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The investigation of the dynamics of Purkinje cell (PC) activity is crucial to unravel the role of the cerebellum in motor control, learning and cognitive processes. Within the cerebellar cortex (CC), these neurons receive all the incoming sensory and motor information, transform it and generate the entire cerebellar output. The relatively homogenous and repetitive structure of the CC, common to all vertebrate species, suggests a single computation mechanism shared across all PCs. While PC models have been developed since the 70's, a comprehensive review of contemporary models is currently lacking. Here, we provide an overview of PC models, ranging from the ones focused on single cell intracellular PC dynamics, through complex models which include synaptic and extrasynaptic inputs. We review how PC models can reproduce physiological activity of the neuron, including firing patterns, current and multistable dynamics, plateau potentials, calcium signaling, intrinsic and synaptic plasticity and input/output computations. We consider models focusing both on somatic and on dendritic computations. Our review provides a critical performance analysis of PC models with respect to known physiological data. We expect our synthesis to be useful in guiding future development of computational models that capture real-life PC dynamics in the context of cerebellar computations.

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In classical cerebellar learning, Purkinje cells (PkCs) associate climbing fiber (CF) error signals with predictive granule cells (GrCs) that were active just prior (∼150 ms). The cerebellum also contributes to behaviors characterized by longer timescales. To investigate how GrC-CF-PkC circuits might learn seconds-long predictions, we imaged simultaneous GrC-CF activity over days of forelimb operant conditioning for delayed water reward. As mice learned reward timing, numerous GrCs developed anticipatory activity ramping at different rates until reward delivery, followed by widespread time-locked CF spiking. Relearning longer delays further lengthened GrC activations. We computed CF-dependent GrC→PkC plasticity rules, demonstrating that reward-evoked CF spikes sufficed to grade many GrC synapses by anticipatory timing. We predicted and confirmed that PkCs could thereby continuously ramp across seconds-long intervals from movement to reward. Learning thus leads to new GrC temporal bases linking predictors to remote CF reward signals-a strategy well suited for learning to track the long intervals common in cognitive domains.

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Olov Oscarsson's review on the functional organization of spinocerebellar paths is a prime demonstration of the great skills and huge knowledge base of the electrophysiologists of his era working on communication systems in the brain. Oscarsson describes and characterizes in detail no less than ten different communication lines between the spinal cord and the cerebellum. As such, his work proved to be a highly fertile basis for ongoing physiological and anatomical research. However, even after 50 years of continuing cerebellar research, many questions are still open and even care must be taken that the differentiation in spinocerebellar paths, so carefully demonstrated by Oscarsson, is not lost in present-day research.

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Recent studies have shown that the cerebellum and the basal ganglia are interconnected at subcortical levels. However, a subcortical basal ganglia connection to the inferior olive (IO), being the source of the olivocerebellar climbing fiber system, is not known. We have used classical tracing with CTb, retrograde transneuronal infection with wildtype rabies virus, conditional tracing with genetically modified rabies virus, and examination of material made available by the Allen Brain Institute, to study potential basal ganglia connections to the inferior olive in rats and mice. We show in both species that parvalbumin-positive, and therefore GABAergic, neurons in the entopeduncular nucleus, representing the rodent equivalent of the internal part of the globus pallidus, innervate a group of cells that surrounds the fasciculus retroflexus and that are collectively known as the area parafascicularis prerubralis. As these neurons supply a direct excitatory input to large parts of the inferior olivary complex, we propose that the entopeduncular nucleus, as a main output station of the basal ganglia, provides an inhibitory influence on olivary excitability. As such, this connection may influence olivary involvement in cerebellar learning and/or could be involved in transmission of reward properties that have recently been established for olivocerebellar signaling.

