Neuronal firing, synaptic transmission, and its plasticity form the building blocks for processin... more Neuronal firing, synaptic transmission, and its plasticity form the building blocks for processing and storage of information in the brain. It is unknown whether adult human synapses are more efficient in transferring information between neurons than rodent synapses. To test this, we recorded from connected pairs of pyramidal neurons in acute brain slices of adult human and mouse temporal cortex and probed the dynamical properties of use-dependent plasticity. We found that human synaptic connections were purely depressing and that they recovered three to four times more swiftly from depression than synapses in rodent neocortex. Thereby, during realistic spike trains, the temporal resolution of synaptic information exchange in human synapses substantially surpasses that in mice. Using information theory, we calculate that information transfer between human pyramidal neurons exceeds that of mouse pyramidal neurons by four to nine times, well into the beta and gamma frequency range. In addition, we found that human principal cells tracked fine temporal features, conveyed in received synaptic inputs, at a wider bandwidth than for rodents. Action potential firing probability was reliably phase-locked to input transients up to 1,000 cycles/s because of a steep onset of action potentials in human pyramidal neurons during spike trains, unlike in rodent neurons. Our data show that, in contrast to the widely held views of limited information transfer in rodent depressing synapses, fast recovering synapses of human neurons can actually transfer substantial amounts of information during spike trains. In addition, human pyramidal neurons are equipped to encode high synaptic information content. Thus, adult human cortical microcircuits relay information at a wider bandwidth than rodent microcircuits.
Functional genetic analyses in mice rely on efficient and in-depth characterization of the behavi... more Functional genetic analyses in mice rely on efficient and in-depth characterization of the behavioral spectrum. Automated home-cage observation can provide a systematic and efficient screening method to detect unexplored, novel behavioral phenotypes. Here, we analyzed high-throughput automated home-cage data using existing and novel concepts, to detect a plethora of genetic differences in spontaneous behavior in a panel of commonly used inbred strains (129S1/SvImJ, A/J, C3H/ HeJ, C57BL/6J, BALB/cJ, DBA/2J, NOD/LtJ, FVB/NJ, WSB/EiJ, PWK/PhJ and CAST/EiJ). Continuous video-tracking observations of sheltering behavior and locomotor activity were segmented into distinguishable behavioral elements, and studied at different time scales, yielding a set of 115 behavioral parameters of which 105 showed highly significant strain differences. This set of 115 parameters was highly dimensional; principal component analysis identified 26 orthogonal components with eigenvalues above one. Especially novel parameters of sheltering behavior and parameters describing aspects of motion of the mouse in the home-cage showed high genetic effect sizes. Multi-day habituation curves and patterns of behavior surrounding dark/light phase transitions showed striking strain differences, albeit with lower genetic effect sizes. This spontaneous home-cage behavior study demonstrates high dimensionality, with a strong genetic contribution to specific sets of behavioral measures. Importantly, spontaneous home-cage behavior analysis detects genetic effects that cannot be studied in conventional behavioral tests, showing that the inclusion of a few days of undisturbed, labor extensive homecage assessment may greatly aid gene function analyses and drug target discovery.
The brain needs mechanisms able to correlate plastic changes with local circuit activity and inte... more The brain needs mechanisms able to correlate plastic changes with local circuit activity and internal functional states. At the cerebellum input stage, uncontrolled induction of long-term potentiation or depression (LTP or LTD) between mossy fibres and granule cells can saturate synaptic capacity and impair cerebellar functioning, which suggests that neuromodulators are required to gate plasticity processes. Cholinergic systems innervating the cerebellum are thought to enhance procedural learning and memory. Here we show that a specific subtype of acetylcholine receptors, the a7-nAChRs, are distributed both in cerebellar mossy fibre terminals and granule cell dendrites and contribute substantially to synaptic regulation. Selective a7-nAChR activation enhances the postsynaptic calcium increase, allowing weak mossy fibre bursts, which would otherwise cause LTD, to generate robust LTP. The local microperfusion of a7-nAChR agonists could also lead to in vivo switching of LTD to LTP following sensory stimulation of the whisker pad. In the cerebellar flocculus, a7-nAChR pharmacological activation impaired vestibulo-ocular-reflex adaptation, probably because LTP was saturated, preventing the fine adjustment of synaptic weights. These results show that gating mechanisms mediated by specific subtypes of nicotinic receptors are required to control the LTD/LTP balance at the mossy fibre-granule cell relay in order to regulate cerebellar plasticity and behavioural adaptation.
