Climbing Fiber Input Research Articles

A Patterned Architecture of Monoaminergic Afferents in the Cerebellar Cortex: Noradrenergic and Serotonergic Fibre Distributions within Lobules and Parasagittal Zones

The geometry of the glutamatergic mossy-parallel fibre and climbing fibre inputs to cerebellar cortical Purkinje cells has powerfully influenced thinking about cerebellar functions. The compartmentation of the cerebellum into parasagittal zones, identifiable in olivo-cortico-nuclear projections, and the trajectories of the parallel fibres, transverse to these zones and following the long axes of the cortical folia, are particularly important. Two monoaminergic afferent systems, the serotonergic and noradrenergic, are major inputs to the cerebellar cortex but their architecture and relationship with the cortical geometry are poorly understood. Immunohistochemistry for the serotonin transporter (SERT) and for the noradrenaline transporter (NET) revealed strong anisotropy of these afferent fibres in the molecular layer of rat cerebellar cortex. Individual serotonergic fibres travel predominantly medial–lateral, along the long axes of the cortical folia, similar to parallel fibres and Zebrin II immunohistochemistry revealed that they can influence multiple zones. In contrast, individual noradrenergic fibres run predominantly parasagittally with rostral-caudal extents significantly longer than their medial–lateral deviations. Their local area of influence has similarities in form and size to those of identified microzones. Within the molecular layer, the orthogonal trajectories of these two afferent systems suggest different information processing. An individual serotonergic fibre must influence all zones and microzones within its medial–lateral trajectory. In contrast, noradrenergic fibres can influence smaller cortical territories, potentially as limited as a microzone. Evidence is emerging that these monoaminergic systems may not supply a global signal to all of their targets and their potential for cerebellar cortical functions is discussed.

Is Purkinje Neuron Hyperpolarisation Important for Cerebellar Synaptic Plasticity? A Retrospective and Prospective Analysis

Two recent studies have demonstrated that the dendritic Ca2+ signal associated with a climbing fibre (CF) input to the cerebellar Purkinje neuron (PN) depends on the membrane potential (Vm). Specifically, when the cell is hyperpolarised, this signal is mediated by T-type voltage-gated Ca2+ channels; in contrast, when the cell is firing, the CF-PN signal is mediated by P/Q-type voltage-gated Ca2+ channels. When the CF input is paired with parallel fibre (PF) activity, the signal is locally amplified at the sites of PF-activated synapses according to the Vm at the time of the CF input, suggesting that the standing Vm is a critical parameter for the induction of PF synaptic plasticity. In this review, I analyse how the Vm can potentially play a role in cerebellar learning focussing, in particular, on the hyperpolarised state that appears to occur episodically, since PNs are mostly firing under physiological conditions. By revisiting the recent literature reporting in vivo recordings and synaptic plasticity studies, I speculate on how a putative role of the PN Vm can provide an interpretation for the results of these studies.

Principles of operation of a cerebellar learning circuit.

We provide behavioral evidence using monkey smooth pursuit eye movements for four principles of cerebellar learning. Using a circuit-level model of the cerebellum, we link behavioral data to learning's neural implementation. The four principles are: (1) early, fast, acquisition driven by climbing fiber inputs to the cerebellar cortex, with poor retention; (2) learned responses of Purkinje cells guide transfer of learning from the cerebellar cortex to the deep cerebellar nucleus, with excellent retention; (3) functionally different neural signals are subject to learning in the cerebellar cortex versus the deep cerebellar nuclei; and (4) negative feedback from the cerebellum to the inferior olive reduces the magnitude of the teaching signal in climbing fibers and limits learning. Our circuit-level model, based on these four principles, explains behavioral data obtained by strategically manipulating the signals responsible for acquisition and recall of direction learning in smooth pursuit eye movements across multiple timescales.

Microcircuit Rules Governing Impact of Single Interneurons on Purkinje Cell Output In Vivo

SummaryThe functional impact of single interneurons on neuronal output in vivo and how interneurons are recruited by physiological activity patterns remain poorly understood. In the cerebellar cortex, molecular layer interneurons and their targets, Purkinje cells, receive excitatory inputs from granule cells and climbing fibers. Using dual patch-clamp recordings from interneurons and Purkinje cells in vivo, we probe the spatiotemporal interactions between these circuit elements. We show that single interneuron spikes can potently inhibit Purkinje cell output, depending on interneuron location. Climbing fiber input activates many interneurons via glutamate spillover but results in inhibition of those interneurons that inhibit the same Purkinje cell receiving the climbing fiber input, forming a disinhibitory motif. These interneuron circuits are engaged during sensory processing, creating diverse pathway-specific response functions. These findings demonstrate how the powerful effect of single interneurons on Purkinje cell output can be sculpted by various interneuron circuit motifs to diversify cerebellar computations.

