Cerebellar Nuclei Neurons Research Articles

Controlling absence seizures from the cerebellar nuclei via activation of the Gq signaling pathway

Absence seizures (ASs) are characterized by pathological electrographic oscillations in the cerebral cortex and thalamus, which are called spike-and-wave discharges (SWDs). Subcortical structures, such as the cerebellum, may well contribute to the emergence of ASs, but the cellular and molecular underpinnings remain poorly understood. Here we show that the genetic ablation of P/Q-type calcium channels in cerebellar granule cells (quirky) or Purkinje cells (purky) leads to recurrent SWDs with the purky model showing the more severe phenotype. The quirky mouse model showed irregular action potential firing of their cerebellar nuclei (CN) neurons as well as rhythmic firing during the wave of their SWDs. The purky model also showed irregular CN firing, in addition to a reduced firing rate and rhythmicity during the spike of the SWDs. In both models, the incidence of SWDs could be decreased by increasing CN activity via activation of the Gq-coupled designer receptor exclusively activated by designer drugs (DREADDs) or via that of the Gq-coupled metabotropic glutamate receptor 1. In contrast, the incidence of SWDs was increased by decreasing CN activity via activation of the inhibitory Gi/o-coupled DREADD. Finally, disrupting CN rhythmic firing with a closed-loop channelrhodopsin-2 stimulation protocol confirmed that ongoing SWDs can be ceased by activating CN neurons. Together, our data highlight that P/Q-type calcium channels in cerebellar granule cells and Purkinje cells can be relevant for epileptogenesis, that Gq-coupled activation of CN neurons can exert anti-epileptic effects and that precisely timed activation of the CN can be used to stop ongoing SWDs.

TMEM106B deficiency impairs cerebellar myelination and synaptic integrity with Purkinje cell loss

TMEM106B, a type II lysosomal transmembrane protein, has recently been associated with brain aging, hypomyelinating leukodystrophy, frontotemporal lobar degeneration (FTLD) and several other brain disorders. TMEM106B is critical for proper lysosomal function and TMEM106B deficiency leads to myelination defects, FTLD related pathology, and motor coordination deficits in mice. However, the physiological and pathological functions of TMEM106B in the brain are still not well understood. In this study, we investigate the role of TMEM106B in the cerebellum, dysfunction of which has been associated with FTLD and other brain disorders. We found that TMEM106B is ubiquitously expressed in neurons in the cerebellum, with the highest levels in the Purkinje neurons. Aged TMEM106B-deficient mice show significant loss of Purkinje neurons specifically in the anterior lobe of the cerebellum. Increased microglia and astrocyte activation, as well as an accumulation of ubiquitinated proteins, p62 and TDP-43 were also detected in the cerebellum of aged TMEM106B deficient mice. In the young mice, myelination defects and a significant loss of synapses between Purkinje and deep cerebellar nuclei neurons were observed. Interestingly, TMEM106B deficiency causes distinct lysosomal phenotypes in different types of neurons and glia in the cerebellum and frontal cortex. In humans, TMEM106B rs1990622 risk allele (T/T) is associated with increased Purkinje neuron loss. Taken together, our studies support that TMEM106B regulates lysosomal function in a cell-type-specific manner and TMEM106B is critical for maintaining synaptic integrity and neural functions in the cerebellum.

Electrophysiological alterations of the Purkinje cells and deep cerebellar neurons in a mouse model of Alzheimer disease (electrophysiology on cerebellum of AD mice).

Alzheimer's disease is histopathologically well defined by the presence of amyloid deposits and tau-related neurofibrillary tangles in crucial regions of the brain. Interest is growing in revealing and determining possible pathological markers also in the cerebellum as its involvement in cognitive functions is now well supported. Despite the central position of the Purkinje cell in the cerebellum, its electrophysiological behaviour in mouse models of Alzheimer's disease is scarce in the literature. Our first aim was here to focus on the electrophysiological behaviour of the cerebellum in awake mouse model of Alzheimer's disease (APPswe/PSEN1dE9) and the related performance on the water-maze test classically used in behavioural studies. We found prevalent signs of electrophysiological alterations in both Purkinje cells and deep cerebellar nuclei neurons which might explain the behavioural deficits reported during the water-maze test. The alterations of neurons firing were accompanied by a dual (~16 and ~228 Hz) local field potential's oscillation in the Purkinje cell layer of Alzheimer's disease mice which was concomitant to an important increase of both the simple and the complex spikes. In addition, β-amyloid deposits were present in the molecular layer of the cerebellum. These results highlight the importance of the output firing modification of the AD cerebellum that may indirectly impact the activity of its subcortical and cortical targets.