The inferior olivary nucleus (IO) forms the gateway to the cerebellar cortex and receives feedbac... more The inferior olivary nucleus (IO) forms the gateway to the cerebellar cortex and receives feedback information from the cerebellar nuclei (CN), thereby occupying a central position in the olivo-cerebellar loop. Here, we investigated the feedback input from the CN to the IO in vivo in mice using the whole-cell patch-clamp technique. This approach allows us to study how the CN-feedback input is integrated with the activity of olivary neurons, while the olivo-cerebellar system and its connections are intact. Our results show how IO neurons respond to CN stimulation sequentially with: i) a short depolarization (EPSP), ii) a hyperpolarization (IPSP) and iii) a rebound depolarization. The latter two phenomena can also be evoked without the EPSPs. The IPSP is sensitive to a GABA A receptor blocker. The IPSP suppresses suprathreshold and subthreshold activity and is generated mainly by activation of the GABA A receptors. The rebound depolarization re-initiates and temporarily phase locks the subthreshold oscillations. Lack of electrotonical coupling does not affect the IPSP of individual olivary neurons, nor the sensitivity of its GABA A receptors to blockers. The GABAergic feedback input from the CN does not only temporarily block the transmission of signals through the IO, it also isolates neurons from the network by shunting the junction current and re-initiates the temporal pattern after a fixed time point. These data suggest that the IO not only functions as a cerebellar controlled gating device, but also operates as a pattern generator for controlling motor timing and/or learning.
might play a role in experiencing and/or controlling emphatic emotions, but it remains to be dete... more might play a role in experiencing and/or controlling emphatic emotions, but it remains to be determined whether there is a distinction between positive and negative emotions, and, if so, which specific parts of the cerebellum are involved in these types of emotions. Here, we visualized activations of the cerebellum and extracerebellar regions using high-field fMRI, while we asked participants to observe and imitate images with pictures of human faces expressing different emotional states or with moving geometric shapes as control. The state of the emotions could be positive (happiness and surprise), negative (anger and disgust), or neutral. The positive emotional faces only whereas the negative emotional faces evoked prominent activations in lobules VI and VIIa in its hemispheres and lobules VIII and IX in the vermis. The cerebellar activations associated with negative emotions occurred concomitantly with activations of mirror neuron domains such as the insula and amygdala. These data suggest that the potential role of the cerebellum in control of emotions may be particularly relevant for goal-directed behavior that is required for observing and reacting to another person's (negative) expressions.
This article explores dynamical properties of the olivo-cerebellar system that arise from the spe... more This article explores dynamical properties of the olivo-cerebellar system that arise from the specific wiring of inferior olive (IO), cerebellar cortex, and deep cerebellar nuclei (DCN). We show that the irregularity observed in the firing pattern of the IO neurons is not necessarily produced by noise but can instead be the result of a purely deterministic network effect. We propose that this effect can serve as a dynamical working memory or as a neuronal clock with a characteristic timescale of about 100 ms that is determined by the slow calcium dynamics of IO and DCN neurons. This concept provides a novel explanation of how the cerebellum can solve timing tasks on a timescale that is two orders of magnitude longer than the millisecond timescale usually attributed to neuronal dynamics. One of the key ingredients of our model is the observation that due to postinhibitory rebound, DCN neurons can be driven by GABAergic (“inhibitory”) input from cerebellar Purkinje cells. Topographic ...
The dorsal cap and ventrolateral outgrowth of the inferior olive are involved in the control of e... more The dorsal cap and ventrolateral outgrowth of the inferior olive are involved in the control of eye movements. The caudal dorsal cap is predominantly involved in the horizontal optokinetic reflex; it receives most of its GABAergic input from the nucleus prepositus hypoglossi. In the present study, we determined the source of a major inhibitory input to the rostral dorsal cap and the ventrolateral outgrowth, which are the olivary subnuclei mainly involved in the "vertical" optokinetic reflexes. We studied these subnuclei in the rabbit with the use of retrograde tracing of horseradish peroxidase and anterograde tracing of wheat germ agglutinin-coupled horseradish peroxidase combined with postembedding immunocytochemistry. The ventral dentate nucleus of the cerebellum and dorsal group y project contralaterally to the rostral dorsal cap and ventrolateral outgrowth; this projection is entirely GABAergic. The terminals of this input form predominantly symmetric synapses with extraglomerular and intraglomerular dendrites; the remaining terminals are axosomatic. In addition, the dorsal cap and ventrolateral outgrowth contain significantly more crest synapses than any other olivary subnucleus. The terminals that form these crest synapses are derived from dorsal group y and/or the ventral dentate nucleus. None of the terminals in the dorsal cap or ventrolateral outgrowth was glycinergic.