A model for time interval learning in the Purkinje cell.

Recent experimental findings indicate that Purkinje cells in the cerebellum represent time intervals by mechanisms other than conventional synaptic weights. These findings add to the theoretical and experimental observations suggesting the presence of intra-cellular mechanisms for adaptation and processing. To account for these experimental results we propose a new biophysical model for time interval learning in a Purkinje cell. The numerical model focuses on a classical delay conditioning task (e.g. eyeblink conditioning) and relies on a few computational steps. In particular, the model posits the activation by the parallel fiber input of a local intra-cellular calcium store which can be modulated by intra-cellular pathways. The reciprocal interaction of the calcium signal with several proteins forming negative and positive feedback loops ensures that the timing of inhibition in the Purkinje cell anticipates the interval between parallel and climbing fiber inputs during training. We systematically test the model ability to learn time intervals at the 150-1000 ms time scale, while observing that learning can also extend to the multiple seconds scale. In agreement with experimental observations we also show that the number of pairings required to learn increases with inter-stimulus interval. Finally, we discuss how this model would allow the cerebellum to detect and generate specific spatio-temporal patterns, a classical theory for cerebellar function.

Publisher Correction: Predictive and reactive reward signals conveyed by climbing fiber inputs to cerebellar Purkinje cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The Origin of Physiological Local mGluR1 Supralinear Ca2+ Signals in Cerebellar Purkinje Neurons.

In mouse cerebellar Purkinje neurons (PNs), the climbing fiber (CF) input provides a signal to parallel fiber (PF) synapses, triggering PF synaptic plasticity. This signal is given by supralinear Ca2+ transients, associated with the CF synaptic potential and colocalized with the PF Ca2+ influx, occurring only when PF activity precedes the CF input. Here, we unravel the biophysical determinants of supralinear Ca2+ signals associated with paired PF-CF synaptic activity. We used membrane potential (Vm) and Ca2+ imaging to investigate the local CF-associated Ca2+ influx following a train of PF synaptic potentials in two cases: (1) when the dendritic Vm is hyperpolarized below the resting Vm, and (2) when the dendritic Vm is at rest. We found that supralinear Ca2+ signals are mediated by type-1 metabotropic glutamate receptors (mGluR1s) when the CF input is delayed by 100-150 ms from the first PF input in both cases. When the dendrite is hyperpolarized only, however, mGluR1s boost neighboring T-type channels, providing a mechanism for local coincident detection of PF-CF activity. The resulting Ca2+ elevation is locally amplified by saturation of endogenous Ca2+ buffers produced by the PF-associated Ca2+ influx via the mGluR1-mediated nonselective cation conductance. In contrast, when the dendritic Vm is at rest, mGluR1s increase dendritic excitability by inactivating A-type K+ channels, but this phenomenon is not restricted to the activated PF synapses. Thus, Vm is likely a crucial parameter in determining PF synaptic plasticity, and the occurrence of hyperpolarization episodes is expected to play an important role in motor learning.SIGNIFICANCE STATEMENT In Purkinje neurons, parallel fiber synaptic plasticity, determined by coincident activation of the climbing fiber input, underlies cerebellar learning. We unravel the biophysical mechanisms allowing the CF input to produce a local Ca2+ signal exclusively at the sites of activated parallel fibers. We show that when the membrane potential is hyperpolarized with respect to the resting membrane potential, type-1 metabotropic glutamate receptors locally enhance Ca2+ influx mediated by T-type Ca2+ channels, and that this signal is amplified by saturation of endogenous buffer also mediated by the same receptors. The combination of these two mechanisms is therefore capable of producing a Ca2+ signal at the activated parallel fiber sites, suggesting a role of Purkinje neuron membrane potential in cerebellar learning.

Cerebellar climbing fibers encode expected reward size.