Loss of Flot2 Expression in Deep Cerebellar Nuclei Neurons of Mice with Niemann-Pick Disease Type C

Loss of Flot2 Expression in Deep Cerebellar Nuclei Neurons of Mice with Niemann-Pick Disease Type C

Molecular Identity and Location Influence Purkinje Cell Vulnerability in Autosomal-Recessive Spastic Ataxia of Charlevoix-Saguenay Mice.

Patterned cell death is a common feature of many neurodegenerative diseases. In patients with autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and mouse models of ARSACS, it has been observed that Purkinje cells in anterior cerebellar vermis are vulnerable to degeneration while those in posterior vermis are resilient. Purkinje cells are known to express certain molecules in a highly stereotyped, patterned manner across the cerebellum. One patterned molecule is zebrin, which is expressed in distinctive stripes across the cerebellar cortex. The different zones delineated by the expression pattern of zebrin and other patterned molecules have been implicated in the patterning of Purkinje cell death, raising the question of whether they contribute to cell death in ARSACS. We found that zebrin patterning appears normal prior to disease onset in Sacs–/– mice, suggesting that zebrin-positive and -negative Purkinje cell zones develop normally. We next observed that zebrin-negative Purkinje cells in anterior lobule III were preferentially susceptible to cell death, while anterior zebrin-positive cells and posterior zebrin-negative and -positive cells remained resilient even at late disease stages. The patterning of Purkinje cell innervation to the target neurons in the cerebellar nuclei (CN) showed a similar pattern of loss: neurons in the anterior CN, where inputs are predominantly zebrin-negative, displayed a loss of Purkinje cell innervation. In contrast, neurons in the posterior CN, which is innervated by both zebrin-negative and -positive puncta, had normal innervation. These results suggest that the location and the molecular identity of Purkinje cells determine their susceptibility to cell death in ARSACS.

Reverse-translational identification of a cerebellar satiation network.

The brain is the seat of body weight homeostasis. However, our inability to control the increasing prevalence of obesity highlights a need to look beyond canonical feeding pathways to broaden our understanding of body weight control1-3. Here we used a reverse-translational approach to identify and anatomically, molecularly and functionally characterize a neural ensemble that promotes satiation. Unbiased, task-based functional magnetic resonance imaging revealed marked differences in cerebellar responses to food in people with a genetic disorder characterized by insatiable appetite. Transcriptomic analyses in mice revealed molecularly and topographically-distinct neurons in the anterior deep cerebellar nuclei (aDCN) that are activated by feeding or nutrient infusion in the gut. Selective activation of aDCN neurons substantially decreased food intake by reducing meal size without compensatory changes to metabolic rate. We found that aDCN activity terminates food intake by increasing striatal dopamine levels and attenuating the phasic dopamine response to subsequent food consumption. Our study defines a conserved satiation centre that may represent a novel therapeutic target for the management of excessive eating, and underscores the utility of a 'bedside-to-bench' approach for the identification of neural circuits that influence behaviour.

Distinct Fastigial Output Channels and Their Impact on Temporal Lobe Seizures.

Despite being canonically considered a motor control structure, the cerebellum is increasingly recognized for important roles in processes beyond this traditional framework, including seizure suppression. Excitatory fastigial neurons project to a large number of downstream targets, and it is unclear whether this broad targeting underlies seizure suppression, or whether a specific output may be sufficient. To address this question, we used the intrahippocampal kainic acid mouse model of temporal lobe epilepsy, male and female animals, and a dual-virus approach to selectively label and manipulate fastigial outputs. We examined fastigial neurons projecting to the superior colliculus, medullary reticular formation, and central lateral nucleus of the thalamus, and found that these comprise largely nonoverlapping populations of neurons that send collaterals to unique sets of additional, somewhat overlapping, thalamic and brainstem regions. We found that neither optogenetic stimulation of superior colliculus nor reticular formation output channels attenuated hippocampal seizures. In contrast, on-demand stimulation of fastigial neurons targeting the central lateral nucleus robustly inhibited seizures. Our results indicate that fastigial control of hippocampal seizures does not require simultaneous modulation of many fastigial output channels. Rather, selective modulation of the fastigial output channel to the central lateral thalamus, specifically, is sufficient for seizure control. More broadly, our data highlight the concept of specific cerebellar output channels, whereby discrete cerebellar nucleus neurons project to specific aggregates of downstream targets, with important consequences for therapeutic interventions.SIGNIFICANCE STATEMENT The cerebellum has an emerging relationship with nonmotor systems and may represent a powerful target for therapeutic intervention in temporal lobe epilepsy. We find, as previously reported, that fastigial neurons project to numerous brain regions via largely segregated output channels, and that projection targets cannot be predicted simply by somatic locations within the nucleus. We further find that on-demand optogenetic excitation of fastigial neurons projecting to the central lateral nucleus of the thalamus-but not fastigial neurons projecting to the reticular formation, superior colliculus, or ventral lateral thalamus-is sufficient to attenuate hippocampal seizures.

