (VLPO) and median preoptic nucleus (MnPO) as sleep-
Activity of the orexin neurons is high during active waking and promoting cells (Saper et al., 2005; Sherin et al., 1996; Szymu-
low during sleep (Lee et al., 2005b; Mileykovskiy et al., 2005). siak and McGinty, 2008). These neurons are more active during
Optogenetic activation of orexin neurons induces wakefulness sleep than wakefulness, and lesion of the VLPO causes insomnia

Neuron
Review
Figure 3. Effect of Basal Forebrain
Stimulation on Multiunit Activity in the Visual
Cortex
(A) Schematic illustration of experimental setup.
(B) Time-frequency analysis of LFP before and
after basal forebrain stimulation from an example
experiment, averaged over 30 trials. Amplitude is
color coded. Vertical lines indicate the period of
basal forebrain stimulation.
(C) Multiunit spike rate (color coded) in response to
the natural movie stimulation recorded by a multi-
channel silicon probe plotted against cortical
depth. Bottom: the responses to ten trials of visual
stimuli before (control) and 0–5 s after basal fore-
brain (BF) stimulation. Basal forebrain stimulation
decreased correlation between cortical neurons
and increased response reliability during visual
stimulation (adapted and reproduced from Goard
and Dan, 2009).
results may be related to the functional

diversity of the basal forebrain neurons.
In terms of their outputs, a subset of the
GABAergic neurons innervate the cortex
along with the cholinergic neurons (Henny
and Jones, 2008; Sarter and Bruno,
2002), and others project to the hypothal-
amus and brainstem (Gritti et al., 1994).
Electrophysiological and electron micro-
scopic studies have also shown extensive
local synaptic interactions among basal
forebrain neurons (Momiyama and Za-
borszky, 2006; Zaborszky and Duque,
2003). This raises the possibility that
in addition to the long-range connec-
tions between the VLPO and ascending
arousal system, sleep-wake switches
also depend on the local reciprocal
inhibition between the sleep- and wake-
active GABAergic neurons and between
GABAergic and cholinergic neurons
within the basal forebrain/preoptic area
(Lu et al., 2000). The projections from VLPO and MnPO to the (Figure 2, light red and blue arrows). Furthermore, the wake-
ascending arousal system and lateral hypothalamus allow active neurons in this region may also project to the brainstem
them to effectively shut down the activity of the wake-promoting and hypothalamus, innervating the cholinergic, monoaminergic,
neurons (Sherin et al., 1998; Suntsova et al., 2007), and neuro- as well as glutamatergic or GABAergic neurons (Figure 2, light
modulators from the ascending arousal system can in turn red arrows). Thus, the flip-flop circuit for sleep-wake switches
inhibit these sleep-active neurons (Gallopin et al., 2000; Manns may involve multiple loops of excitation and inhibition.
et al., 2003). This has led to the proposal of an elegant flip-flop Given the large number of GABAergic neurons in the basal
circuit for sleep-wake switches based on the mutual inhibition forebrain/preoptic area and the importance of GABAergic trans-
between the VLPO and ascending arousal system (Saper et al., mission in sleep-wake regulation (Monti et al., 2010), delineating
2010). the functional organization of these neurons may be a key step
Outside of the VLPO and MnPO, however, wake- and sleep- toward understanding the subcortical circuits controlling brain
active GABAergic neurons seem largely intermingled in the basal states. Studies in the neocortex and hippocampus have shown
forebrain/preoptic area (Manns et al., 2000; Takahashi et al., that GABAergic neurons with distinct molecular markers exhibit
2009). Although several studies in the rat showed that basal different physiological properties and innervation patterns (As-
forebrain lesion causes behavioral unresponsiveness and coli et al., 2008; Fishell and Rudy, 2011), and they play different
EEG synchronization (Berntson et al., 2002; Buzsáki et al., roles in sensory processing (Lee et al., 2012; Wilson et al., 2012).
1988; Fuller et al., 2011), in the cat the lesion was found to induce In the basal forebrain, juxtacellular recordings from a small
severe insomnia (Szymusiak and McGinty, 1986). These mixed number of immunocytochemically identified neurons suggest

Neuron
Review
A B Figure 4. Optogenetic Manipulation of

Optical stimulation ChR2-mediated eNpHR-mediated Neuronal Activity In Vivo
activation inactivation (A) Channelrhodopsin-2 (ChR2) was expressed in
cortical neurons. Optical stimulation was applied
to the area of ChR2 expression and recording site
(marked by lesion caused by electrode) (figures
reproduced from Lee et al., 2012).
(B) Bidirectional modulation of neuronal activity
by optical stimulation of ChR2 or halorhodopsin
40 20 (eNpHR) in the same neuron in primary visual
spk/s
spk/s
20 10 cortex expressing both ChR2 and eNpHR (S.-H.L.,

100µm
unpublished data).
0 0
0 5 10 15 s 0 5 10 15 s (C) Schematic showing simultaneous LFP re-
cording in the visual cortex and optogenetic
C D Activation of Inactivation of manipulation of cholinergic neurons in the basal
Optical stimulation of cholinergic neurons cholinergic neurons forebrain.
cholinergic neurons V1 (D) Activation (left) of cholinergic neurons causes
Recording cortical desynchronization, while inactivation
(right) caused more synchronized activity (L. Pinto,
personal communication).
1 mV
1s
that cells with different sleep-wake activity patterns may also cortical spindles (Halassa et al., 2011). On the other hand,
express distinct molecular markers (Duque et al., 2000). Since increasing the tonic activity of thalamocortical neurons by local
a large number of Cre driver mouse lines targeting different application of a cholinergic agonist can desynchronize the
subtypes of GABAergic neurons have now become available cortical area receiving their input (Hirata and Castro-Alamancos,
(Taniguchi et al., 2011), a promising approach is to make a tar- 2010). In brain slices, electrical or chemical stimulation of the
geted recording from each cell type to determine their sleep- thalamus can effectively trigger cortical UP states (Rigas and
wake activity patterns. Optogenetic manipulation of their activity Castro-Alamancos, 2007) (Figures 5A and 5B), and in vivo
in a bidirectional manner (Chow et al., 2010; Deisseroth, 2011), optogenetic activation of thalamocortical neurons during quiet
which has been achieved in various neuronal circuits, can further wakefulness leads to desynchronized cortical activity normally
establish the causal role of these neurons in brain state regula- observed in an aroused state (Poulet et al., 2012). Surprisingly,
tion (Figure 4). Moreover, recent advances in viral tracing tech- extensive lesion in the thalamus does not prevent cortical
niques (Wickersham et al., 2007) may greatly facilitate the desynchronization measured by EEG (Buzsáki et al., 1988; Fuller
dissection of synaptic connectivity among the various neuronal et al., 2011) or intracellular recording from cortical neurons
subtypes. (Constantinople and Bruno, 2011). These experiments suggest
Thalamus and Cortex that while an intact thalamus is not required for cortical activa-
The thalamus is the gateway of sensory inputs to the cortex, tion, perturbation of thalamic activity is often sufficient to alter
and it receives massive cortical feedback. The thalamocortical the cortical state.
loop, composed of the highly interconnected thalamocortical, Cortical neurons can also exert strong influences on global
thalamic reticular, and cortical neurons, plays a pivotal role in brain state. Slow oscillations during NREM sleep originate in
setting the global brain state and controlling the flow of sensory the cortex (Sanchez-Vives and McCormick, 2000; Steriade
information (Castro-Alamancos, 2004b; Sherman, 2005). The et al., 1993b), and cortico-cortical connections are necessary
thalamus also receives strong inputs from the ascending acti- for synchronizing the oscillations across brain areas (Amzica
vating system and basal forebrain (Bickford et al., 1994; Levey and Steriade, 1995). In brain slices, low-intensity cortical stimu-
et al., 1987; Manning et al., 1996), and it serves as a major lation can trigger UP state, while high-intensity stimulation
pathway through which the neuromodulatory inputs regulate suppresses UP state (Rigas and Castro-Alamancos, 2007). Inter-
cortical function. estingly, in anesthetized rat, high-frequency burst firing of
The thalamic neurons exhibit distinct modes of firing in a single cortical neuron is sufficient to induce a global brain state
different brain states, with tonic spiking during alertness and transition, either from a synchronized to desynchronized state or
rhythmic bursting during NREM sleep or drowsiness (Bezdud- vice versa (Li et al., 2009) (Figures 5C and 5D). Based on two-
naya et al., 2006; McCormick and Bal, 1997; Sherman, 2005; photon calcium imaging, burst of a single pyramidal neuron
Stoelzel et al., 2009). Thalamic activity can directly influence was estimated to activate 14 nearby excitatory neurons and
cortical state. Delta and spindle oscillations observed in the 3–9 somatostatin-positive GABAergic interneurons (Kwan and
cortex during drowsiness/sleep are both generated in the Dan, 2012) (Figure 5E). It would be interesting to find out whether
thalamus, by the intrinsic biophysical properties of thalamocort- the brain state switches triggered by single neuron burst in vivo is
ical and thalamic reticular neurons (McCormick and Pape, 1990) related to the bidirectional effects of cortical stimulation on the
and through their synaptic interactions (McCormick and Bal, occurrence of UP states in slices (Rigas and Castro-Alamancos,
1997). Even during wakefulness, a brief activation of the thalamic 2007) (Figure 5B). Cortical neurons are also highly intercon-
reticular nucleus is sufficient to evoke thalamic bursts and nected with thalamic neurons, and those from the prefrontal