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Crocodilians (alligators, crocodiles, and gharials) are the closet living relatives to birds and, as such, represent a key clade to understand the evolution of the avian brain. However, many aspects of crocodilian neurobiology remain unknown. In this paper, we address an important knowledge gap as there are no published studies of cerebellar connections in any crocodilian species. We used injections of retrograde tracers into the cerebellum of the American alligator (Alligator mississippiensis) to describe for the first time the origin of climbing and mossy fiber inputs. We found that inputs to the cerebellum in the American alligator are similar to those of other nonavian reptiles and birds. Retrograde labeled cells were found in the spinal cord, inferior olive, reticular formation, vestibular and cerebellar nuclei, as well as in nucleus ruber and surrounding tegmentum. Additionally, we found no retrogradely labeled cells in the anterior rhombencephalon which suggest that, like other nonavian reptiles, crocodilians may lack pontine nuclei. Similar to birds and other nonavian reptiles, we found inputs to the cerebellum from the pretectal nucleus lentiformis mesencephali. Additionally, we found retrogradely labeled neurons in two nuclei in the pretectum: the nucleus circularis and the interstitial nucleus of the posterior commissure. These pretectal projections have not been described in any other nonavian reptile to date, but they do resemble projections from the nucleus spiriformis medialis of birds. Our results show that many inputs to the cerebellum are highly conserved among sauropsids and that extensive pretectal inputs to the cerebellum are not exclusive to the avian brain. Finally, we suggest that the pontine nuclei of birds are an evolutionary novelty that may have evolved after the last common ancestor between birds and crocodilians, and may represent an intriguing case of convergent evolution with mammals.

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The olivocerebellar circuitry is important to convey both motor and non-motor information from the inferior olive (IO) to the cerebellar cortex. Several methods are currently established to observe the dynamics of the olivocerebellar circuitry, largely by recording the complex spike activity of cerebellar Purkinje cells; however, these techniques can be technically challenging to apply in vivo and are not always possible in freely behaving animals. Here, we developed a method for the direct, accessible, and robust recording of climbing fiber (CF) Ca2+ signals based on optical fiber photometry. We first verified the IO stereotactic coordinates and the organization of contralateral CF projections using tracing techniques and then injected Ca2+ indicators optimized for axonal labeling, followed by optical fiber-based recordings. We demonstrated this method by recording CF Ca2+ signals in lobule IV/V of the cerebellar vermis, comparing the resulting signals in freely moving mice. We found various movement-evoked CF Ca2+ signals, but the onset of exploratory-like behaviors, including rearing and tiptoe standing, was highly synchronous with recorded CF activity. Thus, we have successfully established a robust and accessible method to record the CF Ca2+ signals in freely behaving mice, which will extend the toolbox for studying cerebellar function and related disorders.

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Essential tremor (ET) represents one of the commonest movement disorder worldwide and is the most common tremor disorder. ET manifests with various combinations of motor and nonmotor symptoms. The clinical hallmark is a kinetic tremor of upper limbs. Historically, the pathogenesis of ET has been based on the hypothesis of an overactivity of the inferior olive (inferior olive hypothesis: IOH) where the inferior olive would act as the central pace-maker of ET, resulting in impaired electrophysiological discharges of the olivo-cerebellar tract. The absence of structural alterations in post-mortem studies of the inferior olive is a striking argument against the IOH. Furthermore, neuroimaging studies point towards the implication of the cerebello-thalamo-cerebral pathway rather than the IO, and the harmaline model which has been considered as an animal model of ET presents important weaknesses. By contrast, a series of experiments by Louis et al. have provided convincing evidence of impaired wiring of the Purkinje cell microcircuitry and progressive neurodegeneration of the cerebellar cortex. The Purkinje neuron appears as the primary culprit (Purkinjopathy). The cerebellar cortex hypothesis (CCH) has solid neuropathological signatures, unlike the purely physiological IOH. Rather than a dysregulatory electrophysiological disorder suggested by IOH, ET is a clinical-pathological entity similar to late onset neurodegenerative disorders such as Parkinson's disease or Alzheimer's disease. The CCH emphasizes the need to develop novel therapeutic strategies in order to maintain or promote the cerebellar reserve. The modern reconceptualization of ET in a genuine cerebellar disorder is cleaning the IOH to the light of histopathological studies. ET falls in the large basket of the neurodegenerative diseases and we have entered into a novel formulation of the disease pathogenesis with direct impacts on future therapies.