Activity of Cerebellar Nuclei Neurons Correlates with ZebrinII Identity of Their Purkinje Cell Afferents.

Purkinje cells (PCs) in the cerebellar cortex can be divided into at least two main subpopulations: one subpopulation that prominently expresses ZebrinII (Z+), and shows a relatively low simple spike firing rate, and another that hardly expresses ZebrinII (Z–) and shows higher baseline firing rates. Likewise, the complex spike responses of PCs, which are evoked by climbing fiber inputs and thus reflect the activity of the inferior olive (IO), show the same dichotomy. However, it is not known whether the target neurons of PCs in the cerebellar nuclei (CN) maintain this bimodal distribution. Electrophysiological recordings in awake adult mice show that the rate of action potential firing of CN neurons that receive input from Z+ PCs was consistently lower than that of CN neurons innervated by Z– PCs. Similar in vivo recordings in juvenile and adolescent mice indicated that the firing frequency of CN neurons correlates to the ZebrinII identity of the PC afferents in adult, but not postnatal stages. Finally, the spontaneous action potential firing pattern of adult CN neurons recorded in vitro revealed no significant differences in intrinsic pacemaking activity between ZebrinII identities. Our findings indicate that all three main components of the olivocerebellar loop, i.e., PCs, IO neurons and CN neurons, operate at a higher rate in the Z– modules.

Cerebellar nuclei neurons display aberrant oscillations during harmaline-induced tremor

SummaryEssential tremor, a common, debilitating motor disorder, is thought to be caused by cerebellar malfunction. It has been shown that rhythmic Purkinje cell firing is both necessary and sufficient to induce body tremor. During tremor, cerebellar nuclei (CN) cells also display oscillatory activity. This study examined whether rhythmic activity in the CN characterizes the occurrence of body tremor, or alternatively, whether aberrant bursting activity underlies body tremor. Cerebellar nuclei activity was chronically recorded and analyzed in freely moving and in harmaline treated rats. CN neurons displayed rhythmic activity in both conditions, but the number of oscillatory neurons and the relative oscillation time were significantly higher under harmaline. The dominant frequencies of the oscillations were broadly distributed under harmaline and the likelihood that two simultaneously recorded neurons would co-oscillate and their oscillation coherence were significantly lower. It is argued that these alterations rather than neuronal rhythmicity per se underlie harmaline-induced body tremor.

The Clp1 R140H mutation alters tRNA metabolism and mRNA 3′ processing in mouse models of pontocerebellar hypoplasia

Homozygous mutation of the RNA kinase CLP1 (cleavage factor polyribonucleotide kinase subunit 1) causes pontocerebellar hypoplasia type 10 (PCH10), a pediatric neurodegenerative disease. CLP1 is associated with the transfer RNA (tRNA) splicing endonuclease complex and the cleavage and polyadenylation machinery, but its function remains unclear. We generated two mouse models of PCH10: one homozygous for the disease-associated Clp1 mutation, R140H, and one heterozygous for this mutation and a null allele. Both models exhibit loss of lower motor neurons and neurons of the deep cerebellar nuclei. To explore whether Clp1 mutation impacts tRNA splicing, we profiled the products of intron-containing tRNA genes. While mature tRNAs were expressed at normal levels in mutant mice, numerous other products of intron-containing tRNA genes were dysregulated, with pre-tRNAs, introns, and certain tRNA fragments up-regulated, and other fragments down-regulated. However, the spatiotemporal patterns of dysregulation do not correlate with pathogenicity for most altered tRNA products. To elucidate the effect of Clp1 mutation on precursor messenger RNA (pre-mRNA) cleavage, we analyzed poly(A) site (PAS) usage and gene expression in Clp1 R140H/- spinal cord. PAS usage was shifted from proximal to distal sites in the mutant mouse, particularly in short and closely spaced genes. Many such genes were also expressed at lower levels in the Clp1 R140H/- mouse, possibly as a result of impaired transcript maturation. These findings are consistent with the hypothesis that select genes are particularly dependent upon CLP1 for proper pre-mRNA cleavage, suggesting that impaired mRNA 3' processing may contribute to pathogenesis in PCH10.