Climbing fiber inputs to the cerebellum encode error signals that instruct learning. Recently, evidence has accumulated to suggest that the cerebellum is also involved in the processing of reward. To study how rewarding events are encoded, we recorded the activity of climbing fibers when monkeys were engaged in an eye movement task. At the beginning of each trial, the monkeys were cued to the size of the reward that would be delivered upon successful completion of the trial. Climbing fiber activity increased when the monkeys were presented with a cue indicating a large reward, but not a small reward. Reward size did not modulate activity at reward delivery or during eye movements. Comparison between climbing fiber and simple spike activity indicated different interactions for coding of movement and reward. These results indicate that climbing fibers encode the expected reward size and suggest a general role of the cerebellum in associative learning beyond error correction.

Modular organization of cerebellar climbing fiber inputs during goal-directed behavior.

The cerebellum has a parasagittal modular architecture characterized by precisely organized climbing fiber (CF) projections that are congruent with alternating aldolase C/zebrin II expression. However, the behavioral relevance of CF inputs into individual modules remains poorly understood. Here, we used two-photon calcium imaging in the cerebellar hemisphere Crus II in mice performing an auditory go/no-go task to investigate the functional differences in CF inputs to modules. CF signals in medial modules show anticipatory decreases, early increases, secondary increases, and reward-related increases or decreases, which represent quick motor initiation, go cues, fast motor behavior, and positive reward outcomes. CF signals in lateral modules show early increases and reward-related decreases, which represent no-go and/or go cues and positive reward outcomes. The boundaries of CF functions broadly correspond to those of aldolase C patterning. These results indicate that spatially segregated CF inputs in different modules play distinct roles in the execution of goal-directed behavior.

Response Dynamics in an Olivocerebellar Spiking Neural Network With Non-linear Neuron Properties.

Sensorimotor signals are integrated and processed by the cerebellar circuit to predict accurate control of actions. In order to investigate how single neuron dynamics and geometrical modular connectivity affect cerebellar processing, we have built an olivocerebellar Spiking Neural Network (SNN) based on a novel simplification algorithm for single point models (Extended Generalized Leaky Integrate and Fire, EGLIF) capturing essential non-linear neuronal dynamics (e.g., pacemaking, bursting, adaptation, oscillation and resonance). EGLIF models specifically tuned for each neuron type were embedded into an olivocerebellar scaffold reproducing realistic spatial organization and physiological convergence and divergence ratios of connections. In order to emulate the circuit involved in an eye blink response to two associated stimuli, we modeled two adjacent olivocerebellar microcomplexes with a common mossy fiber input but different climbing fiber inputs (either on or off). EGLIF-SNN model simulations revealed the emergence of fundamental response properties in Purkinje cells (burst-pause) and deep nuclei cells (pause-burst) similar to those reported in vivo. The expression of these properties depended on the specific activation of climbing fibers in the microcomplexes and did not emerge with scaffold models using simplified point neurons. This result supports the importance of embedding SNNs with realistic neuronal dynamics and appropriate connectivity and anticipates the scale-up of EGLIF-SNN and the embedding of plasticity rules required to investigate cerebellar functioning at multiple scales.

Climbing Fibers Provide Graded Error Signals in Cerebellar Learning.

The cerebellum plays a critical role in coordinating and learning complex movements. Although its importance has been well recognized, the mechanisms of learning remain hotly debated. According to the classical cerebellar learning theory, depression of parallel fiber synapses instructed by error signals from climbing fibers, drives cerebellar learning. The uniqueness of long-term depression (LTD) in cerebellar learning has been challenged by evidence showing multi-site synaptic plasticity. In Purkinje cells, long-term potentiation (LTP) of parallel fiber synapses is now well established and it can be achieved with or without climbing fiber signals, making the role of climbing fiber input more puzzling. The central question is how individual Purkinje cells extract global errors based on climbing fiber input. Previous data seemed to demonstrate that climbing fibers are inefficient instructors, because they were thought to carry “binary” error signals to individual Purkinje cells, which significantly constrains the efficiency of cerebellar learning in several regards. In recent years, new evidence has challenged the traditional view of “binary” climbing fiber responses, suggesting that climbing fibers can provide graded information to efficiently instruct individual Purkinje cells to learn. Here we review recent experimental and theoretical progress regarding modulated climbing fiber responses in Purkinje cells. Analog error signals are generated by the interaction of varying climbing fibers inputs with simultaneous other synaptic input and with firing states of targeted Purkinje cells. Accordingly, the calcium signals which trigger synaptic plasticity can be graded in both amplitude and spatial range to affect the learning rate and even learning direction. We briefly discuss how these new findings complement the learning theory and help to further our understanding of how the cerebellum works.