Neuron
Review
Figure 5. Effects of Thalamic and Cortical Stimulation on Brain States

(A) UP or DOWN states were measured in brain slices with intact thalamocortical circuits (TC slice).
(B) Population data showing probability of triggering a cortical UP state (left) and overall membrane potential depolarization measured by area (right) in response
to stimulation of the thalamus, cortex, or both as a function of stimulation intensity. Figures adapted and reproduced with permission from Rigas and Castro-
Alamancos (2007).
(C) Schematic illustration of simultaneous whole-cell and LFP recordings measuring brain state change in response to single-cell stimulation.
(D) Brain state switch measured by change in LFP power spectrum from synchronized to desyncrhronized state or vice versa induced by single-cell stimulation
(adapted from Li et al., 2009).
(E) Local excitatory influence of single-cell stimulation in the visual cortex. Blue cross, stimulated cell. Each circle represents a cell and the diameter represents the
magnitude of excitation (DdF/Fpost-pre) measured by two-photon calcium imaging in layer 2/3 cortical neurons (red, SOM+; green, PV+; black, unidentified
neurons; adapted from Kwan and Dan, 2012).
cortex provide strong descending inputs to the neuromodulatory synchronized, as measured by both LFP (Bezdudnaya et al.,
circuits in the basal forebrain (Golmayo et al., 2003; Sarter et al., 2006; Niell and Stryker, 2010) and intracellular recordings
2005; Zaborszky et al., 1997) and brainstem (Jodo and Aston- (Crochet and Petersen, 2006; Okun et al., 2010; Poulet and
Jones, 1997). Thus, the brain state switch triggered by single- Petersen, 2008) (Figures 1A and 1B). In addition to the general
neuron stimulation could also be mediated by the activation of arousal, selective attention to specific stimuli is also associated
thalamic neurons or the neuromodulatory circuits. with changes in ensemble cortical activity, although at a more
In addition to the areas reviewed above, which are core local level. Attention to visual stimuli within the receptive fields
components of the neural machinery controlling sleep and of recorded neurons is accompanied by decreases in the low-
wake states, many other brain structures also play modulatory frequency LFP activity (Fries et al., 2001; Khayat et al., 2010),
roles. For example, sleep is strongly regulated by the circadian and it can cause either increase or decrease in gamma activity
rhythms, which are controlled by the suprachiasmatic nucleus (30–80 Hz), depending on the cortical area (Chalk et al., 2010;
(SCN) in the hypothalamus. Dissecting the synaptic pathways Fries et al., 2001).
between these structures and the core components described Role of Neuromodulatory Systems
above will be essential for understanding how sleep-wake tran- The subcortical neuromodulatory circuits involved in sleep-wake
sitions are regulated by both internal and environmental factors. control also play important roles in the regulation of arousal and
attention, and malfunctioning of these circuits causes a variety of
Mechanisms for Arousal and Attention cognitive impairments. Both the monoaminergic and cholinergic
Wakefulness is not a unitary brain state, and the ensemble neural neurons in the brainstem and basal forebrain receive inputs from
activity exhibits clear changes at different levels of vigilance. the prefrontal cortex (Berridge, 2008; Jodo and Aston-Jones,
When the animal is drowsy or quietly resting, there is consider- 1997; Sarter et al., 2005), a key circuit exerting cognitive control
able delta-band activity in EEG and LFP, although the power is of behavior (Miller and Cohen, 2001) (Figure 6). The activity of
generally lower than that during NREM sleep. When the animal these neurons could thus be modulated in a task-dependent
is in an aroused/attentive state (e.g., actively engaged in sensory manner. For example, while the monkey performs a visual
processing or motor tasks), the cortical activity is highly de- discrimination task, the noradrenergic neurons in the LC exhibit

Neuron
Review
Figure 6. Schematic Diagram Showing
Potential Pathways for Attentional
Modulation of Sensory Processing
Arrows indicate major pathways connecting brain
areas. Red arrows, top-down connections from
prefrontal cortex to sensory areas; blue arrows,
projections from prefrontal cortex to brainstem
and basal forebrain neuromodulatory centers;
green arrows, projections from neuromodulatory
centers to the cortex.
that attention also causes a decrease in

stimulus-independent correlated firing
between neurons (Cohen and Maunsell,
2009; Mitchell et al., 2009), which
may improve sensory encoding at the
ensemble level (Zohary et al., 1994). In
both phasic and tonic modes of firing, which are correlated with fact, analysis of the population signal-to-noise ratio showed
good and bad performance (Usher et al., 1999). Subsequent that the attention-related improvement in neural coding is attrib-
experiments showed that the phasic activity of LC neurons utable more to the decrease in interneuronal correlation than to
occurs specifically before the behavioral response, and it may the increase in single neuron firing rate (Cohen and Maunsell,
serve to facilitate the task-related decision process (Clayton 2009; Mitchell et al., 2009).
et al., 2004). In a study in the rat performing an odor-guided deci- Interestingly, basal forebrain activation also causes a decrease
sion task, serotonergic neurons in the DRN showed transient in interneuronal correlation and increase in sensory-driven
firing precisely time locked to a variety of task-related events response reliability in the visual cortex (Figure 3C), and both
(Ranade and Mainen, 2009). Another study in the monkey effects contribute to improved coding of natural scenes (Goard
showed that firing rates of the DRN neurons were modulated and Dan, 2009). The strong similarity between the effects of
by both the expected and received reward sizes (Nakamura attention and basal forebrain activation again suggests an
et al., 2008). Neurons in the primate basal forebrain are also involvement of the cholinergic system in selective attention.
modulated by novel or reinforced stimuli (Wilson and Rolls, The decrease in interneuronal correlation may be mediated by
1990). In behaving rats, the noncholinergic basal forebrain mAChRs within the cortex (Goard and Dan, 2009; Metherate
neurons showed strong burst responses to both reward- and et al., 1992), whereas the improved visual responses of single
punishment-predicting stimuli, and the occurrence of the burst cortical neurons could involve enhanced responses of thalamic
is strongly correlated with successful sensory detection (Lin neurons (Goard and Dan, 2009), nAChR-dependent augmenta-
and Nicolelis, 2008). tion of thalamocortical transmission (Disney et al., 2007), and/
The neuromodulator especially linked to vigilance and atten- or mAChR-dependent firing rate increase within the cortex
tion is ACh. In the rat, behaviorally relevant sensory cues can (Herrero et al., 2008; Soma et al., 2012). The recent finding that
evoke transient increases in ACh concentration in the prefrontal cholinergic activity can be modulated in a task-dependent
cortex at the time scale of seconds (Parikh et al., 2007), and acti- manner (Parikh et al., 2007) further supports the plausibility of
vating cholinergic transmission in the prefrontal cortex improves its involvement in attentional modulation.
the performance of a sustained attention task (St Peters et al., Of course, it is possible that the cholinergic input plays a
2011). A recent study based on genetic manipulation with re- permissive rather than instructive role. Selective attention is
combinant viral vectors in the prefrontal cortex further demon- associated with local activity changes in neurons encoding the
strated the importance of nicotinic ACh receptors (nAChRs) in attended stimuli, but the neuromodulatory systems in general
sustained attention (Guillem et al., 2011). Cholinergic signaling project diffusely to multiple brain regions. Although there is
is also involved in selective attention. In the monkey performing some topographical organization of the basal forebrain projec-
a top-down spatial attention task, local application of ACh in the tions to the cortex (Zaborszky et al., 1999), whether there is
primary visual cortex was found to enhance the attentional sufficient spatial precision to support the local modulation by
modulation of neuronal firing rates, whereas mAChR antagonist selective attention remains unclear. Another candidate pathway
had the opposite effect (Herrero et al., 2008). Together, these is the top-down feedback from higher-order cortical areas,
studies indicate that in addition to the daily sleep-wake cycle, such as the frontal eye field (FEF), to the visual cortical areas
the subcortical neuromodulatory circuits also serve to regulate (Gregoriou et al., 2009; Moore and Fallah, 2004; Zhou and
arousal and attention on a faster time scale. Desimone, 2011) (Figure 6). Interestingly, firing rate increases
Changes in Sensory Neuron Activity in the FEF induced by local application of a dopamine receptor
Numerous studies in monkeys performing selective attention antagonist mimicked the attentional modulation of V4 neuronal
tasks have shown increased neuronal responses (Reynolds responses (Noudoost and Moore, 2011), suggesting that the
and Chelazzi, 2004), which are thought to enhance the percep- effect of neuromodulators could also be mediated by activating
tual saliency of the attended stimuli. Recent studies have shown the cortico-cortical glutamatergic pathways.