A quantitative analysis of cerebellar anatomy in birds.

The cerebellum is largely conserved in its circuitry, but varies greatly in size and shape across species. The extent to which differences in cerebellar morphology is driven by changes in neuron numbers, neuron sizes or both, remains largely unknown. To determine how species variation in cerebellum size and shape is reflective of neuron sizes and numbers requires the development of a suitable comparative data set and one that can effectively separate different neuronal populations. Here, we generated the largest comparative dataset to date on neuron numbers, sizes, and volumes of cortical layers and surface area of the cerebellum across 54 bird species. Across different cerebellar sizes, the cortical layers maintained relatively constant proportions to one another and variation in cerebellum size was largely due to neuron numbers rather than neuron sizes. However, the rate at which neuron numbers increased with cerebellum size varied across Purkinje cells, granule cells, and cerebellar nuclei neurons. We also examined the relationship among neuron numbers, cerebellar surface area and cerebellar folding. Our estimate of cerebellar folding, the midsagittal foliation index, was a poor predictor of surface area and number of Purkinje cells, but surface area was the best predictor of Purkinje cell numbers. Overall, this represents the first comprehensive, quantitative analysis of cerebellar anatomy in a comparative context of any vertebrate. The extent to which these relationships occur in other vertebrates requires a similar approach and would determine whether the same scaling principles apply throughout the evolution of the cerebellum.

Modulatory Effects of Monoamines and Perineuronal Nets on Output of Cerebellar Purkinje Cells.

Classically, the cerebellum has been thought to play a significant role in motor coordination. However, a growing body of evidence for novel neural connections between the cerebellum and various brain regions indicates that the cerebellum also contributes to other brain functions implicated in reward, language, and social behavior. Cerebellar Purkinje cells (PCs) make inhibitory GABAergic synapses with their target neurons: other PCs and Lugaro/globular cells via PC axon collaterals, and neurons in the deep cerebellar nuclei (DCN) via PC primary axons. PC-Lugaro/globular cell connections form a cerebellar cortical microcircuit, which is driven by serotonin and noradrenaline. PCs’ primary outputs control not only firing but also synaptic plasticity of DCN neurons following the integration of excitatory and inhibitory inputs in the cerebellar cortex. Thus, strong PC-mediated inhibition is involved in cerebellar functions as a key regulator of cerebellar neural networks. In this review, we focus on physiological characteristics of GABAergic transmission from PCs. First, we introduce monoaminergic modulation of GABAergic transmission at synapses of PC-Lugaro/globular cell as well as PC-large glutamatergic DCN neuron, and a Lugaro/globular cell-incorporated microcircuit. Second, we review the physiological roles of perineuronal nets (PNNs), which are organized components of the extracellular matrix and enwrap the cell bodies and proximal processes, in GABA release from PCs to large glutamatergic DCN neurons and in cerebellar motor learning. Recent evidence suggests that alterations in PNN density in the DCN can regulate cerebellar functions.