Cerebellar Contribution to Preparatory Activity in Motor Neocortex

SummaryIn motor neocortex, preparatory activity predictive of specific movements is maintained by a positive feedback loop with the thalamus. Motor thalamus receives excitatory input from the cerebellum, which learns to generate predictive signals for motor control. The contribution of this pathway to neocortical preparatory signals remains poorly understood. Here, we show that, in a virtual reality conditioning task, cerebellar output neurons in the dentate nucleus exhibit preparatory activity similar to that in anterolateral motor cortex prior to reward acquisition. Silencing activity in dentate nucleus by photoactivating inhibitory Purkinje cells in the cerebellar cortex caused robust, short-latency suppression of preparatory activity in anterolateral motor cortex. Our results suggest that preparatory activity is controlled by a learned decrease of Purkinje cell firing in advance of reward under supervision of climbing fiber inputs signaling reward delivery. Thus, cerebellar computations exert a powerful influence on preparatory activity in motor neocortex.

Large Scale Calcium Imaging of the Cerebellar Vermis During Sensory Stimulus Unravels Two Response's Components That Differ in Their Spatiotemporal Properties.

The well documented precision of the cerebellar sagittal organization is commonly used to compose a comprehensive view on principles of cerebellar function. However, the physiological manifestation of this organization is either limited to information derived from single unit recordings or from imaging of a small group of closely located neurons. Here we used large scale imaging to monitor calcium concentration changes in the entire vermal area of folia V and VI in anesthetized mice. We found that the response to a strong auditory input or electrical shock to the tail area is composed of an early and a late component that differ in their spatiotemporal properties. The early component occurs throughout the scanned area whereas the late component reflects synchronous activation of Purkinje cells located along symmetric parasagittal bands that correspond well to sagittal band 2+ (Sugihara and Shinoda, 2004). Similar organization was found in the rigorously disorganized cerebellum of Cxcr4 KO mice, suggesting that the sagittal organization is determined by the climbing fiber inputs to the cerebellar cortex. The responses for both stimuli are followed by a prolonged recovery period but the rate of recovery from auditory stimulus is much longer, reflecting a different site for the adapting process. We suggest that these sensory inputs, which are commonly used to evoke startle response, activate two sets of climbing fiber inputs that differ in their spatiotemporal properties and contribute to the motor organization and habituation of the startle response.Significance Statement:The ensemble activity of neurons in the brain is one of the current challenges of neuroscience. Here we use a fast and large-scale calcium imaging system to monitor ensemble activity in the cerebellar cortex following auditory stimuli or electric shocks to the tail. The system, which enables the detection of the response to a single trail, reveals the robustness of the functional organization of the olivo-cerebellar system in sagittal bands that is preserved in genetically induced disorganized cerebellar cortex. Furthermore, the response, which represents the activation of two sets of climbing fibers inputs, is followed by a prolonged recovery process that indicates the cerebellar involvement in startle response.

Predictive and reactive reward signals conveyed by climbing fiber inputs to cerebellar Purkinje cells.

There is increasing evidence for a cerebellar contribution to cognitive processing, but the specific input pathways conveying this information remain unclear. We probed the role of climbing fiber inputs to Purkinje cells in generating and evaluating predictions about associations between motor actions, sensory stimuli and reward. We trained mice to perform a visuomotor integration task to receive a reward and interleaved cued and random rewards between task trials. Using two-photon calcium imaging and Neuropixels probe recordings of Purkinje cell activity, we show that climbing fibers signal reward expectation, delivery and omission. These signals map onto cerebellar microzones, with reward delivery activating some microzones and suppressing others, and with reward omission activating both reward-activated and reward-suppressed microzones. Moreover, responses to predictable rewards are progressively suppressed during learning. Our findings elucidate a specific input pathway for cerebellar contributions to reward signaling and provide a mechanistic link between cerebellar activity and the creation and evaluation of predictions.

Neurons of the inferior olive respond to broad classes of sensory input while subject to homeostatic control.