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Essential tremor (ET) is a highly prevalent neurologic disease and is the most common of the many tremor disorders. ET is a progressive condition with marked clinical heterogeneity, associated with a spectrum of both motor and non-motor features. However, its disease mechanisms remain poorly understood. Much debate has centered on whether ET should be considered a degenerative disorder, with underlying pathological changes in brain causing progressive disease manifestations, or an electric disorder, with overactivity of intrinsically oscillatory motor networks that occur without underlying structural brain abnormalities. Converging data from clinical, neuroimaging and pathological studies in ET now provide considerable evidence for the neurodegenerative hypothesis. A major turning point in this debate is that rigorous tissue-based studies have recently identified a series of structural changes in the ET cerebellum. Most of these pathological changes are centered on the Purkinje cell and connected neuronal populations, which can result in partial loss of Purkinje cells and circuitry reorganizations that would disturb cerebellar function. There is significant overlap in clinical and pathological features of ET with other disorders of cerebellar degeneration, and an increased risk of developing other degenerative diseases in ET. The combined implication of these studies is that ET could be degenerative. The evidence in support of the degenerative hypothesis is presented.

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Coordination of bilateral movements is essential for a large variety of animal behaviors. The olivocerebellar system is critical for the control of movement, but its role in bilateral coordination has yet to be elucidated. Here, we examined whether Purkinje cells encode and influence synchronicity of left-right whisker movements. We found that complex spike activity is correlated with a prominent left-right symmetry of spontaneous whisker movements within parts, but not all, of Crus1 and Crus2. Optogenetic stimulation of climbing fibers in the areas with high and low correlations resulted in symmetric and asymmetric whisker movements, respectively. Moreover, when simple spike frequency prior to the complex spike was higher, the complex spike-related symmetric whisker protractions were larger. This finding alludes to a role for rebound activity in the cerebellar nuclei, which indeed turned out to be enhanced during symmetric protractions. Tracer injections suggest that regions associated with symmetric whisker movements are anatomically connected to the contralateral cerebellar hemisphere. Together, these data point toward the existence of modules on both sides of the cerebellar cortex that can differentially promote or reduce the symmetry of left and right movements in a context-dependent fashion.

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The climbing fiber input to the cerebellum conveys instructive signals that can induce synaptic plasticity and learning by triggering complex spikes accompanied by large calcium transients in Purkinje cells. In the cerebellar flocculus, which supports oculomotor learning, complex spikes are driven by image motion on the retina, which could indicate an oculomotor error. In the same neurons, complex spikes also can be driven by nonvisual signals. It has been shown that the calcium transients accompanying each complex spike can vary in amplitude, even within a given cell, therefore, we compared the calcium responses associated with the visual and nonvisual inputs to floccular Purkinje cells. The calcium indicator GCaMP6f was selectively expressed in Purkinje cells, and fiber photometry was used to record the calcium responses from a population of Purkinje cells in the flocculus of awake behaving mice. During visual (optokinetic) stimuli and pairing of vestibular and visual stimuli, the calcium level increased during contraversive retinal image motion. During performance of the vestibulo-ocular reflex in the dark, calcium increased during contraversive head rotation and the associated ipsiverse eye movements. The amplitude of this nonvisual calcium response was comparable to that during conditions with retinal image motion present that induce oculomotor learning. Thus, population calcium responses of Purkinje cells in the cerebellar flocculus to visual and nonvisual input are similar to what has been reported previously for complex spikes, suggesting that multimodal instructive signals control the synaptic plasticity supporting oculomotor learning.NEW & NOTEWORTHY It was long known that the climbing fiber input to Purkinje cells in the cerebellar flocculus conveys visual feedback about the accuracy of image-stabilizing oculomotor reflexes. More recently, the same climbing fibers were reported to carry nonvisual signals. Here, we report that both visual and nonvisual inputs can elicit robust calcium responses in the Purkinje cells, suggesting that the instructive signals guiding oculomotor plasticity are multimodal.