EUROFIBROMATOSIS TYPE 1 (NF1) is a common autosomal-dominant genetic disorder (incidence 1:3000) ... more EUROFIBROMATOSIS TYPE 1 (NF1) is a common autosomal-dominant genetic disorder (incidence 1:3000) 1 caused by a mutation in the gene encoding neurofibromin, a protein that activates the hydrolysis of RAS-bound guanosine triphosphate. 2 Neurofibromatosis type 1 is characterized by various neurocutaneous manifestations, problems in fine and gross motor functioning, 3 as well as the frequent occurrence of cognitive disabilities. Children with NF1 have a lower mean IQ (86-94) with particular deficits in visual-spatial skills, nonverbal longterm memory, executive functions, and attention. 4-7 These problems have a large
Knowledge about the statistical regularities of the world is essential for cognitive and sensorim... more Knowledge about the statistical regularities of the world is essential for cognitive and sensorimotor function. In the domain of timing, prior statistics are crucial for optimal prediction, adaptation and planning. Where and how the nervous system encodes temporal statistics, however, is not known. Deriving from physiological and anatomical evidence for cerebellar learning, we develop a computational model that demonstrates how the cerebellum could learn prior distributions of time intervals and support Bayesian temporal estimation. The model shows that salient features observed in human Bayesian time interval estimates can be readily captured by learning in the cerebellar cortex and circuit level computations in the cerebellar deep nuclei.
Absence seizures are characterized by a temporary lapse of consciousness, which typically lasts u... more Absence seizures are characterized by a temporary lapse of consciousness, which typically lasts up to ten seconds, and they are accompanied by spike-wave discharges (SWDs) in cerebral electroencephalogram (EEG) recordings. The oscillatory activity that underlies cortical SWDs has been shown to often originate from a specific focus
For many decades, the predominant view in the cerebellar field has been that the olivocerebellar ... more For many decades, the predominant view in the cerebellar field has been that the olivocerebellar system's primary function is to induce plasticity in the cerebellar cortex, specifically, at the parallel fiber-Purkinje cell synapse. However, it has also long been proposed that the olivocerebellar system participates directly in motor control by helping to shape ongoing motor commands being issued by the cerebellum. Evidence consistent with both hypotheses exists; however, they are often investigated as mutually exclusive alternatives. In contrast, here, we take the perspective that the olivocerebellar system can contribute to both the motor learning and motor control functions of the cerebellum and might also play a role in development. We then consider the potential problems and benefits of it having multiple functions. Moreover, we discuss how its distinctive characteristics (e.g., low firing rates, synchronization, and variable complex spike waveforms) make it more or less sui...
The inferior olive provides climbing fibres to Purkinje cells in the cerebellar cortex and gives ... more The inferior olive provides climbing fibres to Purkinje cells in the cerebellar cortex and gives off axon collaterals to the cerebellar nuclei. The cerebellar nuclei contain GABAergic neurons that provide an inhibitory projection to the inferior olive and excitatory neurons that influence behaviour through various other premotor nuclei in the brainstem and diencephalon. Whether the olivary axon collaterals innervate the GABAergic neurons in the cerebellar nuclei is unknown. In the present study we investigated this projection in mice at the ultrastructural level using post-embedding GABA immunocytochemistry and anterograde and retrograde tracing of biotinylated dextrane amine and gold-lectin. It is demonstrated that the olivary axon collaterals do not only innervate non-GABAergic neurons in the cerebellar nuclei, but also GABAergic nucleo-olivary cells, thus establishing a direct feedback loop to the inferior olive.
Disrupting thalamocortical activity patterns has proven to be a promising approach to stop genera... more Disrupting thalamocortical activity patterns has proven to be a promising approach to stop generalized spike-and-wave discharges (GSWDs) characteristic of absence seizures. Here, we investigated to what extent modulation of neuronal firing in cerebellar nuclei (CN), which are anatomically in an advantageous position to disrupt cortical oscillations through their innervation of a wide variety of thalamic nuclei, is effective in controlling absence seizures. Two unrelated mouse models of generalized absence seizures were used; the natural mutant tottering, which is characterized by a missense mutation in Cacna1a, and inbred C3H/HeOuJ. While simultaneously recording single CN neuron activity and electrocorticogram (ECoG) in awake animals, we investigated to what extent pharmacologically increased or decreased CN neuron activity could modulate GSWD occurrence and short-lasting on-demand CN stimulation could disrupt epileptic seizures. We found that a subset of CN neurons shows phase-loc...