Key points Purkinje cells in the cerebellum integrate input from sensory organs with that from premotor centres.Purkinje cells use a variety of sensory inputs relaying information from the environment to modify motor control.Here we investigated to what extent the climbing fibre inputs to Purkinje cells signal mono‐ or multi‐sensory information, and to what extent this signalling is subject to recent history of activity.We show that individual climbing fibres convey multiple types of sensory information, together providing a rich mosaic projection pattern of sensory signals across the cerebellar cortex.Moreover, firing probability of climbing fibres following sensory stimulation depends strongly on the recent history of activity, showing a tendency to homeostatic dampening. Cerebellar Purkinje cells integrate sensory information with motor efference copies to adapt movements to behavioural and environmental requirements. They produce complex spikes that are triggered by the activity of climbing fibres originating in neurons of the inferior olive. These complex spikes can shape the onset, amplitude and direction of movements and the adaptation of such movements to sensory feedback. Clusters of nearby inferior olive neurons project to parasagittally aligned stripes of Purkinje cells, referred to as ‘microzones’. It is currently unclear to what extent individual Purkinje cells within a single microzone integrate climbing fibre inputs from multiple sources of different sensory origins, and to what extent sensory‐evoked climbing fibre responses depend on the strength and recent history of activation. Here we imaged complex spike responses in cerebellar lobule crus 1 to various types of sensory stimulation in awake mice. We find that different sensory modalities and receptive fields have a mild, but consistent, tendency to converge on individual Purkinje cells, with climbing fibres showing some degree of input‐specificity. Purkinje cells encoding the same stimulus show increased events with coherent complex spike firing and tend to lie close together. Moreover, whereas complex spike firing is only mildly affected by variations in stimulus strength, it depends strongly on the recent history of climbing fibre activity. Our data point towards a mechanism in the olivo‐cerebellar system that regulates complex spike firing during mono‐ or multi‐sensory stimulation around a relatively low set‐point, highlighting an integrative coding scheme of complex spike firing under homeostatic control.

Graded Control of Climbing-Fiber-Mediated Plasticity and Learning by Inhibition in the Cerebellum

Purkinje cell dendrites convert excitatory climbing fiber input into signals that instruct plasticity and motor learning. Modulation of instructive signaling may increase the range in which learning is encoded, yet the mechanisms that allow for this are poorly understood. We found that optogenetic activation of molecular layer interneurons (MLIs) that inhibit Purkinje cells suppressed climbing-fiber-evoked dendritic Ca2+ spiking. Inhibitory suppression of Ca2+ spiking depended on the level of MLI activation and influenced the induction of associative synapticplasticity, converting climbing-fiber-mediated potentiation of parallel fiber-evoked responses into depression. In awake mice, optogenetic activation of floccular climbing fibers in association with head rotation produced an adaptive increase in the vestibulo-ocular reflex (VOR). However, when climbing fibers were co-activated with MLIs, adaptation occurred in the opposite direction, decreasing the VOR. Thus, MLIs can direct a continuous spectrum of plasticity and learning through their influence on Purkinje cell dendritic Ca2+ signaling.

Voltage- and Branch-Specific Climbing Fiber Responses in Purkinje Cells

Climbing fibers (CFs) provide instructive signals driving cerebellar learning, but mechanisms causing the variable CF responses in Purkinje cells (PCs) are not fully understood. Using a new experimentally validated PC model, we unveil the ionic mechanisms underlying CF-evoked distinct spike waveforms on different parts of the PC. We demonstrate that voltage can gate both the amplitude and the spatial range of CF-evoked Ca2+ influx by the availability of K+ currents. This makes the energy consumed during a complex spike (CS) also voltage dependent. PC dendrites exhibit inhomogeneous excitability with individual branches as computational units for CF input. The variability of somatic CSs can be explained by voltage state, CF activation phase, and instantaneous CF firing rate. Concurrent clustered synaptic inputs affect CSs by modulating dendritic responses in a spatially precise way. The voltage- and branch-specific CF responses can increase dendritic computational capacity and enable PCs to actively integrate CF signals.