Neuron
Review
While selective attention is typically associated with firing rate activity during NREM sleep (Dworak et al., 2010). However, the
increase of the relevant neurons, behavioral arousal or task cause for this energy surge may not be a simple reduction of
engagement in general does not always lead to enhanced neuronal activity. We know that during NREM sleep many
responses. In the barrel cortex, behavioral arousal or engage- neurons remain highly active, and the difference from the awake
ment in the learning of a new task was found to suppress state resides more in the spatiotemporal pattern than in the over-
whisker-evoked responses (Castro-Alamancos, 2004a; Castro- all level of neural activity.
Alamancos and Oldford, 2002). Similarly, smaller responses to Another idea that is gaining traction in recent years is that
brief tactile stimuli were observed in the rat during exploratory sleep is critical for learning and memory (Diekelmann and
whisker movement than during quiet immobility (Fanselow and Born, 2010; Maquet, 2001; Stickgold, 2005). Several studies
Nicolelis, 1999). In the auditory cortex, neuronal response to on human subjects have shown that sleep shortly after practicing
a sound stimulus was also lower when the rat was engaged in visual discrimination (Gais et al., 2000; Stickgold et al., 2000) or
an auditory task than when the stimulus was perceived passively motor skills (Fischer et al., 2002; Walker et al., 2002) can signifi-
(Otazu et al., 2009). These studies suggest that while selective cantly enhance the practice-induced improvement in task
attention can preferentially enhance the responses to the performance. Both NREM and REM sleep states seem to
attended stimuli, a general increase in vigilance may in fact contribute to this enhancement, but an equal period of wakeful-
reduce the overall response in order to accentuate representa- ness after practice has little effect. Task practicing is also found
tion of the relevant stimulus (Atiani et al., 2009). to affect brain activity during subsequent sleep. For example,
In contrast to the findings above, a study in mouse visual after training on a visuomotor task, the brain region activated
cortex showed that the neuronal responses to drifting grating during the training is specifically reactivated during REM sleep
stimuli are much higher when the mouse was behaviorally active (Maquet et al., 2000). Learning of a motor adaptation task can
(running) than inactive (standing still) (Niell and Stryker, 2010). cause a local increase in slow- and delta-wave EEG activity
One factor that may contribute to the discrepancy among these during NREM sleep, and the degree of increase is correlated
experiments is the use of transient (e.g., a brief sound or tactile with the performance improvement after sleep (Huber et al.,
stimulus) versus sustained (e.g., drifting gratings) sensory 2004). To evaluate the role of synchronized slow brain activity
stimuli, which evoke different degrees of neuronal adaptation per se in learning and memory, Marshall et al. (2006) applied
(Harris and Thiele, 2011), as strong adaptation is observed transcranial slow oscillating potential (<1 Hz) to human subjects
primarily in behaviorally inactive states (Castro-Alamancos, during NREM sleep. The stimulation, which increased both
2004a). More importantly, the modulation of sensory responses NREM sleep and slow-wave EEG activity, enhanced the reten-
by different behaviors—selective attention to a single stimulus, tion of declarative memory, indicating a direct contribution of
nonselective increase in vigilance, and general behavioral slow-wave activity to memory consolidation.
arousal (e.g., running)—may be mediated by different mecha- How does the neuronal activity during sleep contribute to
nisms, involving partially overlapping but nonidentical sets of memory consolidation? An important clue came from the studies
neuromodulatory inputs. Testing this hypothesis will require of spike sequence replay. Multielectrode recordings in the rat
simultaneous measurement of activity of both the neuromodu- hippocampus have shown that sequential firing among a group
latory systems and the sensory neurons under the different of neurons observed during active exploration recurs spontane-
behavioral paradigms. Optogenetic manipulation of each ously during subsequent sleep (Lee and Wilson, 2002; Louie and
neuromodulatory system (Figures 4C and 4D) will also reveal Wilson, 2001; Nádasdy et al., 1999; Skaggs and McNaughton,
its impact on the activity of sensory neurons within each behav- 1996; Wilson and McNaughton, 1994). Similar replay was also
ioral context. observed in the neocortex (Euston et al., 2007; Ji and Wilson,
2007; Ribeiro et al., 2004). During NREM sleep, the temporal
Function of Sleep and Quiet Wakefulness order of spiking among the neurons is preserved in each replay,
While it is well accepted that the aroused, attentive states are but the sequences occur at a faster time scale than that during
favorable for sensory processing, what are the functions of the active exploration. As a result, the different neurons fire within
synchronized brain states? In particular, why is sleep so a few milliseconds of each other. A widely observed form of
universal in the animal kingdom (Cirelli and Tononi, 2008), given synaptic plasticity in both the hippocampus and neocortex is
that the loss of responsiveness to environmental stimuli makes spike-timing-dependent plasticity (STDP), in which presynaptic
the animal more vulnerable to predator attacks? spiking within tens of milliseconds before postsynaptic spiking
Function of Sleep induces long-term potentiation, whereas spikes in the reverse
The importance of sleep can be appreciated from the severe order result in depression (Dan and Poo, 2004). The time-
effects of sleep deprivation on cognitive functions and general compressed spike sequence replay observed during NREM
health. Prolonged total sleep deprivation is known to be lethal sleep is thus well suited for the induction of long-term circuit
in flies (Shaw et al., 2002) and rats (Rechtschaffen and Berg- modifications through STDP.
mann, 2002), although some of the harmful effects may be attrib- In addition to the neuronal activity representing exploratory
utable to the stress induced by the experimental methods of experience, sensory-evoked responses can also reverberate in
deprivation. Specifically, one function of sleep may be energy brain circuits. Voltage-sensitive dye imaging showed that in the
conservation or brain recuperation (Siegel, 2005). A recent study visual cortex of anesthetized rats, both spontaneous and visually
showed that the ATP concentration surges in the first few hours evoked activity manifest as propagating waves. Repeated visual
of sleep, and the level of surge is correlated with the EEG delta stimulation caused an increase in the number of spontaneous

