Timing and plasticity in the cerebellum: focus on the granular layer

doi:10.1016/j.tins.2008.09.007

Trends in Neurosciences

Volume 32, Issue 1, January 2009, Pages 30-40

https://doi.org/10.1016/j.tins.2008.09.007 Get rights and content

Two of the most striking properties of the cerebellum are its control in timing of motor operations and its ability to adapt behavior to new sensorimotor associations. Here, we propose a ‘time-window matching’ hypothesis for granular layer processing. Our hypothesis states that mossy fiber inputs to the granular layer are transformed into well-timed spike bursts by intrinsic granule cell processing, that feedforward Golgi cell inhibition sets a limit to the duration of such bursts and that these activities are spread over particular fields in the granular layer so as to generate ongoing time-windows for proper control of interacting motor domains. The role of synaptic plasticity would be that of fine-tuning pre-wired circuits favoring activation of specific granule cell groups in relation to particular time windows. This concept has wide implications for processing in the olivo-cerebellar system as a whole.

Section snippets

The cerebellum and timing of movements

The cerebellum is a brain structure of crucial importance for sensorimotor control, and its disruption causes a dramatic neurological syndrome called ataxia (the paradigmatic symptoms were first outlined by L. Luciani in 1891 [1] and then extended by clinicians such as J.F.F. Babinski, P. Marie and G. Holmes; for a review including a historical recollection see Ref. [2]). Over the last decades the cerebellum has also been suggested to be involved in cognitive and emotional functions 3, 4, 5,

Principles of granular layer processing: highlights and problems

The perspective that we will take in this review is to consider cerebellar processing starting from the granular layer circuit. Understanding how the granular layer processes incoming information is crucial because its sole output, the granule cell axon (parallel fiber system), forms one of the main inputs to the Purkinje cell, which, in turn, forms the sole output unit of the cerebellar cortex as a whole (Figure 1). The granular layer receives many sorts of converging information originating

The impact of inhibition on timing in the granular layer

It wasn’t until the potential roles of the Golgi cells were considered in detail that the granular layer was proposed to process input temporal patterns 44, 45. In fact, systematic analysis of the potential effects of Golgi cell inhibition enables the identification of the fundamental properties of inhibition that can influence temporal aspects of network properties [46], namely feedforward inhibition, feedback inhibition and lateral inhibition. In addition, by controlling the level of granule

The impact of neuronal electroresponsiveness on timing in the granular layer

Together with circuit organization, neuronal electroresponsiveness can also have a profound impact on timing. A main consequence of the intrinsic properties of granule cells and Golgi cells is to enhance burst generation. The importance of this mechanism could be that of generating reliable and strong responses to the high-frequency bursts of impulses entering the granular layer through the mossy fibers 29, 38, 39, 53. Bursts are intensified by specific ionic mechanisms including the resurgent

The impact of plasticity on temporal processing in the granular layer: the ‘window-matching’ hypothesis

The cerebellum has several forms of synaptic plasticity and intrinsic excitable mechanisms that might fine-tune its temporal control, the most renown of which is LTD at the parallel fiber–Purkinje cell synapse 57, 58, 59. To date, in the granular layer, the most robust form is the bidirectional NMDA-receptor-dependent plasticity that has been described at the mossy fiber to granule cell synapse 47, 60, 61, 62, 63, 64, 65 (Figure 2). At this synapse, both LTP and also, probably, LTD are

Transferring temporal codes to Purkinje cells and molecular layer interneurons

To process the afferent signals generated during ongoing movements, the cerebellar network needs to be tuned toward the appropriate spike codes 69, 41. The temporal resolution of somatosensory processing in afferent pathways is typically in the range of ∼5 ms, in that the latency to the first spikes shows such a level of variation [40]. Interestingly, this resolution matches the minimum time window that can be set by Golgi cells and the regulatory range of the LTP/LTD mechanism. The precision in

Temporal patterns in Purkinje cells and behavioural relevance

In the previous sections, we explained why cellular and network properties of the granular layer are well designed to control the distribution of temporally relevant mossy fiber signals. The question remains as to how this function of the granule cell layer might contribute to the overall function of the cerebellum. Because Purkinje cells form the sole output of the cerebellar cortex, it is parsimonious to also explain the role of the granule cell layer from the perspective of Purkinje cell

Timing and the modular organization of cerebellar motor output

If it is indeed the precise temporal coding in Purkinje cells that plays an important part in controlling motor behavior, it becomes difficult to understand how Purkinje cells influence the DCN neurons unless they do so in a coherent fashion within a cerebellar module (we recall that modules assemble cortical microzones within specific extracerebellar circuits comprising the inferior olive and DCN; for anatomical and functional definitions see Refs 5, 8, 10). In other words, if Purkinje cells