Cerebellar Processing Common to Delay and Trace Eyelid Conditioning

Results from previous lesion studies have been interpreted as evidence that the cerebellar cortex plays different roles for delay and trace conditioning of eyelid responses. However, the cerebellar cortex is organized by parasagittal stripes of Purkinje cells (PCs) that converge onto common deep nucleus neurons and receive common or related climbing fiber inputs. Based on this organization, we hypothesized that cerebellar tasks involving the same response system, such as delay and trace eyelid conditioning, would engage the same PCs and that the relationships between PC activity and expression of behavioral responses would be similar for both tasks. To test these hypotheses, we used tetrode recordings from eyelid PCs in rabbits during expression of delay- and trace-conditioned eyelid responses. Previous recording studies during delay conditioning described a strong relationship between eyelid PC activity and the kinematics of conditioned eyelid responses. The present results replicate these findings for delay conditioning and show that the same relationship exists during trace eyelid conditioning. During transitions from delay to trace responding, the relationship between eyelid PCs and behavioral responses was relatively stable. We found that an inverse firing rate model tuned to predict PC activity during one training paradigm could then predict equally well the PC activity during the other training paradigm. These results provide strong evidence that cerebellar cortex processing is similar for delay and trace eyelid conditioning and that the parasagittal organization of the cerebellum, not the conditioning paradigm, dictate which neurons are engaged to produce adaptively timed conditioned responses.SIGNIFICANCE STATEMENT A variety of evidence from eyelid conditioning and other cerebellar-dependent behaviors indicates that the cerebellar cortex is necessary for learning and proper timing of cerebellar learned responses. Debates exist about whether trace eyelid conditioning data show that fundamentally different mechanisms operate in the cerebellum during tasks when input from the forebrain is necessary for learning. We show here that learning-related changes in a specific population of Purkinje cells control the timing and amplitude of cerebellar responses the same way regardless of the inputs necessary to learn the task. Our results indicate the parasagittal organization of the cerebellar cortex, not the complexity of inputs to the cerebellum, determines which neurons are engaged in the learning and execution of cerebellar-mediated responses.

Cell type-specific plasticity at parallel fiber synapses onto Purkinje cells in the posterior caudal lobe of the mormyrid fish cerebellum.

It has been demonstrated that there are two morphological subtypes of Purkinje cells (PCs)-fan-shaped Purkinje cells (fPCs) and multipolar Purkinje cells (mPCs)-in the posterior caudal lobe of the mormyrid fish cerebellum, but whether these cell types are also functionally distinct is unknown. Here, we have used electrophysiological and pharmacological tools in a slice preparation to demonstrate that pairing parallel fiber (PF) and climbing fiber (CF) inputs at a low frequency induces long-term depression (LTD) in fPCs but long-term potentiation (LTP) in mPCs. The induction of plasticity in both cell types required postsynaptic Ca2+ and type 1α metabotropic glutamate receptors. However, the LTD in fPCs was inducted via a calcium/calmodulin-dependent protein kinase II cascade, whereas LTP induction in mPCs required calcineurin. Moreover, the LTD in fPCs and LTP in mPCs were accompanied by changes to the corresponding paired-pulse ratios and their coefficients of variation, suggesting presynaptic modes of expression for the plasticity at PF terminals for both cell types. Hence, the synaptic plasticity at PF synapses onto PCs in the posterior caudal lobe of the mormyrid cerebellum is cell type specific, with both pre- and postsynaptic mechanisms contributing to its induction and expression. NEW & NOTEWORTHY Much has been learnt about the cerebellar long-term depression (LTD) in the cortex. More recent work has shown that long-term potentiation (LTP) is equally important for cerebellar motor learning. Here we report for the first time that plasticity in the mormyrid cerebellum is cell type specific, e.g., following the conventional pairing of parallel and climbing fiber inputs in an in vitro preparation leads to LTD in one Purkinje cell subtype and LTP in another.

Physiological and Morphological Principles Underpinning Recruitment of the Cerebellar Reserve.

Background: In order to optimize outcomes of novel therapies for cerebellar ataxias (CAs), it is desirable to start these therapies while declined functions are restorable: i.e. while the so-called cere-bellar reserve remains.Objective: In this mini-review, we tried to define and discuss the cerebellar reserve from physiological and morphological points of view.Method: The cerebellar neuron circuitry is designed to generate spatiotemporally organized outputs, re-gardless of the region. Therefore, the cerebellar reserve may be defined as a mechanism to restore its proper input-output organization of the cerebellar neuron circuitry, when it is damaged. Then, the follow-ing four components are essential for recruitment of the cerebellar reserve: operational local neuron cir-cuitry; proper combination of mossy fiber inputs to be integrated; climbing fiber inputs to instruct favor-able reorganization of the integration; deep cerebellar nuclei to generate reorganized outputs.Results: We discussed three topics related to these resources, 1) principles of generating organized cere-bellar outputs, 2) redundant mossy fiber inputs to the cerebellum, 3) plasticity of the cerebellar neuron circuitry.Conclusion: To make most of the cerebellar reserve, it is desirable to start any intervention as early as possible when the cerebellar cell loss is minimal or even negligible. Therefore, an ideal future therapy for degenerative cerebellar diseases should start before consuming the cerebellar reserve at all. In the meantime, our real challenge is to establish a reliable method to identify the decrease in the cerebellar re-serve as early as possible.