Neuron
Review
waves that resemble the stimulus-evoked waves (Han et al., firing of these neurons similar to that evoked by the moving
2008), reminiscent of the notion of reverberation proposed by spot. Interestingly, in awake animals, this cue-triggered recall
Lorente de No (1938) and Hebb (1949). Although in this experi- of spike sequence was observed during a synchronized quiet
ment the reverberatory activity was found under anesthesia, wakeful state, but not in a desynchronized active state (Xu
the prevalence of spontaneous waves propagating across large et al., 2012), reminiscent of the hippocampal replay during quiet
cortical areas is similar to that during NREM sleep. Since corre- immobility (Diba and Buzsáki, 2007; Foster and Wilson, 2006;
lated activation of a large number of neurons is conducive to Karlsson and Frank, 2009).
long-term synaptic modifications (Bi and Poo, 2001; Weliky, Together, these studies suggest that while the desynchron-
2000), the synchronized brain states may be particularly suited ized brain state favors faithful representation of sensory inputs,
for circuit modification through memory reactivation. the synchronized state may be more suited for either sponta-
There is also direct evidence that sleep can facilitate activity- neous or cue-triggered reactivation of previous experience.
dependent synaptic modification. For example, a well-estab- Optimal control of behavior depends on the integration of current
lished model for experience-dependent circuit refinement during sensory information with predictions based on prior experience.
early development is ocular dominance plasticity, in which The relative weights of sensory and memory signals may be
monocular deprivation of visual inputs can cause a drastic shift adjusted by changing the brain states through neuromodulatory
in the relative strengths of inputs from the two eyes to the visual inputs (Yu and Dayan, 2005).
cortex. Studies have shown that sleep significantly enhances the
effect of monocular deprivation (Frank et al., 2001), and the Concluding Remarks
degree of enhancement is correlated with the amount of Studies over the last century have led to tremendous progress in
NREM sleep. At the synaptic level, some studies found net our understanding of the neural control and functions of different
synaptic strengthening during wakefulness and depression states. Many key structures regulating brain states have been
during sleep (Vyazovskiy et al., 2008). This led to the suggestion identified by measuring the effects of their disruption, and the
that while the potentiation of specific synapses encoding awake firing patterns of those neurons under different brain states
experience leads to an imbalance of synaptic strength, a global have been characterized. A major new challenge is to dissect
depression of all synapses during sleep serves to restore the microcircuitry within each structure and the long-range
the balance. This overall depression may also increase the connections between them. These efforts will be greatly facili-
signal-to-noise ratio of the memory by leaving only the most tated by the newly developed optogenetic and circuit tracing
important connections intact. Furthermore, synaptic plasticity tools. Functionally, the effects of vigilance and attention on
is strongly influenced by neuromodulators (Pawlak et al., 2010; sensory processing have been studied extensively through
Rasmusson, 2000). A recent study showed that the firing rates electrophysiological experiments in awake behaving animals.
of LC noradrenergic neurons are increased during NREM sleep There is also accumulating evidence for the importance of
after learning (Eschenko and Sara, 2008), which could in turn synchronized brain states in learning and memory. Future
enhance synaptic plasticity and facilitate memory consolidation studies combining the recording and selective manipulation of
(Sara, 2009). the reactivated memory traces should provide a definitive test
Quiet Wakefulness of this hypothesis.
Although spike sequence replay was initially discovered during
sleep, recent studies have shown that it also occurs during ACKNOWLEDGMENTS
wakefulness, especially during quiet immobility or consumma-
tory behaviors (Diba and Buzsáki, 2007; Foster and Wilson, We thank L. Pinto and D. Bliss for helpful discussions and comments on the
2006; Karlsson and Frank, 2009). In both sleep and awake manuscript.
states, the replay events occur during sharp wave ripples in
LFP (Buzsáki et al., 1992; O’Neill et al., 2006), which are strongly REFERENCES
associated with slow oscillations (Mölle et al., 2006). Selective
Adamantidis, A.R., Zhang, F., Aravanis, A.M., Deisseroth, K., and de Lecea, L.
interruption of hippocampal ripple events during wakefulness
(2007). Neural substrates of awakening probed with optogenetic control of
impairs spatial learning (Jadhav et al., 2012), similar to the effect hypocretin neurons. Nature 450, 420–424.
of ripple disruption during sleep (Ego-Stengel and Wilson, 2010;
Amzica, F., and Steriade, M. (1995). Disconnection of intracortical synaptic
Girardeau et al., 2009). Thus, the quiet wakeful state may linkages disrupts synchronization of a slow oscillation. J. Neurosci. 15,
contribute to spatial learning through a similar spike sequence 4658–4677.
reactivation mechanism. Ascoli, G.A., Alonso-Nanclares, L., Anderson, S.A., Barrionuevo, G.,
While the sequential activation of hippocampal place cells is Benavides-Piccione, R., Burkhalter, A., Buzsáki, G., Cauli, B., Defelipe, J.,
evoked by locomotion of the animal, sequential spiking of visual Fairén, A., et al; Petilla Interneuron Nomenclature Group. (2008). Petilla termi-
nology: nomenclature of features of GABAergic interneurons of the cerebral
neurons can be evoked by a moving stimulus sweeping across cortex. Nat. Rev. Neurosci. 9, 557–568.
their receptive fields. Multielectrode recording in the visual
cortex of both anesthetized and awake rats showed that stimu- Aston-Jones, G., and Bloom, F.E. (1981). Activity of norepinephrine-containing
locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-
lation with a moving spot evoked sequential firing of an ensemble waking cycle. J. Neurosci. 1, 876–886.
of neurons whose receptive fields fell along the motion path.
Atiani, S., Elhilali, M., David, S.V., Fritz, J.B., and Shamma, S.A. (2009). Task
After repeated stimulation with the moving spot, a brief light flash difficulty and performance induce diverse adaptive patterns in gain and shape
at the starting point of the motion path evoked more sequential of primary auditory cortical receptive fields. Neuron 61, 467–480.

Neuron
Review
Bacci, A., Huguenard, J.R., and Prince, D.A. (2005). Modulation of neocortical Cohen, M.R., and Maunsell, J.H.R. (2009). Attention improves performance
interneurons: extrinsic influences and exercises in self-control. Trends primarily by reducing interneuronal correlations. Nat. Neurosci. 12, 1594–
Neurosci. 28, 602–610. 1600.
Bazhenov, M., Timofeev, I., Steriade, M., and Sejnowski, T.J. (2002). Model of Constantinople, C.M., and Bruno, R.M. (2011). Effects and mechanisms of
thalamocortical slow-wave sleep oscillations and transitions to activated wakefulness on local cortical networks. Neuron 69, 1061–1068.
States. J. Neurosci. 22, 8691–8704.
Crochet, S., and Petersen, C.C. (2006). Correlating whisker behavior with
Berger, H. (1929). Electroencephalogram in humans. Arch. Psychiatr. membrane potential in barrel cortex of awake mice. Nat. Neurosci. 9, 608–610.
Nervenkr. 87, 527–570.
Dan, Y., and Poo, M.M. (2004). Spike timing-dependent plasticity of neural
Berntson, G.G., Shafi, R., and Sarter, M. (2002). Specific contributions of the circuits. Neuron 44, 23–30.
basal forebrain corticopetal cholinergic system to electroencephalographic
activity and sleep/waking behaviour. Eur. J. Neurosci. 16, 2453–2461. Deisseroth, K. (2011). Optogenetics. Nat. Methods 8, 26–29.
Diba, K., and Buzsáki, G. (2007). Forward and reverse hippocampal place-cell
Berridge, C.W. (2008). Noradrenergic modulation of arousal. Brain Res. Brain
sequences during ripples. Nat. Neurosci. 10, 1241–1242.
Res. Rev. 58, 1–17.
Diekelmann, S., and Born, J. (2010). The memory function of sleep. Nat. Rev.
Bezdudnaya, T., Cano, M., Bereshpolova, Y., Stoelzel, C.R., Alonso, J.M., and
Neurosci. 11, 114–126.
Swadlow, H.A. (2006). Thalamic burst mode and inattention in the awake
LGNd. Neuron 49, 421–432. Disney, A.A., Aoki, C., and Hawken, M.J. (2007). Gain modulation by nicotine in
macaque v1. Neuron 56, 701–713.
Bi, G., and Poo, M. (2001). Synaptic modification by correlated activity: Hebb’s
postulate revisited. Annu. Rev. Neurosci. 24, 139–166. Dringenberg, H.C., and Vanderwolf, C.H. (1998). Involvement of direct and
indirect pathways in electrocorticographic activation. Neurosci. Biobehav.
Bickford, M.E., Günlük, A.E., Van Horn, S.C., and Sherman, S.M. (1994). Rev. 22, 243–257.
GABAergic projection from the basal forebrain to the visual sector of the
thalamic reticular nucleus in the cat. J. Comp. Neurol. 348, 481–510. Dugovic, C., Wauquier, A., Leysen, J.E., Marrannes, R., and Janssen, P.A.J.
(1989). Functional role of 5-HT2 receptors in the regulation of sleep and wake-
Boucetta, S., and Jones, B.E. (2009). Activity profiles of cholinergic and fulness in the rat. Psychopharmacology (Berl.) 97, 436–442.
intermingled GABAergic and putative glutamatergic neurons in the pontome-
sencephalic tegmentum of urethane-anesthetized rats. J. Neurosci. 29, 4664– Duque, A., Balatoni, B., Detari, L., and Zaborszky, L. (2000). EEG correlation of
4674. the discharge properties of identified neurons in the basal forebrain. J. Neuro-
physiol. 84, 1627–1635.
Boutrel, B., Franc, B., Hen, R., Hamon, M., and Adrien, J. (1999). Key role of
5-HT1B receptors in the regulation of paradoxical sleep as evidenced in Dworak, M., McCarley, R.W., Kim, T., Kalinchuk, A.V., and Basheer, R. (2010).
5-HT1B knock-out mice. J. Neurosci. 19, 3204–3212. Sleep and brain energy levels: ATP changes during sleep. J. Neurosci. 30,
9007–9016.
Buzsáki, G., Bickford, R.G., Ponomareff, G., Thal, L.J., Mandel, R., and Gage,
F.H. (1988). Nucleus basalis and thalamic control of neocortical activity in the Edeline, J.M. (2012). Beyond traditional approaches to understanding the
freely moving rat. J. Neurosci. 8, 4007–4026. functional role of neuromodulators in sensory cortices. Front. Behav. Neurosci.
6, 45.
Buzsáki, G., Horváth, Z., Urioste, R., Hetke, J., and Wise, K. (1992). High-
frequency network oscillation in the hippocampus. Science 256, 1025–1027. Ego-Stengel, V., and Wilson, M.A. (2010). Disruption of ripple-associated
hippocampal activity during rest impairs spatial learning in the rat. Hippo-
Carter, M.E., Yizhar, O., Chikahisa, S., Nguyen, H., Adamantidis, A., Nishino, campus 20, 1–10.
S., Deisseroth, K., and de Lecea, L. (2010). Tuning arousal with optogenetic
modulation of locus coeruleus neurons. Nat. Neurosci. 13, 1526–1533. Eschenko, O., and Sara, S.J. (2008). Learning-dependent, transient increase
of activity in noradrenergic neurons of locus coeruleus during slow wave sleep
Castro-Alamancos, M.A. (2004a). Absence of rapid sensory adaptation in in the rat: brain stem-cortex interplay for memory consolidation? Cereb.
neocortex during information processing states. Neuron 41, 455–464. Cortex 18, 2596–2603.
Castro-Alamancos, M.A. (2004b). Dynamics of sensory thalamocortical Euston, D.R., Tatsuno, M., and McNaughton, B.L. (2007). Fast-forward
synaptic networks during information processing states. Prog. Neurobiol. playback of recent memory sequences in prefrontal cortex during sleep.
74, 213–247. Science 318, 1147–1150.
Fanselow, E.E., and Nicolelis, M.A. (1999). Behavioral modulation of tactile