ABSTRACT Mice heavily rely on their whiskers to orient themselves in their environment and to det... more ABSTRACT Mice heavily rely on their whiskers to orient themselves in their environment and to determine the position, size and texture of objects. They have large facial whiskers that can be moved rhythmically. In line with its behavioural importance, a substantial part of the mouse brain is devoted to the whisker system. Although most attention has been directed towards ascending trigemino-thalamo-cortical pathways and the descending pathways from motor cortex to brainstem, many other brain regions are also implicated in the whisker system: I will discuss the sensory, motor and cognitive roles of the cerebellum. The cerebellum receives strong whisker input, both directly via the brainstem and indirectly via the cerebral cortex. The spatial and temporal organization of whisker input will be discussed. Furthermore, evidence is accumulating that the cerebellum also affects whisker movements. This will be demonstrated by means of electrophysiological recordings in awake, behaving mice. Finally, we recently demonstrated that mutant mice specifically impaired in the synaptic and intrinsic plasticity of cerebellar Purkinje cells have severe problems learning a whisker based object localization task. This shows that the cerebellum is also crucially involved in cognitive aspects of behaviour.
The vestibulocerebellum is involved in the control of compensatory eye movements. To investigate ... more The vestibulocerebellum is involved in the control of compensatory eye movements. To investigate its role in Correspondence Chris I. De Zeeuw the learning and timing of motor behaviour, eye movements in normal and mutant mice were investigated for the first time with the use of search coils. Wild-type mice showed the ability to increase the gain of their 1 These authors vestibulo-ocular reflex by visuo-vestibular training. This adaptation did not occur in lurcher mice, a natural contributed equally to mouse mutant that completely lacks Purkinje cells. During the optokinetic reflex the phase (timing) of the the present study. eye movements of lurchers lagged behind that of wild-type littermates, whereas during the vestibulo-ocular reflex it led that of the wild types. Ablations of different parts of the vestibulocerebellum indicated that the flocculus is necessary for the adaptation and the phase-leading effects of the cerebellum, whereas the nodulus might contribute to its phase-lagging effects. We conclude that Purkinje cells in the vestibulocerebellum are necessary for both learning and timing of compensatory eye movements in mice, and that the flocculus and nodulus may play antagonistic roles in these processes. The present description of the basic principles of cerebellar eye-movement control opens up the possibility to investigate the mechanisms of this motor behaviour at the molecular level in genetically manipulated mutant mice.
Eye movements are very important in order to track an object or to stabilize an image on the reti... more Eye movements are very important in order to track an object or to stabilize an image on the retina during movement. Animals without a fovea, such as the mouse, have a limited capacity to lock their eyes onto a target. In contrast to these target directed eye movements, compensatory ocular eye movements are easily elicited in afoveate animals 1,2,3,4. Compensatory ocular movements are generated by processing vestibular and optokinetic information into a command signal that will drive the eye muscles. The processing of the vestibular and optokinetic information can be investigated separately and together, allowing the specification of a deficit in the oculomotor system. The oculomotor system can be tested by evoking an optokinetic reflex (OKR), vestibulo-ocular reflex (VOR) or a visually-enhanced vestibulo-ocular reflex (VVOR). The OKR is a reflex movement that compensates for "full-field" image movements on the retina, whereas the VOR is a reflex eye movement that compensates head movements. The VVOR is a reflex eye movement that uses both vestibular as well as optokinetic information to make the appropriate compensation. The cerebellum monitors and is able to adjust these compensatory eye movements. Therefore, oculography is a very powerful tool to investigate brain-behavior relationship under normal as well as under pathological conditions (f.e. of vestibular, ocular and/or cerebellar origin). Testing the oculomotor system, as a behavioral paradigm, is interesting for several reasons. First, the oculomotor system is a well understood neural system 5. Second, the oculomotor system is relative simple 6
Understanding how neurons encode information in sequences of action potentials is of fundamental ... more Understanding how neurons encode information in sequences of action potentials is of fundamental importance to neuroscience. The cerebellum is widely recognized for its involvement in the coordination of movements, which requires muscle activation patterns to be controlled with millisecond precision. Understanding how cerebellar neurons accomplish such high temporal precision is critical to understanding cerebellar function. Inhibitory Purkinje cells, the only output neurons of the cerebellar cortex, and their postsynaptic target neurons in the cerebellar nuclei, fire action potentials at high, sustained frequencies, suggesting spike rate modulation as a possible code. Yet, millisecond precise spatiotemporal spike activity patterns in Purkinje cells and inferior olivary neurons have also been observed. These results and ongoing studies suggest that the neuronal code used by cerebellar neurons may span a wide time scale from millisecond precision to slow rate modulations, likely depending on the behavioral context.