Single-pulse stimulation of cerebellar nuclei stops epileptic thalamic activity

BackgroundEpileptic (absence) seizures in the cerebral cortex can be stopped by pharmacological and optogenetic stimulation of the cerebellar nuclei (CN) neurons that innervate the thalamus. However, it is unclear how such stimulation can modify underlying thalamo-cortical oscillations. HypothesisHere we tested whether rhythmic synchronized thalamo-cortical activity during absence seizures can be desynchronized by single-pulse optogenetic stimulation of CN neurons to stop seizure activity. MethodsWe performed simultaneous thalamic single-cell and electrocorticographical recordings in awake tottering mice, a genetic model of absence epilepsy, to investigate the rhythmicity and synchronicity. Furthermore, we tested interictally the impact of single-pulse optogenetic CN stimulation on thalamic and cortical recordings. ResultsWe show that thalamic firing is highly rhythmic and synchronized with cortical spike-and-wave discharges during absence seizures and that this phase-locked activity can be desynchronized upon single-pulse optogenetic stimulation of CN neurons. Notably, this stimulation of CN neurons was more effective in stopping seizures than direct, focal stimulation of groups of afferents innervating the thalamus. During interictal periods, CN stimulation evoked reliable but heterogeneous responses in thalamic cells in that they could show an increase or decrease in firing rate at various latencies, bi-phasic responses with an initial excitatory and subsequent inhibitory response, or no response at all. ConclusionOur data indicate that stimulation of CN neurons and their fibers in thalamus evokes differential effects in its downstream pathways and desynchronizes phase-locked thalamic neuronal firing during seizures, revealing a neurobiological mechanism that may explain how cerebellar stimulation can stop seizures.

A model of on/off transitions in neurons of the deep cerebellar nuclei: deciphering the underlying ionic mechanisms

The neurons of the deep cerebellar nuclei (DCNn) represent the main functional link between the cerebellar cortex and the rest of the central nervous system. Therefore, understanding the electrophysiological properties of DCNn is of fundamental importance to understand the overall functioning of the cerebellum. Experimental data suggest that DCNn can reversibly switch between two states: the firing of spikes (F state) and a stable depolarized state (SD state). We introduce a new biophysical model of the DCNn membrane electro-responsiveness to investigate how the interplay between the documented conductances identified in DCNn give rise to these states. In the model, the F state emerges as an isola of limit cycles, i.e. a closed loop of periodic solutions disconnected from the branch of SD fixed points. This bifurcation structure endows the model with the ability to reproduce the text{F}to text{SD} transition triggered by hyperpolarizing current pulses. The model also reproduces the text{F}to text{SD} transition induced by blocking Ca currents and ascribes this transition to the blocking of the high-threshold Ca current. The model suggests that intracellular current injections can trigger fully reversible text{F}leftrightarrow text{SD} transitions. Investigation of low-dimension reduced models suggests that the voltage-dependent Na current is prominent for these dynamical features. Finally, simulations of the model suggest that physiological synaptic inputs may trigger text{F}leftrightarrow text{SD} transitions. These transitions could explain the puzzling observation of positively correlated activities of connected Purkinje cells and DCNn despite the former inhibit the latter.

Influence of various temporal recoding on pavlovian eyeblink conditioning in the cerebellum

We consider the Pavlovian eyeblink conditioning (EBC) via repeated presentation of paired conditioned stimulus (tone) and unconditioned stimulus (US; airpuff). In an effective cerebellar ring network, we change the connection probability from Golgi to granule (GR) cells, and make a dynamical classification of various firing patterns of the GR cells. Individual GR cells are thus found to show various well- and ill-matched firing patterns relative to the US timing signal. Then, these variously-recoded signals are fed into the Purkinje cells (PCs) through the parallel-fibers (PFs). Based on such unique dynamical classification of various firing patterns, we make intensive investigations on the influence of various temporal recoding (i.e., firing patterns) of the GR cells on the synaptic plasticity of the PF-PC synapses and the subsequent learning process for the EBC. We first note that the variously-recoded PF signals are effectively depressed by the (error-teaching) instructor climbing-fiber (CF) signals from the inferior olive neuron. In the case of well-matched PF signals, they are strongly depressed through strong long-term depression (LTD) by the instructor CF signals due to good association between the in-phase PF and the instructor CF signals. On the other hand, practically no LTD occurs for the ill-matched PF signals because most of them have no association with the instructor CF signals. This kind of "effective" depression at the PF-PC synapses coordinates firings of PCs effectively, which then makes effective inhibitory coordination on the cerebellar nucleus neuron [which elicits conditioned response (CR; eyeblink)]. When the learning trial passes a threshold, acquisition of CR begins. In this case, the timing degree of CR becomes good due to presence of the ill-matched firing group which plays a role of protection barrier for the timing. With further increase in the number of trials, strength of CR (corresponding to the amplitude of eyelid closure) increases due to strong LTD in the well-matched firing group, while its timing degree decreases. In this way, the well- and the ill-matched firing groups play their own roles for the strength and the timing of CR, respectively. Thus, with increasing the number of learning trials, the (overall) learning efficiency degree (taking into consideration both timing and strength of CR) for the CR is increased, and eventually it becomes saturated. Finally, we also discuss dependence of the variety degree for firing patterns of the GR cells and the saturated learning efficiency degree of the CR on and their relations.