Castro-Alamancos, M.A., and Oldford, E. (2002). Cortical sensory suppression
responses in the rat somatosensory system. J. Neurosci. 19, 7603–7616.
during arousal is due to the activity-dependent depression of thalamocortical
synapses. J. Physiol. 541, 319–331.
Fischer, S., Hallschmid, M., Elsner, A.L., and Born, J. (2002). Sleep forms
memory for finger skills. Proc. Natl. Acad. Sci. USA 99, 11987–11991.
Chalk, M., Herrero, J.L., Gieselmann, M.A., Delicato, L.S., Gotthardt, S., and
Thiele, A. (2010). Attention reduces stimulus-driven gamma frequency Fishell, G., and Rudy, B. (2011). Mechanisms of inhibition within the telenceph-
oscillations and spike field coherence in V1. Neuron 66, 114–125. alon: ‘‘where the wild things are’’. Annu. Rev. Neurosci. 34, 535–567.
Chemelli, R.M., Willie, J.T., Sinton, C.M., Elmquist, J.K., Scammell, T., Lee, C., Ford, B., Holmes, C.J., Mainville, L., and Jones, B.E. (1995). GABAergic
Richardson, J.A., Williams, S.C., Xiong, Y.M., Kisanuki, Y., et al. (1999). Narco- neurons in the rat pontomesencephalic tegmentum: codistribution with
lepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, cholinergic and other tegmental neurons projecting to the posterior lateral
437–451. hypothalamus. J. Comp. Neurol. 363, 177–196.
Chow, B.Y., Han, X., Dobry, A.S., Qian, X., Chuong, A.S., Li, M., Henninger, Foster, D.J., and Wilson, M.A. (2006). Reverse replay of behavioural
M.A., Belfort, G.M., Lin, Y., Monahan, P.E., and Boyden, E.S. (2010). High- sequences in hippocampal place cells during the awake state. Nature 440,
performance genetically targetable optical neural silencing by light-driven 680–683.
proton pumps. Nature 463, 98–102.
Frank, M.G., Issa, N.P., and Stryker, M.P. (2001). Sleep enhances plasticity in
Cirelli, C., and Tononi, G. (2008). Is sleep essential? PLoS Biol. 6, e216. the developing visual cortex. Neuron 30, 275–287.
Clayton, E.C., Rajkowski, J., Cohen, J.D., and Aston-Jones, G. (2004). Phasic Fries, P., Reynolds, J.H., Rorie, A.E., and Desimone, R. (2001). Modulation of
activation of monkey locus ceruleus neurons by simple decisions in a forced- oscillatory neuronal synchronization by selective visual attention. Science 291,
choice task. J. Neurosci. 24, 9914–9920. 1560–1563.

Neuron
Review
Fuller, P.M., Sherman, D., Pedersen, N.P., Saper, C.B., and Lu, J. (2011). Hobson, J.A. (2005). Sleep is of the brain, by the brain and for the brain. Nature
Reassessment of the structural basis of the ascending arousal system. J. 437, 1254–1256.
Comp. Neurol. 519, 933–956.
Holstege, J.C., and Kuypers, H.G.J.M. (1987). Brainstem projections to spinal
Gais, S., Plihal, W., Wagner, U., and Born, J. (2000). Early sleep triggers motoneurons: an update. Neuroscience 23, 809–821.
memory for early visual discrimination skills. Nat. Neurosci. 3, 1335–1339.
Hsieh, C.Y., Cruikshank, S.J., and Metherate, R. (2000). Differential modulation
Gallopin, T., Fort, P., Eggermann, E., Cauli, B., Luppi, P.H., Rossier, J., of auditory thalamocortical and intracortical synaptic transmission by cholin-
Audinat, E., Mühlethaler, M., and Serafin, M. (2000). Identification of sleep- ergic agonist. Brain Res. 880, 51–64.
promoting neurons in vitro. Nature 404, 992–995.
Huber, R., Ghilardi, M.F., Massimini, M., and Tononi, G. (2004). Local sleep and
Gervasoni, D., Lin, S.C., Ribeiro, S., Soares, E.S., Pantoja, J., and Nicolelis, learning. Nature 430, 78–81.
M.A.L. (2004). Global forebrain dynamics predict rat behavioral states and their
transitions. J. Neurosci. 24, 11137–11147. Jacobs, B.L., and Fornal, C.A. (1991). Activity of brain serotonergic neurons in
the behaving animal. Pharmacol. Rev. 43, 563–578.
Gil, Z., Connors, B.W., and Amitai, Y. (1997). Differential regulation of neocor-
tical synapses by neuromodulators and activity. Neuron 19, 679–686. Jadhav, S.P., Kemere, C., German, P.W., and Frank, L.M. (2012). Awake
hippocampal sharp-wave ripples support spatial memory. Science 336,
Girardeau, G., Benchenane, K., Wiener, S.I., Buzsáki, G., and Zugaro, M.B. 1454–1458.
(2009). Selective suppression of hippocampal ripples impairs spatial memory.
Nat. Neurosci. 12, 1222–1223. Ji, D., and Wilson, M.A. (2007). Coordinated memory replay in the visual cortex
and hippocampus during sleep. Nat. Neurosci. 10, 100–107.
Goard, M., and Dan, Y. (2009). Basal forebrain activation enhances cortical
coding of natural scenes. Nat. Neurosci. 12, 1444–1449. Jodo, E., and Aston-Jones, G. (1997). Activation of locus coeruleus by
prefrontal cortex is mediated by excitatory amino acid inputs. Brain Res.
Golmayo, L., Nuñez, A., and Zaborszky, L. (2003). Electrophysiological 768, 327–332.
evidence for the existence of a posterior cortical-prefrontal-basal forebrain
circuitry in modulating sensory responses in visual and somatosensory rat Jones, B.E. (2003). Arousal systems. Front. Biosci. 8, s438–s451.
cortical areas. Neuroscience 119, 597–609.
Jones, B.E., and Cuello, A.C. (1989). Afferents to the basal forebrain cholin-
Gregoriou, G.G., Gotts, S.J., Zhou, H., and Desimone, R. (2009). High- ergic cell area from pontomesencephalic—catecholamine, serotonin, and
frequency, long-range coupling between prefrontal and visual cortex during acetylcholine—neurons. Neuroscience 31, 37–61.
attention. Science 324, 1207–1210.
Jones, B.E., and Yang, T.Z. (1985). The efferent projections from the reticular
formation and the locus coeruleus studied by anterograde and retrograde
Gritti, I., Mainville, L., and Jones, B.E. (1994). Projections of GABAergic and
axonal transport in the rat. J. Comp. Neurol. 242, 56–92.
cholinergic basal forebrain and GABAergic preoptic-anterior hypothalamic
neurons to the posterior lateral hypothalamus of the rat. J. Comp. Neurol.
Kajikawa, Y., and Schroeder, C.E. (2011). How local is the local field potential?
339, 251–268.
Neuron 72, 847–858.
Guillem, K., Bloem, B., Poorthuis, R.B., Loos, M., Smit, A.B., Maskos, U., Karlsson, M.P., and Frank, L.M. (2009). Awake replay of remote experiences in
Spijker, S., and Mansvelder, H.D. (2011). Nicotinic acetylcholine receptor the hippocampus. Nat. Neurosci. 12, 913–918.
b2 subunits in the medial prefrontal cortex control attention. Science 333,
888–891. Katzner, S., Nauhaus, I., Benucci, A., Bonin, V., Ringach, D.L., and Carandini,
M. (2009). Local origin of field potentials in visual cortex. Neuron 61, 35–41.
Halassa, M.M., Siegle, J.H., Ritt, J.T., Ting, J.T., Feng, G., and Moore, C.I.
(2011). Selective optical drive of thalamic reticular nucleus generates thalamic Khayat, P.S., Niebergall, R., and Martinez-Trujillo, J.C. (2010). Frequency-
bursts and cortical spindles. Nat. Neurosci. 14, 1118–1120. dependent attentional modulation of local field potential signals in macaque
area MT. J. Neurosci. 30, 7037–7048.
Hallanger, A.E., Levey, A.I., Lee, H.J., Rye, D.B., and Wainer, B.H. (1987). The
origins of cholinergic and other subcortical afferents to the thalamus in the rat. Kimura, F., Fukuda, M., and Tsumoto, T. (1999). Acetylcholine suppresses
J. Comp. Neurol. 262, 105–124. the spread of excitation in the visual cortex revealed by optical recording:
possible differential effect depending on the source of input. Eur. J. Neurosci.
Han, F., Caporale, N., and Dan, Y. (2008). Reverberation of recent visual 11, 3597–3609.
experience in spontaneous cortical waves. Neuron 60, 321–327.
Kocsis, B., Varga, V., Dahan, L., and Sik, A. (2006). Serotonergic neuron
Hara, J., Beuckmann, C.T., Nambu, T., Willie, J.T., Chemelli, R.M., Sinton, diversity: identification of raphe neurons with discharges time-locked to the
C.M., Sugiyama, F., Yagami, K.-i., Goto, K., Yanagisawa, M., and Sakurai, T. hippocampal theta rhythm. Proc. Natl. Acad. Sci. USA 103, 1059–1064.
(2001). Genetic ablation of orexin neurons in mice results in narcolepsy,
hypophagia, and obesity. Neuron 30, 345–354. Kwan, A.C., and Dan, Y. (2012). Dissection of cortical microcircuits by single-
neuron stimulation in vivo. Curr. Biol. 22, 1459–1467.
Harris, K.D., and Thiele, A. (2011). Cortical state and attention. Nat. Rev.
Neurosci. 12, 509–523. Lee, A.K., and Wilson, M.A. (2002). Memory of sequential experience in the
hippocampus during slow wave sleep. Neuron 36, 1183–1194.
Hebb, D.O. (1949). The Organization of Behavior (New York: Wiley).
Lee, M.G., Hassani, O.K., Alonso, A., and Jones, B.E. (2005a). Cholinergic
Henny, P., and Jones, B.E. (2008). Projections from basal forebrain to basal forebrain neurons burst with theta during waking and paradoxical sleep.
prefrontal cortex comprise cholinergic, GABAergic and glutamatergic inputs J. Neurosci. 25, 4365–4369.
to pyramidal cells or interneurons. Eur. J. Neurosci. 27, 654–670.
Lee, M.G., Hassani, O.K., and Jones, B.E. (2005b). Discharge of identified
Herrero, J.L., Roberts, M.J., Delicato, L.S., Gieselmann, M.A., Dayan, P., and orexin/hypocretin neurons across the sleep-waking cycle. J. Neurosci. 25,
Thiele, A. (2008). Acetylcholine contributes through muscarinic receptors to 6716–6720.
attentional modulation in V1. Nature 454, 1110–1114.
Lee, S., Hjerling-Leffler, J., Zagha, E., Fishell, G., and Rudy, B. (2010). The
Hirata, A., and Castro-Alamancos, M.A. (2010). Neocortex network activation largest group of superficial neocortical GABAergic interneurons expresses
and deactivation states controlled by the thalamus. J. Neurophysiol. 103, ionotropic serotonin receptors. J. Neurosci. 30, 16796–16808.
1147–1157.
Lee, S.-H., Kwan, A.C., Zhang, S., Phoumthipphavong, V., Flannery, J.G.,
Hirata, A., Aguilar, J., and Castro-Alamancos, M.A. (2006). Noradrenergic Masmanidis, S.C., Taniguchi, H., Huang, Z.J., Zhang, F., Boyden, E.S., et al.
activation amplifies bottom-up and top-down signal-to-noise ratios in sensory (2012). Activation of specific interneurons improves V1 feature selectivity
thalamus. J. Neurosci. 26, 4426–4436. and visual perception. Nature 488, 379–383.