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Neuroligin is a postsynaptic cell-adhesion molecule that is involved in synapse formation and maturation by interacting with presynaptic neurexin. Mutations in neuroligin genes, including the arginine to cystein substitution at the 451st amino acid residue (R451C) of neuroligin-3 (NLGN3), have been identified in patients with autism spectrum disorder (ASD). Functional magnetic resonance imaging and examination of post-mortem brain in ASD patients implicate alteration of cerebellar morphology and Purkinje cell (PC) loss. In the present study, we examined possible association between the R451C mutation in NLGN3 and synaptic development and function in the mouse cerebellum. In NLGN3-R451C mutant mice, the expression of NLGN3 protein in the cerebellum was reduced to about 10% of the level of wild-type mice. Elimination of redundant climbing fiber (CF) to PC synapses was impaired from postnatal day 10-15 (P10-15) in NLGN3-R451C mutant mice, but majority of PCs became mono-innervated as in wild-type mice after P16. In NLGN3-R451C mutant mice, selective strengthening of a single CF relative to the other CFs in each PC was impaired from P16, which persisted into juvenile stage. Furthermore, the inhibition to excitation (I/E) balance of synaptic inputs to PCs was elevated, and calcium transients in the soma induced by strong and weak CF inputs were reduced in NLGN3-R451C mutant mice. These results suggest that a single point mutation in NLGN3 significantly influences the synapse development and refinement in cerebellar circuitry, which might be related to the pathogenesis of ASD.

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In motor neuroscience, state changes are hypothesized to time-lock neural assemblies coordinating complex movements, but evidence for this remains slender. We tested whether a discrete change from more autonomous to coherent spiking underlies skilled movement by imaging cerebellar Purkinje neuron complex spikes in mice making targeted forelimb-reaches. As mice learned the task, millimeter-scale spatiotemporally coherent spiking emerged ipsilateral to the reaching forelimb, and consistent neural synchronization became predictive of kinematic stereotypy. Before reach onset, spiking switched from more disordered to internally time-locked concerted spiking and silence. Optogenetic manipulations of cerebellar feedback to the inferior olive bi-directionally modulated neural synchronization and reaching direction. A simple model explained the reorganization of spiking during reaching as reflecting a discrete bifurcation in olivary network dynamics. These findings argue that to prepare learned movements, olivo-cerebellar circuits enter a self-regulated, synchronized state promoting motor coordination. State changes facilitating behavioral transitions may generalize across neural systems.

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The stromal interaction molecule 1 (STIM1) is an ER-Ca2+ sensor and an essential component of ER-Ca2+ store operated Ca2+ entry. Loss of STIM1 affects metabotropic glutamate receptor 1 (mGluR1)-mediated synaptic transmission, neuronal Ca2+ homeostasis, and intrinsic plasticity in Purkinje neurons (PNs). Long-term changes of intracellular Ca2+ signaling in PNs led to neurodegenerative conditions, as evident in individuals with mutations of the ER-Ca2+ channel, the inositol 1,4,5-triphosphate receptor. Here, we asked whether changes in such intrinsic neuronal properties, because of loss of STIM1, have an age-dependent impact on PNs. Consequently, we analyzed mRNA expression profiles and cerebellar morphology in PN-specific STIM1 KO mice (STIM1PKO ) of both sexes across ages. Our study identified a requirement for STIM1-mediated Ca2+ signaling in maintaining the expression of genes belonging to key biological networks of synaptic function and neurite development among others. Gene expression changes correlated with altered patterns of dendritic morphology and greater innervation of PN dendrites by climbing fibers, in aging STIM1PKO mice. Together, our data identify STIM1 as an important regulator of Ca2+ homeostasis and neuronal excitability in turn required for maintaining the optimal transcriptional profile of PNs with age. Our findings are significant in the context of understanding how dysregulated calcium signals impact cellular mechanisms in multiple neurodegenerative disorders.SIGNIFICANCE STATEMENT In Purkinje neurons (PNs), the stromal interaction molecule 1 (STIM1) is required for mGluR1-dependent synaptic transmission, refilling of ER Ca2+ stores, regulation of spike frequency, and cerebellar memory consolidation. Here, we provide evidence for a novel role of STIM1 in maintaining the gene expression profile and optimal synaptic connectivity of PNs. Expression of genes related to neurite development and synaptic organization networks is altered in PNs with persistent loss of STIM1. In agreement with these findings the dendritic morphology of PNs and climbing fiber innervations on PNs also undergo significant changes with age. These findings identify a new role for dysregulated intracellular calcium signaling in neurodegenerative disorders and provide novel therapeutic insights.