Neuronal firing, synaptic transmission, and its plasticity form the building blocks for processin... more Neuronal firing, synaptic transmission, and its plasticity form the building blocks for processing and storage of information in the brain. It is unknown whether adult human synapses are more efficient in transferring information between neurons than rodent synapses. To test this, we recorded from connected pairs of pyramidal neurons in acute brain slices of adult human and mouse temporal cortex and probed the dynamical properties of use-dependent plasticity. We found that human synaptic connections were purely depressing and that they recovered three to four times more swiftly from depression than synapses in rodent neocortex. Thereby, during realistic spike trains, the temporal resolution of synaptic information exchange in human synapses substantially surpasses that in mice. Using information theory, we calculate that information transfer between human pyramidal neurons exceeds that of mouse pyramidal neurons by four to nine times, well into the beta and gamma frequency range. In addition, we found that human principal cells tracked fine temporal features, conveyed in received synaptic inputs, at a wider bandwidth than for rodents. Action potential firing probability was reliably phase-locked to input transients up to 1,000 cycles/s because of a steep onset of action potentials in human pyramidal neurons during spike trains, unlike in rodent neurons. Our data show that, in contrast to the widely held views of limited information transfer in rodent depressing synapses, fast recovering synapses of human neurons can actually transfer substantial amounts of information during spike trains. In addition, human pyramidal neurons are equipped to encode high synaptic information content. Thus, adult human cortical microcircuits relay information at a wider bandwidth than rodent microcircuits.
Functional genetic analyses in mice rely on efficient and in-depth characterization of the behavi... more Functional genetic analyses in mice rely on efficient and in-depth characterization of the behavioral spectrum. Automated home-cage observation can provide a systematic and efficient screening method to detect unexplored, novel behavioral phenotypes. Here, we analyzed high-throughput automated home-cage data using existing and novel concepts, to detect a plethora of genetic differences in spontaneous behavior in a panel of commonly used inbred strains (129S1/SvImJ, A/J, C3H/ HeJ, C57BL/6J, BALB/cJ, DBA/2J, NOD/LtJ, FVB/NJ, WSB/EiJ, PWK/PhJ and CAST/EiJ). Continuous video-tracking observations of sheltering behavior and locomotor activity were segmented into distinguishable behavioral elements, and studied at different time scales, yielding a set of 115 behavioral parameters of which 105 showed highly significant strain differences. This set of 115 parameters was highly dimensional; principal component analysis identified 26 orthogonal components with eigenvalues above one. Especially novel parameters of sheltering behavior and parameters describing aspects of motion of the mouse in the home-cage showed high genetic effect sizes. Multi-day habituation curves and patterns of behavior surrounding dark/light phase transitions showed striking strain differences, albeit with lower genetic effect sizes. This spontaneous home-cage behavior study demonstrates high dimensionality, with a strong genetic contribution to specific sets of behavioral measures. Importantly, spontaneous home-cage behavior analysis detects genetic effects that cannot be studied in conventional behavioral tests, showing that the inclusion of a few days of undisturbed, labor extensive homecage assessment may greatly aid gene function analyses and drug target discovery.
The brain needs mechanisms able to correlate plastic changes with local circuit activity and inte... more The brain needs mechanisms able to correlate plastic changes with local circuit activity and internal functional states. At the cerebellum input stage, uncontrolled induction of long-term potentiation or depression (LTP or LTD) between mossy fibres and granule cells can saturate synaptic capacity and impair cerebellar functioning, which suggests that neuromodulators are required to gate plasticity processes. Cholinergic systems innervating the cerebellum are thought to enhance procedural learning and memory. Here we show that a specific subtype of acetylcholine receptors, the a7-nAChRs, are distributed both in cerebellar mossy fibre terminals and granule cell dendrites and contribute substantially to synaptic regulation. Selective a7-nAChR activation enhances the postsynaptic calcium increase, allowing weak mossy fibre bursts, which would otherwise cause LTD, to generate robust LTP. The local microperfusion of a7-nAChR agonists could also lead to in vivo switching of LTD to LTP following sensory stimulation of the whisker pad. In the cerebellar flocculus, a7-nAChR pharmacological activation impaired vestibulo-ocular-reflex adaptation, probably because LTP was saturated, preventing the fine adjustment of synaptic weights. These results show that gating mechanisms mediated by specific subtypes of nicotinic receptors are required to control the LTD/LTP balance at the mossy fibre-granule cell relay in order to regulate cerebellar plasticity and behavioural adaptation.