Neuron
Review
Levey, A.I., Hallanger, A.E., and Wainer, B.H. (1987). Cholinergic nucleus Mileykovskiy, B.Y., Kiyashchenko, L.I., and Siegel, J.M. (2005). Behavioral
basalis neurons may influence the cortex via the thalamus. Neurosci. Lett. correlates of activity in identified hypocretin/orexin neurons. Neuron 46,
74, 7–13. 787–798.
Li, Y., Gao, X.-B., Sakurai, T., and van den Pol, A.N. (2002). Hypocretin/ Miller, E.K., and Cohen, J.D. (2001). An integrative theory of prefrontal cortex
Orexin excites hypocretin neurons via a local glutamate neuron-A potential function. Annu. Rev. Neurosci. 24, 167–202.
mechanism for orchestrating the hypothalamic arousal system. Neuron 36,
1169–1181. Mitchell, J.F., Sundberg, K.A., and Reynolds, J.H. (2009). Spatial attention
decorrelates intrinsic activity fluctuations in macaque area V4. Neuron 63,
Li, C.Y., Poo, M.M., and Dan, Y. (2009). Burst spiking of a single cortical neuron 879–888.
modifies global brain state. Science 324, 643–646.
Mölle, M., Yeshenko, O., Marshall, L., Sara, S.J., and Born, J. (2006). Hippo-
Lin, S.-C., and Nicolelis, M.A.L. (2008). Neuronal ensemble bursting in the campal sharp wave-ripples linked to slow oscillations in rat slow-wave sleep.
basal forebrain encodes salience irrespective of valence. Neuron 59, 138–149. J. Neurophysiol. 96, 62–70.
Lin, L., Faraco, J., Li, R., Kadotani, H., Rogers, W., Lin, X., Qiu, X., de Jong, Momiyama, T., and Zaborszky, L. (2006). Somatostatin presynaptically inhibits
P.J., Nishino, S., and Mignot, E. (1999). The sleep disorder canine narcolepsy both GABA and glutamate release onto rat basal forebrain cholinergic
is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98, neurons. J. Neurophysiol. 96, 686–694.
365–376.
Monti, J.M. (1993). Involvement of histamine in the control of the waking state.
Lorente de No, R. (1938). Analysis of the activity of the chains of internuncial Life Sci. 53, 1331–1338.
neurons. J. Neurophysiol. 1, 207–244.
Monti, J.M., and Jantos, H. (2008). The roles of dopamine and serotonin, and of
Louie, K., and Wilson, M.A. (2001). Temporally structured replay of awake their receptors, in regulating sleep and waking. Prog. Brain Res. 172, 625–646.
hippocampal ensemble activity during rapid eye movement sleep. Neuron
29, 145–156. Monti, J.M., Pandi-Perumal, S.R., and Mohler, H. (2010). GABA and Sleep:
Molecular, Functional and Clinical Aspects (Basel: Springer Basel AG).
Lu, J., Greco, M.A., Shiromani, P., and Saper, C.B. (2000). Effect of lesions of
the ventrolateral preoptic nucleus on NREM and REM sleep. J. Neurosci. 20, Moore, T., and Fallah, M. (2004). Microstimulation of the frontal eye field and its
3830–3842. effects on covert spatial attention. J. Neurophysiol. 91, 152–162.
Mahowald, M.W., and Schenck, C.H. (2005). Insights from studying human Moruzzi, G., and Magoun, H.W. (1949). Brain stem reticular formation and acti-
sleep disorders. Nature 437, 1279–1285. vation of the EEG. Electroencephalogr. Clin. Neurophysiol. 1, 455–473.
Maloney, K.J., Mainville, L., and Jones, B.E. (1999). Differential c-Fos Nádasdy, Z., Hirase, H., Czurkó, A., Csicsvari, J., and Buzsáki, G. (1999).
expression in cholinergic, monoaminergic, and GABAergic cell groups of the Replay and time compression of recurring spike sequences in the hippo-
pontomesencephalic tegmentum after paradoxical sleep deprivation and campus. J. Neurosci. 19, 9497–9507.
recovery. J. Neurosci. 19, 3057–3072.
Nakamura, K., Matsumoto, M., and Hikosaka, O. (2008). Reward-dependent
Manning, K.A., Wilson, J.R., and Uhlrich, D.J. (1996). Histamine-immunoreac- modulation of neuronal activity in the primate dorsal raphe nucleus. J.
tive neurons and their innervation of visual regions in the cortex, tectum, and Neurosci. 28, 5331–5343.
thalamus in the primate Macaca mulatta. J. Comp. Neurol. 373, 271–282.
Niell, C.M., and Stryker, M.P. (2010). Modulation of visual responses by
Manns, I.D., Alonso, A., and Jones, B.E. (2000). Discharge profiles of behavioral state in mouse visual cortex. Neuron 65, 472–479.
juxtacellularly labeled and immunohistochemically identified GABAergic basal
forebrain neurons recorded in association with the electroencephalogram in Nishikawa, M., Munakata, M., and Akaike, N. (1994). Muscarinic acetylcholine
anesthetized rats. J. Neurosci. 20, 9252–9263. response in pyramidal neurones of rat cerebral cortex. Br. J. Pharmacol. 112,
1160–1166.
Manns, I.D., Lee, M.G., Modirrousta, M., Hou, Y.P., and Jones, B.E. (2003).
Alpha 2 adrenergic receptors on GABAergic, putative sleep-promoting basal Noudoost, B., and Moore, T. (2011). Control of visual cortical signals by
forebrain neurons. Eur. J. Neurosci. 18, 723–727. prefrontal dopamine. Nature 474, 372–375.
Maquet, P. (2001). The role of sleep in learning and memory. Science 294, O’Neill, J., Senior, T., and Csicsvari, J. (2006). Place-selective firing of CA1
1048–1052. pyramidal cells during sharp wave/ripple network patterns in exploratory
behavior. Neuron 49, 143–155.
Maquet, P., Laureys, S., Peigneux, P., Fuchs, S., Petiau, C., Phillips, C., Aerts,
J., Del Fiore, G., Degueldre, C., Meulemans, T., et al. (2000). Experience- Okun, M., Naim, A., and Lampl, I. (2010). The subthreshold relation between
dependent changes in cerebral activation during human REM sleep. Nat. cortical local field potential and neuronal firing unveiled by intracellular record-
Neurosci. 3, 831–836. ings in awake rats. J. Neurosci. 30, 4440–4448.
Marshall, L., Helgadóttir, H., Mölle, M., and Born, J. (2006). Boosting slow Otazu, G.H., Tai, L.-H., Yang, Y., and Zador, A.M. (2009). Engaging in an
oscillations during sleep potentiates memory. Nature 444, 610–613. auditory task suppresses responses in auditory cortex. Nat. Neurosci. 12,
646–654.
McCarley, R.W., and Hobson, J.A. (1975). Discharge patterns of cat pontine
brain stem neurons during desynchronized sleep. J. Neurophysiol. 38, Pal, D., and Mallick, B.N. (2009). GABA in pedunculopontine tegmentum
751–766. increases rapid eye movement sleep in freely moving rats: possible role of
GABA-ergic inputs from substantia nigra pars reticulata. Neuroscience 164,
McCormick, D.A., and Bal, T. (1997). Sleep and arousal: thalamocortical 404–414.
mechanisms. Annu. Rev. Neurosci. 20, 185–215.
Parikh, V., Kozak, R., Martinez, V., and Sarter, M. (2007). Prefrontal acetyl-
McCormick, D.A., and Pape, H.C. (1990). Properties of a hyperpolarization- choline release controls cue detection on multiple timescales. Neuron 56,
activated cation current and its role in rhythmic oscillation in thalamic relay 141–154.
neurones. J. Physiol. 431, 291–318.
Pawlak, V., Wickens, J.R., Kirkwood, A., and Kerr, J.N. (2010). Timing is not
McCormick, D.A., and Prince, D.A. (1985). Two types of muscarinic response everything: neuromodulation opens the STDP gate. Front. Synaptic Neurosci.
to acetylcholine in mammalian cortical neurons. Proc. Natl. Acad. Sci. USA 82, 2, 146.
6344–6348.
Peyron, C., Faraco, J., Rogers, W., Ripley, B., Overeem, S., Charnay, Y.,
Metherate, R., Cox, C.L., and Ashe, J.H. (1992). Cellular bases of neocortical Nevsimalova, S., Aldrich, M., Reynolds, D., Albin, R., et al. (2000). A mutation
activation: modulation of neural oscillations by the nucleus basalis and endog- in a case of early onset narcolepsy and a generalized absence of hypocretin
enous acetylcholine. J. Neurosci. 12, 4701–4711. peptides in human narcoleptic brains. Nat. Med. 6, 991–997.