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Septins are cytoskeletal proteins that can assemble to form heteromeric filamentous complexes and regulate a range of membrane-associated cellular functions. SEPT7, a member of the septin family, functions as a negative regulator of the plasma membrane-localized store-operated Ca2+ entry (SOCE) channel, Orai in Drosophila neurons, and in human neural progenitor cells. Knockdown of STIM, a Ca2+ sensor in the endoplasmic reticulum (ER) and an integral component of SOCE, leads to flight deficits in Drosophila that can be rescued by partial loss of SEPT7 in neurons. Here, we tested the effect of reducing and removing SEPT7 in mouse Purkinje neurons (PNs) with the loss of STIM1. Mice with the complete knockout of STIM1 in PNs exhibit several age-dependent changes. These include altered gene expression in PNs, which correlates with increased synapses between climbing fiber (CF) axons and Purkinje neuron (PN) dendrites and a reduced ability to learn a motor coordination task. Removal of either one or two copies of the SEPT7 gene in STIM1 KO PNs restored the expression of a subset of genes, including several in the category of neuron projection development. Importantly, the rescue of gene expression in these animals is accompanied by normal CF-PN innervation and an improved ability to learn a motor coordination task in aging mice. Thus, the loss of SEPT7 in PNs further modulates cerebellar circuit function in STIM1 KO animals. Our findings are relevant in the context of identifying SEPT7 as a putative therapeutic target for various neurodegenerative diseases caused by reduced intracellular Ca2+ signaling.

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The cerebellum forms regular neural network structures consisting of a few major types of neurons, such as Purkinje cells, granule cells, and molecular layer interneurons, and receives two major inputs from climbing fibers and mossy fibers. Its regular structures consist of three well-defined layers, with each type of neuron designated to a specific location and forming specific synaptic connections. During the first few weeks of postnatal development in rodents, the cerebellum goes through dynamic changes via proliferation, migration, differentiation, synaptogenesis, and maturation, to create such a network structure. The development of this organized network structure presumably relies on the communication between developing elements in the network, including not only individual neurons, but also their dendrites, axons, and synapses. Therefore, it is reasonable that extracellular signaling via synaptic transmission, secreted molecules, and cell adhesion molecules, plays important roles in cerebellar network development. Although it is not yet clear as to how overall cerebellar development is orchestrated, there is indeed accumulating lines of evidence that extracellular signaling acts toward the development of individual elements in the cerebellar networks. In this article, we introduce what we have learned from many studies regarding the extracellular signaling required for cerebellar network development, including our recent study suggesting the importance of unbiased synaptic inputs from parallel fibers.

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Spinocerebellar ataxia type 23 (SCA23) is a late-onset neurodegenerative disorder characterized by slowly progressive gait and limb ataxia, for which there is no therapy available. It is caused by pathogenic variants in PDYN, which encodes prodynorphin (PDYN). PDYN is processed into the opioid peptides α-neoendorphin and dynorphins (Dyn) A and B; inhibitory neurotransmitters that function in pain signaling, stress-induced responses and addiction. Variants causing SCA23 mostly affect Dyn A, leading to loss of secondary structure and increased peptide stability. PDYNR212W mice express human PDYN containing the SCA23 variant p.R212W. These mice show progressive motor deficits from 3 months of age, climbing fiber (CF) deficits from 3 months of age, and Purkinje cell (PC) loss from 12 months of age. A mouse model for SCA1 showed similar CF deficits, and a recent study found additional developmental abnormalities, namely increased GABAergic interneuron connectivity and non-cell autonomous disruption of PC function. As SCA23 mice show a similar pathology to SCA1 mice in adulthood, we hypothesized that SCA23 may also follow SCA1 pathology during development. Examining PDYNR212W cerebella during development, we uncovered developmental deficits from 2 weeks of age, namely a reduced number of GABAergic synapses on PC soma, possibly leading to the observed delay in early phase CF elimination between 2 and 3 weeks of age. Furthermore, CFs did not reach terminal height, leaving proximal PC dendrites open to be occupied by parallel fibers (PFs). The observed increase in vGlut1 protein-a marker for PF-PC synapses-indicates that PFs indeed take over CF territory and have increased connectivity with PCs. Additionally, we detected altered expression of several critical Ca2+ channel subunits, potentially contributing to altered Ca2+ transients in PDYNR212W cerebella. These findings indicate that developmental abnormalities contribute to the SCA23 pathology and uncover a developmental role for PDYN in the cerebellum.