The inferior olivary nucleus (IO) forms the gateway to the cerebellar cortex and receives feedbac... more The inferior olivary nucleus (IO) forms the gateway to the cerebellar cortex and receives feedback information from the cerebellar nuclei (CN), thereby occupying a central position in the olivo-cerebellar loop. Here, we investigated the feedback input from the CN to the IO in vivo in mice using the whole-cell patch-clamp technique. This approach allows us to study how the CN-feedback input is integrated with the activity of olivary neurons, while the olivo-cerebellar system and its connections are intact. Our results show how IO neurons respond to CN stimulation sequentially with: i) a short depolarization (EPSP), ii) a hyperpolarization (IPSP) and iii) a rebound depolarization. The latter two phenomena can also be evoked without the EPSPs. The IPSP is sensitive to a GABA A receptor blocker. The IPSP suppresses suprathreshold and subthreshold activity and is generated mainly by activation of the GABA A receptors. The rebound depolarization re-initiates and temporarily phase locks the subthreshold oscillations. Lack of electrotonical coupling does not affect the IPSP of individual olivary neurons, nor the sensitivity of its GABA A receptors to blockers. The GABAergic feedback input from the CN does not only temporarily block the transmission of signals through the IO, it also isolates neurons from the network by shunting the junction current and re-initiates the temporal pattern after a fixed time point. These data suggest that the IO not only functions as a cerebellar controlled gating device, but also operates as a pattern generator for controlling motor timing and/or learning.
might play a role in experiencing and/or controlling emphatic emotions, but it remains to be dete... more might play a role in experiencing and/or controlling emphatic emotions, but it remains to be determined whether there is a distinction between positive and negative emotions, and, if so, which specific parts of the cerebellum are involved in these types of emotions. Here, we visualized activations of the cerebellum and extracerebellar regions using high-field fMRI, while we asked participants to observe and imitate images with pictures of human faces expressing different emotional states or with moving geometric shapes as control. The state of the emotions could be positive (happiness and surprise), negative (anger and disgust), or neutral. The positive emotional faces only whereas the negative emotional faces evoked prominent activations in lobules VI and VIIa in its hemispheres and lobules VIII and IX in the vermis. The cerebellar activations associated with negative emotions occurred concomitantly with activations of mirror neuron domains such as the insula and amygdala. These data suggest that the potential role of the cerebellum in control of emotions may be particularly relevant for goal-directed behavior that is required for observing and reacting to another person's (negative) expressions.
This article explores dynamical properties of the olivo-cerebellar system that arise from the spe... more This article explores dynamical properties of the olivo-cerebellar system that arise from the specific wiring of inferior olive (IO), cerebellar cortex, and deep cerebellar nuclei (DCN). We show that the irregularity observed in the firing pattern of the IO neurons is not necessarily produced by noise but can instead be the result of a purely deterministic network effect. We propose that this effect can serve as a dynamical working memory or as a neuronal clock with a characteristic timescale of about 100 ms that is determined by the slow calcium dynamics of IO and DCN neurons. This concept provides a novel explanation of how the cerebellum can solve timing tasks on a timescale that is two orders of magnitude longer than the millisecond timescale usually attributed to neuronal dynamics. One of the key ingredients of our model is the observation that due to postinhibitory rebound, DCN neurons can be driven by GABAergic (“inhibitory”) input from cerebellar Purkinje cells. Topographic ...
The dorsal cap and ventrolateral outgrowth of the inferior olive are involved in the control of e... more The dorsal cap and ventrolateral outgrowth of the inferior olive are involved in the control of eye movements. The caudal dorsal cap is predominantly involved in the horizontal optokinetic reflex; it receives most of its GABAergic input from the nucleus prepositus hypoglossi. In the present study, we determined the source of a major inhibitory input to the rostral dorsal cap and the ventrolateral outgrowth, which are the olivary subnuclei mainly involved in the "vertical" optokinetic reflexes. We studied these subnuclei in the rabbit with the use of retrograde tracing of horseradish peroxidase and anterograde tracing of wheat germ agglutinin-coupled horseradish peroxidase combined with postembedding immunocytochemistry. The ventral dentate nucleus of the cerebellum and dorsal group y project contralaterally to the rostral dorsal cap and ventrolateral outgrowth; this projection is entirely GABAergic. The terminals of this input form predominantly symmetric synapses with extraglomerular and intraglomerular dendrites; the remaining terminals are axosomatic. In addition, the dorsal cap and ventrolateral outgrowth contain significantly more crest synapses than any other olivary subnucleus. The terminals that form these crest synapses are derived from dorsal group y and/or the ventral dentate nucleus. None of the terminals in the dorsal cap or ventrolateral outgrowth was glycinergic.