Neuron
Review
Poulet, J.F.A., and Petersen, C.C.H. (2008). Internal brain state regulates St Peters, M., Demeter, E., Lustig, C., Bruno, J.P., and Sarter, M. (2011).
membrane potential synchrony in barrel cortex of behaving mice. Nature Enhanced control of attention by stimulating mesolimbic-corticopetal cholin-
454, 881–885. ergic circuitry. J. Neurosci. 31, 9760–9771.
Poulet, J.F.A., Fernandez, L.M.J., Crochet, S., and Petersen, C.C.H. (2012). Steininger, T.L., Alam, M.N., Gong, H., Szymusiak, R., and McGinty, D. (1999).
Thalamic control of cortical states. Nat. Neurosci. 15, 370–372. Sleep-waking discharge of neurons in the posterior lateral hypothalamus of the
albino rat. Brain Res. 840, 138–147.
Ranade, S.P., and Mainen, Z.F. (2009). Transient firing of dorsal raphe
neurons encodes diverse and specific sensory, motor, and reward events. Steriade, M., Paré, D., Parent, A., and Smith, Y. (1988). Projections of
J. Neurophysiol. 102, 3026–3037. cholinergic and non-cholinergic neurons of the brainstem core to relay and
associational thalamic nuclei in the cat and macaque monkey. Neuroscience
Rasmusson, D.D. (2000). The role of acetylcholine in cortical synaptic 25, 47–67.
plasticity. Behav. Brain Res. 115, 205–218.
Steriade, M., Datta, S., Paré, D., Oakson, G., and Curró Dossi, R.C. (1990).
Rechtschaffen, A., and Bergmann, B.M. (2002). Sleep deprivation in the rat: an Neuronal activities in brain-stem cholinergic nuclei related to tonic activation
update of the 1989 paper. Sleep 25, 18–24. processes in thalamocortical systems. J. Neurosci. 10, 2541–2559.
Reynolds, J.H., and Chelazzi, L. (2004). Attentional modulation of visual Steriade, M., McCormick, D.A., and Sejnowski, T.J. (1993a). Thalamocortical
processing. Annu. Rev. Neurosci. 27, 611–647. oscillations in the sleeping and aroused brain. Science 262, 679–685.
Ribeiro, S., Gervasoni, D., Soares, E.S., Zhou, Y., Lin, S.C., Pantoja, J., Lavine, Steriade, M., Nuñez, A., and Amzica, F. (1993b). Intracellular analysis of
M., and Nicolelis, M.A. (2004). Long-lasting novelty-induced neuronal rever- relations between the slow (< 1 Hz) neocortical oscillation and other sleep
beration during slow-wave sleep in multiple forebrain areas. PLoS Biol. 2, E24. rhythms of the electroencephalogram. J. Neurosci. 13, 3266–3283.
Rigas, P., and Castro-Alamancos, M.A. (2007). Thalamocortical Up states: Steriade, M., Timofeev, I., and Grenier, F. (2001). Natural waking and sleep
differential effects of intrinsic and extrinsic cortical inputs on persistent activity. states: a view from inside neocortical neurons. J. Neurophysiol. 85, 1969–
J. Neurosci. 27, 4261–4272. 1985.
Sanchez-Vives, M.V., and McCormick, D.A. (2000). Cellular and network Stickgold, R. (2005). Sleep-dependent memory consolidation. Nature 437,
mechanisms of rhythmic recurrent activity in neocortex. Nat. Neurosci. 3, 1272–1278.
1027–1034.
Stickgold, R., James, L., and Hobson, J.A. (2000). Visual discrimination
Saper, C.B., Scammell, T.E., and Lu, J. (2005). Hypothalamic regulation of learning requires sleep after training. Nat. Neurosci. 3, 1237–1238.
sleep and circadian rhythms. Nature 437, 1257–1263.
Stoelzel, C.R., Bereshpolova, Y., and Swadlow, H.A. (2009). Stability of thala-
Saper, C.B., Fuller, P.M., Pedersen, N.P., Lu, J., and Scammell, T.E. (2010). mocortical synaptic transmission across awake brain states. J. Neurosci. 29,
Sleep state switching. Neuron 68, 1023–1042. 6851–6859.
Suntsova, N., Guzman-Marin, R., Kumar, S., Alam, M.N., Szymusiak, R., and
Sara, S.J. (2009). The locus coeruleus and noradrenergic modulation of cogni-
McGinty, D. (2007). The median preoptic nucleus reciprocally modulates
tion. Nat. Rev. Neurosci. 10, 211–223.
activity of arousal-related and sleep-related neurons in the perifornical lateral
Sarter, M., and Bruno, J.P. (2002). The neglected constituent of the basal hypothalamus. J. Neurosci. 27, 1616–1630.
forebrain corticopetal projection system: GABAergic projections. Eur. J.
Sutcliffe, J.G., and de Lecea, L. (2002). The hypocretins: setting the arousal
Neurosci. 15, 1867–1873.
threshold. Nat. Rev. Neurosci. 3, 339–349.
Sarter, M., Hasselmo, M.E., Bruno, J.P., and Givens, B. (2005). Unraveling the
Szymusiak, R., and McGinty, D. (1986). Sleep suppression following kainic
attentional functions of cortical cholinergic inputs: interactions between
acid-induced lesions of the basal forebrain. Exp. Neurol. 94, 598–614.
signal-driven and cognitive modulation of signal detection. Brain Res. Brain
Res. Rev. 48, 98–111. Szymusiak, R., and McGinty, D. (1989). Sleep-waking discharge of basal
forebrain projection neurons in cats. Brain Res. Bull. 22, 423–430.
Shaw, P.J., Tononi, G., Greenspan, R.J., and Robinson, D.F. (2002). Stress
response genes protect against lethal effects of sleep deprivation in Szymusiak, R., and McGinty, D. (2008). Hypothalamic regulation of sleep and
Drosophila. Nature 417, 287–291. arousal. Ann. N. Y. Acad. Sci. 1129, 275–286.
Sherin, J.E., Shiromani, P.J., McCarley, R.W., and Saper, C.B. (1996). Activa- Takahashi, K., Lin, J.S., and Sakai, K. (2006). Neuronal activity of histaminergic
tion of ventrolateral preoptic neurons during sleep. Science 271, 216–219. tuberomammillary neurons during wake-sleep states in the mouse. J. Neuro-
sci. 26, 10292–10298.
Sherin, J.E., Elmquist, J.K., Torrealba, F., and Saper, C.B. (1998). Innervation
of histaminergic tuberomammillary neurons by GABAergic and galaninergic Takahashi, K., Lin, J.S., and Sakai, K. (2009). Characterization and mapping
neurons in the ventrolateral preoptic nucleus of the rat. J. Neurosci. 18, of sleep-waking specific neurons in the basal forebrain and preoptic hypothal-
4705–4721. amus in mice. Neuroscience 161, 269–292.
Sherman, S.M. (2005). Thalamic relays and cortical functioning. Prog. Brain Takahashi, K., Kayama, Y., Lin, J.S., and Sakai, K. (2010). Locus coeruleus
Res. 149, 107–126. neuronal activity during the sleep-waking cycle in mice. Neuroscience 169,
1115–1126.
Shouse, M.N., and Siegel, J.M. (1992). Pontine regulation of REM sleep
components in cats: integrity of the pedunculopontine tegmentum (PPT) is Taniguchi, H., He, M., Wu, P., Kim, S., Paik, R., Sugino, K., Kvitsiani, D., Fu, Y.,
important for phasic events but unnecessary for atonia during REM sleep. Lu, J., Lin, Y., et al. (2011). A resource of Cre driver lines for genetic targeting of
Brain Res. 571, 50–63. GABAergic neurons in cerebral cortex. Neuron 71, 995–1013.
Siegel, J.M. (2005). Clues to the functions of mammalian sleep. Nature 437, Thakkar, M.M. (2011). Histamine in the regulation of wakefulness. Sleep Med.
1264–1271. Rev. 15, 65–74.
Skaggs, W.E., and McNaughton, B.L. (1996). Replay of neuronal firing Torterolo, P., Morales, F.R., and Chase, M.H. (2002). GABAergic mechanisms
sequences in rat hippocampus during sleep following spatial experience. in the pedunculopontine tegmental nucleus of the cat promote active (REM)
Science 271, 1870–1873. sleep. Brain Res. 944, 1–9.
Soma, S., Shimegi, S., Osaki, H., and Sato, H. (2012). Cholinergic modulation Usher, M., Cohen, J.D., Servan-Schreiber, D., Rajkowski, J., and Aston-Jones,
of response gain in the primary visual cortex of the macaque. J. Neurophysiol. G. (1999). The role of locus coeruleus in the regulation of cognitive
107, 283–291. performance. Science 283, 549–554.