Abnormal cerebellar function and tremor in a mouse model for non-manifesting partially penetrant dystonia type 6.

Loss-of-function mutations in the Thap1 gene cause partially penetrant dystonia type 6 (DYT6). Some non-manifesting DYT6 mutation carriers have tremor andabnormal cerebello-thalamo-cortical signalling. We show that Thap1 heterozygote mice have action tremor, a reduction in cerebellar neuron number, andabnormal electrophysiological signals in the remaining neurons. These results underscore the importance of Thap1 levels for cerebellar function. These results uncover how cerebellar abnormalities contribute to different dystonia-associated motor symptoms. Loss-of-function mutations in the Thanatos-associated domain-containing apoptosis-associated protein 1 (THAP1) gene cause partially penetrant autosomal dominant dystonia type 6 (DYT6). However, the neural abnormalities that promote the resultant motor dysfunctions remain elusive. Studies in humans show that some non-manifesting DYT6 carriers have altered cerebello-thalamo-cortical function with subtle but reproducible tremor. Here, we uncover that Thap1 heterozygote mice have action tremor that rises above normal baseline values even though they do not exhibit overt dystonia-like twisting behaviour. At the neural circuit level, we show using in vivo recordings in awake Thap1+/- mice that Purkinje cells have abnormal firing patterns and that cerebellar nuclei neurons, which connect the cerebellum to the thalamus, fire at a lower frequency. Although the Thap1+/- mice have fewer Purkinje cells and cerebellar nuclei neurons, the number of long-range excitatory outflow projection neurons is unaltered. The preservation of interregional connectivity suggests that abnormal neural function rather than neuron loss instigates the network dysfunction and the tremor in Thap1+/- mice. Accordingly, we report an inverse correlation between the average firing rate of cerebellar nuclei neurons and tremor power. Our data show that cerebellar circuitry is vulnerable to Thap1 mutations and that cerebellar dysfunction may be a primary cause of tremor in non-manifesting DYT6 carriers and a trigger for the abnormal postures in manifesting patients.

Возможные механизмы взаимозависимого участия базальных ганглиев и мозжечка в функционировании двигательных и сенсорных систем

The article describes a mechanism of functioning of the neural network that includes the neocortex, basal ganglia, cerebellum, and thalamus. This mechanism explains the role of the cerebellum in the performance of tasks previously associated with the basal ganglia and neocortex. Rules for long-term modifications of the efficacy of synaptic inputs to cerebellar neurons and spiny cells of the striatum, an input nucleus of the basal ganglia, have been formulated. These rules differ from those generally accepted. It follows from the proposed modulation rules that the activation of D1 receptors promotes the induction of LTP in synapses formed by mossy fibers carrying sensory information to cerebellar granule cells as well as neurons of the deep cerebellar nuclei (providing that they are inhibited by Purkinje cells). This results in the enhanced disynaptic (through the thalamic nuclei) excitation of the cerebellum target cells in the neocortex, striatum and dopaminergic structures. An increase in thalamo-striatal excitation, as well as the activation of D1 receptors on striatonigral cells and D2 receptors on striatopallidal cells, promotes the induction of LTP and LTD of the efficacy of cortical inputs to these neurons, respectively. As a consequence, synergistic disinhibition via the direct and indirect pathways through the basal ganglia is facilitated for those thalamic cells and associated neocortical neurons that were initially strongly activated by sensory stimuli. Simultaneously, the inhibition of the activity of remaining thalamic and neocortical neurons by the basal ganglia must be increased. The mechanism of functioning is similar for diverse the neuronal networks, each of which includes topographically connected areas of the neocortex, thalamus and basal ganglia. Since cerebellar granule cells as well as dopaminergic neurons respond to a conditioned sensory signal and reinforcing stimulus, it follows from the proposed mechanism that the cerebellum, together with the basal ganglia, may form the patterns of neuronal activity in neocortical areas determining sensory perception and choice of action.