EUROFIBROMATOSIS TYPE 1 (NF1) is a common autosomal-dominant genetic disorder (incidence 1:3000) ... more EUROFIBROMATOSIS TYPE 1 (NF1) is a common autosomal-dominant genetic disorder (incidence 1:3000) 1 caused by a mutation in the gene encoding neurofibromin, a protein that activates the hydrolysis of RAS-bound guanosine triphosphate. 2 Neurofibromatosis type 1 is characterized by various neurocutaneous manifestations, problems in fine and gross motor functioning, 3 as well as the frequent occurrence of cognitive disabilities. Children with NF1 have a lower mean IQ (86-94) with particular deficits in visual-spatial skills, nonverbal longterm memory, executive functions, and attention. 4-7 These problems have a large
Knowledge about the statistical regularities of the world is essential for cognitive and sensorim... more Knowledge about the statistical regularities of the world is essential for cognitive and sensorimotor function. In the domain of timing, prior statistics are crucial for optimal prediction, adaptation and planning. Where and how the nervous system encodes temporal statistics, however, is not known. Deriving from physiological and anatomical evidence for cerebellar learning, we develop a computational model that demonstrates how the cerebellum could learn prior distributions of time intervals and support Bayesian temporal estimation. The model shows that salient features observed in human Bayesian time interval estimates can be readily captured by learning in the cerebellar cortex and circuit level computations in the cerebellar deep nuclei.
Absence seizures are characterized by a temporary lapse of consciousness, which typically lasts u... more Absence seizures are characterized by a temporary lapse of consciousness, which typically lasts up to ten seconds, and they are accompanied by spike-wave discharges (SWDs) in cerebral electroencephalogram (EEG) recordings. The oscillatory activity that underlies cortical SWDs has been shown to often originate from a specific focus
For many decades, the predominant view in the cerebellar field has been that the olivocerebellar ... more For many decades, the predominant view in the cerebellar field has been that the olivocerebellar system's primary function is to induce plasticity in the cerebellar cortex, specifically, at the parallel fiber-Purkinje cell synapse. However, it has also long been proposed that the olivocerebellar system participates directly in motor control by helping to shape ongoing motor commands being issued by the cerebellum. Evidence consistent with both hypotheses exists; however, they are often investigated as mutually exclusive alternatives. In contrast, here, we take the perspective that the olivocerebellar system can contribute to both the motor learning and motor control functions of the cerebellum and might also play a role in development. We then consider the potential problems and benefits of it having multiple functions. Moreover, we discuss how its distinctive characteristics (e.g., low firing rates, synchronization, and variable complex spike waveforms) make it more or less sui...
The inferior olive provides climbing fibres to Purkinje cells in the cerebellar cortex and gives ... more The inferior olive provides climbing fibres to Purkinje cells in the cerebellar cortex and gives off axon collaterals to the cerebellar nuclei. The cerebellar nuclei contain GABAergic neurons that provide an inhibitory projection to the inferior olive and excitatory neurons that influence behaviour through various other premotor nuclei in the brainstem and diencephalon. Whether the olivary axon collaterals innervate the GABAergic neurons in the cerebellar nuclei is unknown. In the present study we investigated this projection in mice at the ultrastructural level using post-embedding GABA immunocytochemistry and anterograde and retrograde tracing of biotinylated dextrane amine and gold-lectin. It is demonstrated that the olivary axon collaterals do not only innervate non-GABAergic neurons in the cerebellar nuclei, but also GABAergic nucleo-olivary cells, thus establishing a direct feedback loop to the inferior olive.
Disrupting thalamocortical activity patterns has proven to be a promising approach to stop genera... more Disrupting thalamocortical activity patterns has proven to be a promising approach to stop generalized spike-and-wave discharges (GSWDs) characteristic of absence seizures. Here, we investigated to what extent modulation of neuronal firing in cerebellar nuclei (CN), which are anatomically in an advantageous position to disrupt cortical oscillations through their innervation of a wide variety of thalamic nuclei, is effective in controlling absence seizures. Two unrelated mouse models of generalized absence seizures were used; the natural mutant tottering, which is characterized by a missense mutation in Cacna1a, and inbred C3H/HeOuJ. While simultaneously recording single CN neuron activity and electrocorticogram (ECoG) in awake animals, we investigated to what extent pharmacologically increased or decreased CN neuron activity could modulate GSWD occurrence and short-lasting on-demand CN stimulation could disrupt epileptic seizures. We found that a subset of CN neurons shows phase-loc...