Neuron
Review
Vanderwolf, C.H., and Pappas, B.A. (1980). Reserpine abolishes movement- Wilson, N.R., Runyan, C.A., Wang, F.L., and Sur, M. (2012). Division
correlated atropine-resistant neocortical low voltage fast activity. Brain Res. and subtraction by distinct cortical inhibitory networks in vivo. Nature 488,
202, 79–94. 343–348.
Von Economo, C. (1930). Sleep as a problem of localization. J. Nerv. Ment. Dis. Xing, D., Yeh, C.-I., and Shapley, R.M. (2009). Spatial spread of the local
71, 249–259. field potential and its laminar variation in visual cortex. J. Neurosci. 29,
11540–11549.
Vyazovskiy, V.V., Cirelli, C., Pfister-Genskow, M., Faraguna, U., and Tononi, G.
(2008). Molecular and electrophysiological evidence for net synaptic potentia- Xu, S., Jiang, W., Poo, M.M., and Dan, Y. (2012). Activity recall in a visual
tion in wake and depression in sleep. Nat. Neurosci. 11, 200–208. cortical ensemble. Nat. Neurosci. 15, 449–455.
Walker, M.P., Brakefield, T., Morgan, A., Hobson, J.A., and Stickgold, R. Yu, A.J., and Dayan, P. (2005). Uncertainty, neuromodulation, and attention.
(2002). Practice with sleep makes perfect: sleep-dependent motor skill Neuron 46, 681–692.
learning. Neuron 35, 205–211.
Zaborszky, L., and Duque, A. (2003). Sleep-wake mechanisms and basal
forebrain circuitry. Front. Biosci. 8, d1146–d1169.
Weliky, M. (2000). Correlated neuronal activity and visual cortical develop-
ment. Neuron 27, 427–430. Zaborszky, L., Gaykema, R.P., Swanson, D.J., and Cullinan, W.E. (1997).
Cortical input to the basal forebrain. Neuroscience 79, 1051–1078.
Wickersham, I.R., Lyon, D.C., Barnard, R.J.O., Mori, T., Finke, S.,
Conzelmann, K.K., Young, J.A.T., and Callaway, E.M. (2007). Monosynaptic Zaborszky, L., Pang, K., Somogyi, J., Nadasdy, Z., and Kallo, I. (1999). The
restriction of transsynaptic tracing from single, genetically targeted neurons. basal forebrain corticopetal system revisited. Ann. N. Y. Acad. Sci. 877,
Neuron 53, 639–647. 339–367.
Wilson, M.A., and McNaughton, B.L. (1994). Reactivation of hippocampal Zhou, H., and Desimone, R. (2011). Feature-based attention in the frontal eye
ensemble memories during sleep. Science 265, 676–679. field and area V4 during visual search. Neuron 70, 1205–1217.
Wilson, F.A.W., and Rolls, E.T. (1990). Learning and memory is reflected in the Zohary, E., Shadlen, M.N., and Newsome, W.T. (1994). Correlated neuronal
responses of reinforcement-related neurons in the primate basal forebrain. J. discharge rate and its implications for psychophysical performance. Nature
Neurosci. 10, 1254–1267. 370, 140–143.

Yang Dan 2012 (Neuromodulation of Brain States)

Uploaded by

Copyright:

Available Formats

Yang Dan 2012 (Neuromodulation of Brain States)

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Yang Dan 2012 (Neuromodulation of Brain States)

Uploaded by

Copyright:

Available Formats

Neuron

Neuromodulation of Brain States

University of California, Berkeley, Berkeley, CA 94720, USA

Neuron 76, October 4, 2012 ª2012 Elsevier Inc. 209

2009). Optogenetic stimulation of the

210 Neuron 76, October 4, 2012 ª2012 Elsevier Inc.

(Adamantidis et al., 2007), whereas loss

Neuron 76, October 4, 2012 ª2012 Elsevier Inc. 211

results may be related to the functional

212 Neuron 76, October 4, 2012 ª2012 Elsevier Inc.

A B Figure 4. Optogenetic Manipulation of

20 10 cortex expressing both ChR2 and eNpHR (S.-H.L.,

Neuron 76, October 4, 2012 ª2012 Elsevier Inc. 213

Figure 5. Effects of Thalamic and Cortical Stimulation on Brain States

214 Neuron 76, October 4, 2012 ª2012 Elsevier Inc.

that attention also causes a decrease in

Neuron 76, October 4, 2012 ª2012 Elsevier Inc. 215

216 Neuron 76, October 4, 2012 ª2012 Elsevier Inc.

Neuron 76, October 4, 2012 ª2012 Elsevier Inc. 217

Fanselow, E.E., and Nicolelis, M.A. (1999). Behavioral modulation of tactile

218 Neuron 76, October 4, 2012 ª2012 Elsevier Inc.

Neuron 76, October 4, 2012 ª2012 Elsevier Inc. 219

220 Neuron 76, October 4, 2012 ª2012 Elsevier Inc.

Neuron 76, October 4, 2012 ª2012 Elsevier Inc. 221

222 Neuron 76, October 4, 2012 ª2012 Elsevier Inc.

You might also like