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Neurons in the inferior olivary nuclei (IO neurons) send climbing fibers to Purkinje cells to elicit functions of the cerebellum. IO neurons and Purkinje cells are derived from neural progenitors expressing the proneural gene ptf1a In this study, we found that the homeobox gene gsx2 was co-expressed with ptf1a in IO progenitors in zebrafish. Both gsx2 and ptf1a zebrafish mutants showed a strong reduction or loss of IO neurons. The expression of ptf1a was not affected in gsx2 mutants, and vice versa. In IO progenitors, the ptf1a mutation increased apoptosis whereas the gsx2 mutation did not, suggesting that ptf1a and gsx2 are regulated independently of each other and have distinct roles. The fibroblast growth factors (Fgf) 3 and 8a, and retinoic acid signals negatively and positively, respectively, regulated gsx2 expression and thereby the development of IO neurons. mafba and Hox genes are at least partly involved in the Fgf- and retinoic acid-dependent regulation of IO neuronal development. Our results indicate that gsx2 mediates the rostro-caudal positional signals to specify the identity of IO neurons from ptf1a-expressing neural progenitors.

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Minimizing errors is an important aspect of learning. However, it is not enough merely to record if an error occurred. For efficient learning, information about the magnitude of errors is critical. Did my tennis swing completely miss the target or did I hit the ball, but not quite in the sweet spot? How can neurons - which have traditionally been thought of as binary units - signal the magnitude of an error? Here I review evidence that eyeblink conditioning - a basic form of motor learning - depends on graded signals from the inferior olive which guides plasticity in the cerebellum and ultimately tunes behavior. Specifically, evidence suggests that: (1) Error signals are conveyed to the cerebellum via the inferior olive; (2) Signals from the inferior olive are graded; (3) The strength of the olivary signal affects learning; (4) Cerebellar feedback influences the strength of the olivary signal. I end the review by exploring how graded error signals might explain some behavioral learning phenomena.

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During postnatal development, cerebellar climbing fibers alter their innervation strengths onto supernumerary Purkinje cell targets, generating a one-to-few connectivity pattern in adulthood. To get insight about the processes responsible for this remapping, we reconstructed serial electron microscopy datasets from mice during the first postnatal week. Between days 3 and 7, individual climbing fibers selectively add many synapses onto a subset of Purkinje targets in a positive-feedback manner, without pruning synapses from other targets. Active zone sizes of synapses associated with powerful versus weak inputs are indistinguishable. Changes in synapse number are thus the predominant form of early developmental plasticity. Finally, the numbers of climbing fibers and Purkinje cells in a local region nearly match. Initial over-innervation of Purkinje cells by climbing fibers is therefore economical: the number of axons entering a region is enough to assure that each ultimately retains a postsynaptic target and that none branched there in vain.

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The postnatal development of cerebellar climbing fiber (CF) to Purkinje neuron (PN) synapses is characterized by a substantial pruning during the first 3 weeks after birth, switching from multiple- to single-CF innervation. Previous studies suggested that CF maturation is governed by bidirectional changes of synaptic plasticity. The strengthening of surviving "winner" CFs, which translocate from the PN soma to the dendrite, is thought to be guided by long-term potentiation (LTP), while weakening of to-be-eliminated "loser" CFs, which remain on the soma, was proposed to be due to long-term depression (LTD). However, there are conflicting results from previous studies, whether or not strengthening of winner and weakening of loser CFs during postnatal development is accompanied by changes in short-term plasticity and, thus, whether pre- or postsynaptic forms of LTD and LTP are operational. We, therefore, analyzed the developmental profile of paired-pulse depression (PPD) in "weak" and "strong" CFs in 3-21-day old Igsf9-eGFP mice, which allow visual identification of GFP-labeled CFs. We found that in 3-8-day old mice strong CFs are marked by a stronger PPD compared to weak CFs. Surprisingly, PPD of strong CFs eases during maturation, while PPD in weak CFs remains unchanged. This easing of PPD is neither due to changes in presynaptic influx-release coupling nor to an increased saturation of postsynaptic receptors. Thus, our results imply that synaptic contacts of CFs show distinct features of PPD depending on their affiliation to winner or loser CFs and depending on their somatic or dendritic location.