ABSTRACT Mice heavily rely on their whiskers to orient themselves in their environment and to det... more ABSTRACT Mice heavily rely on their whiskers to orient themselves in their environment and to determine the position, size and texture of objects. They have large facial whiskers that can be moved rhythmically. In line with its behavioural importance, a substantial part of the mouse brain is devoted to the whisker system. Although most attention has been directed towards ascending trigemino-thalamo-cortical pathways and the descending pathways from motor cortex to brainstem, many other brain regions are also implicated in the whisker system: I will discuss the sensory, motor and cognitive roles of the cerebellum. The cerebellum receives strong whisker input, both directly via the brainstem and indirectly via the cerebral cortex. The spatial and temporal organization of whisker input will be discussed. Furthermore, evidence is accumulating that the cerebellum also affects whisker movements. This will be demonstrated by means of electrophysiological recordings in awake, behaving mice. Finally, we recently demonstrated that mutant mice specifically impaired in the synaptic and intrinsic plasticity of cerebellar Purkinje cells have severe problems learning a whisker based object localization task. This shows that the cerebellum is also crucially involved in cognitive aspects of behaviour.
The vestibulocerebellum is involved in the control of compensatory eye movements. To investigate ... more The vestibulocerebellum is involved in the control of compensatory eye movements. To investigate its role in Correspondence Chris I. De Zeeuw the learning and timing of motor behaviour, eye movements in normal and mutant mice were investigated for the first time with the use of search coils. Wild-type mice showed the ability to increase the gain of their 1 These authors vestibulo-ocular reflex by visuo-vestibular training. This adaptation did not occur in lurcher mice, a natural contributed equally to mouse mutant that completely lacks Purkinje cells. During the optokinetic reflex the phase (timing) of the the present study. eye movements of lurchers lagged behind that of wild-type littermates, whereas during the vestibulo-ocular reflex it led that of the wild types. Ablations of different parts of the vestibulocerebellum indicated that the flocculus is necessary for the adaptation and the phase-leading effects of the cerebellum, whereas the nodulus might contribute to its phase-lagging effects. We conclude that Purkinje cells in the vestibulocerebellum are necessary for both learning and timing of compensatory eye movements in mice, and that the flocculus and nodulus may play antagonistic roles in these processes. The present description of the basic principles of cerebellar eye-movement control opens up the possibility to investigate the mechanisms of this motor behaviour at the molecular level in genetically manipulated mutant mice.
Eye movements are very important in order to track an object or to stabilize an image on the reti... more Eye movements are very important in order to track an object or to stabilize an image on the retina during movement. Animals without a fovea, such as the mouse, have a limited capacity to lock their eyes onto a target. In contrast to these target directed eye movements, compensatory ocular eye movements are easily elicited in afoveate animals 1,2,3,4. Compensatory ocular movements are generated by processing vestibular and optokinetic information into a command signal that will drive the eye muscles. The processing of the vestibular and optokinetic information can be investigated separately and together, allowing the specification of a deficit in the oculomotor system. The oculomotor system can be tested by evoking an optokinetic reflex (OKR), vestibulo-ocular reflex (VOR) or a visually-enhanced vestibulo-ocular reflex (VVOR). The OKR is a reflex movement that compensates for "full-field" image movements on the retina, whereas the VOR is a reflex eye movement that compensates head movements. The VVOR is a reflex eye movement that uses both vestibular as well as optokinetic information to make the appropriate compensation. The cerebellum monitors and is able to adjust these compensatory eye movements. Therefore, oculography is a very powerful tool to investigate brain-behavior relationship under normal as well as under pathological conditions (f.e. of vestibular, ocular and/or cerebellar origin). Testing the oculomotor system, as a behavioral paradigm, is interesting for several reasons. First, the oculomotor system is a well understood neural system 5. Second, the oculomotor system is relative simple 6
Understanding how neurons encode information in sequences of action potentials is of fundamental ... more Understanding how neurons encode information in sequences of action potentials is of fundamental importance to neuroscience. The cerebellum is widely recognized for its involvement in the coordination of movements, which requires muscle activation patterns to be controlled with millisecond precision. Understanding how cerebellar neurons accomplish such high temporal precision is critical to understanding cerebellar function. Inhibitory Purkinje cells, the only output neurons of the cerebellar cortex, and their postsynaptic target neurons in the cerebellar nuclei, fire action potentials at high, sustained frequencies, suggesting spike rate modulation as a possible code. Yet, millisecond precise spatiotemporal spike activity patterns in Purkinje cells and inferior olivary neurons have also been observed. These results and ongoing studies suggest that the neuronal code used by cerebellar neurons may span a wide time scale from millisecond precision to slow rate modulations, likely depending on the behavioral context.
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