Endocannabinoids regulate cerebellar GABAergic transmission in a synapse type‐dependent manner

Endocannabinoids (eCBs) act as ubiquitous modulators of synaptic transmission via the activation of cannabinoid receptors (CBRs). Cerebellar Purkinje cells (PCs) make strong inhibitory synaptic contacts not only with neurons in the deep cerebellar nuclei (DCN) but also with Lugaro cells and globular cells, whose cell bodies are located underneath the PC layer. However, little is known about the modulatory actions of eCBs on GABA release from PC axon terminals. Here, we examined the effects of eCBs on the GABAergic transmission at PC-globular cell synapses and PC-large DCN neuron synapses electrophysiologically using mouse cerebellar slices. We showed that the types 1 and 2 CBR agonist WIN55212 did not affect either spontaneous or miniature inhibitory postsynaptic currents (IPSCs) in globular cells under control conditions and in a state of enhanced synaptic activity. By contrast, another Gi/o protein-coupled receptor agonist, baclofen, significantly reduced the miniature IPSC frequency in globular cells. WIN55212 had no effects on IPSCs in large DCN neurons. A type 2 CBR agonist, HU308, also had no effects on IPSCs in either globular cells or large DCN neurons. Moreover, the PCs' target neurons did not elicit depolarization-induced suppression of inhibition. These results suggest the lack of a functional role of CBRs at PCs' axon terminals. This is in sharp contrast to the fact that PCs receive abundant excitatory and inhibitory inputs that are under eCB-mediated presynaptic inhibitory modulation. The actions of eCBs are selective to distinct synapses and possibly contribute to information processes and rigorous signal transmission in the cerebellum.

Preterm Birth Impedes Structural and Functional Development of Cerebellar Purkinje Cells in the Developing Baboon Cerebellum.

Human cerebellar development occurs late in gestation and is hindered by preterm birth. The fetal development of Purkinje cells, the primary output cells of the cerebellar cortex, is crucial for the structure and function of the cerebellum. However, morphological and electrophysiological features in Purkinje cells at different gestational ages, and the effects of neonatal intensive care unit (NICU) experience on cerebellar development are unexplored. Utilizing the non-human primate baboon cerebellum, we investigated Purkinje cell development during the last trimester of pregnancy and the effect of NICU experience following premature birth on developmental features of Purkinje cells. Immunostaining and whole-cell patch clamp recordings of Purkinje cells in the baboon cerebellum at different gestational ages revealed that molecular layer width, driven by Purkinje dendrite extension, drastically increased and refinement of action potential waveform properties occurred throughout the last trimester of pregnancy. Preterm birth followed by NICU experience for 2 weeks impeded development of Purkinje cells, including action potential waveform properties, synaptic input, and dendrite extension compared with age-matched controls. In addition, these alterations impact Purkinje cell output, reducing the spontaneous firing frequency in deep cerebellar nucleus (DCN) neurons. Taken together, the primate cerebellum undergoes developmental refinements during late gestation, and NICU experience following extreme preterm birth influences morphological and physiological features in the cerebellum that can lead to functional deficits.

Population coding in the cerebellum: a machine learning perspective.

The cere resembles a feedforward, three-layer network of neurons in which the "hidden layer" consists of Purkinje cells (P-cells) and the output layer consists of deep cerebellar nucleus (DCN) neurons. In this analogy, the output of each DCN neuron is a prediction that is compared with the actual observation, resulting in an error signal that originates in the inferior olive. Efficient learning requires that the error signal reach the DCN neurons, as well as the P-cells that project onto them. However, this basic rule of learning is violated in the cerebellum: the olivary projections to the DCN are weak, particularly in adulthood. Instead, an extraordinarily strong signal is sent from the olive to the P-cells, producing complex spikes. Curiously, P-cells are grouped into small populations that converge onto single DCN neurons. Why are the P-cells organized in this way, and what is the membership criterion of each population? Here, I apply elementary mathematics from machine learning and consider the fact that P-cells that form a population exhibit a special property: they can synchronize their complex spikes, which in turn suppress activity of DCN neuron they project to. Thus complex spikes cannot only act as a teaching signal for a P-cell, but through complex spike synchrony, a P-cell population may act as a surrogate teacher for the DCN neuron that produced the erroneous output. It appears that grouping of P-cells into small populations that share a preference for error satisfies a critical requirement of efficient learning: providing error information to the output layer neuron (DCN) that was responsible for the error, as well as the hidden layer neurons (P-cells) that contributed to it. This population coding may account for several remarkable features of behavior during learning, including multiple timescales, protection from erasure, and spontaneous recovery of memory.