Granular layer dynamics with tonic mossy fiber discharge

Although bursting is a characteristic modality of mossy fiber discharge evoked in isolation during punctuate stimulation, more complex sensory inputs can evoke a mixture of phasic, phasic-tonic and tonic patterns along different mossy fibers. This has been shown for various sensory pathways, including those originating from muscle spindles, skin and vestibular organs 59, 95, 96, 97, 98. What will be the impact of tonic discharge on the window-matching mechanism? Computational modeling predicts

A summary of concepts and conclusions

The granular layer has the potential to process incoming mossy fiber signals at the millisecond time scale generating an impressive number of spatio-temporal patterns through learning. Most remarkably, we propose that feedforward Golgi cell inhibition generates a permissive time window of ∼5 ms through which spikes can be optimally channeled to Purkinje cells. LTP and LTD at the mossy-fiber–granule-cell synapse would serve to determine whether excitatory postsynaptic potential temporal summation

Acknowledgements

This work has matured through continuous discussions with members of our laboratories. Particular thanks go to P. Rossi, L. Forti, F. Prestori, J. Mapelli, S. Solinas, S. Diwakar, E. Cesana, D. Gandolfi, P. Lombardo and F. Hoebeek. This work was supported by the joined EU project SENSOPAC, by the EU project CYBERRAT and the CNISM (Consorzio Nazionale Interuniversitario per le Scienze Fisiche della Materia) project NEUROIMAGE to E.D., and by the Prinses Beatrix Fonds, Zon-MW and Neuro-Bsik

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Delay eyeblink conditioning was examined in 20 mildly to moderately affected individuals with SCA3 and 31 healthy controls. After the baseline assessment, patients were randomly assigned to receive ten sessions of cerebellar anodal tDCS or sham tDCS (i.e., five days per week for two consecutive weeks). Patients and investigators were blinded to treatment allocation. The same eyeblink conditioning protocol was administered directly after the last tDCS session. The Scale for the Assessment and Rating of Ataxia (SARA), cerebellar cognitive affective syndrome scale (CCAS-S), and disease duration were used as clinical measures of disease severity.
At baseline, SCA3 patients exhibited significantly fewer CRs than healthy controls. Acquisition was inversely associated with the number of failed CCAS-S test items but not with SARA score. Onset and peak latencies of CRs were longer in SCA3 patients and correlated with disease duration. Repeated sessions of cerebellar anodal tDCS did not affect CR acquisition, but had a significant treatment effect on both timing parameters. While a shift of CRs toward the conditioned stimulus was observed in the sham group (i.e., timing became more similar to that of healthy controls, presumably reflecting the effect of a second eyeblink conditioning session), anodal tDCS induced a shift of CRs in the opposite direction (i.e., toward the unconditioned stimulus).
Our findings provide evidence that cerebellar tDCS is capable of modifying cerebellar function in SCA3 patients. Future studies should assess whether this intervention similarly modulates temporal processing in other degenerative ataxias.
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Rhythmic Auditory Stimulation (RAS) has been shown to be of help in an effective gait training of people with idiopathic Parkinson's disease (PD). The cerebellum may play an important role in RAS aftereffects by compensating the detrimental internal clock for automatic and rhythmic motricity. However, the neurophysiological mechanisms underlying RAS aftereffects are still poorly understood. In the present study, we tested the contribution of the cerebellum to RAS-based gait training aftereffects in people with PD by examining cerebellum-cerebral connectivity indices using standard EEG recording. We enrolled 50 patients with PD who were randomly assigned to two different modalities of treadmill gait training using GaitTrainer3 with and without RAS (non_RAS) during an 8-week training program. We measured clinical and kinematic gait indices and electrophysiological data (standard EEG recording during walking on GaitTrainer3) of both the gait trainings. We found that the greater improvement in gait performance following RAS than non_RAS training, as per clinical and kinematic assessment, was paralleled by a more evident reshape of cerebellum-brain functional connectivity with regard to specific brain areas (pre-motor, sensorimotor and temporal cortices) and gait-cycle phases (mainly 25–75% of the gait cycle duration). These findings suggest that the cerebellum mediates the reshape of sensorimotor rhythms and fronto-centroparietal connectivity in relation to specific gait-cycle phases. This may be consistent with a recovery of the internal timing mechanisms generating and controlling motor rhythmicity, eventually improving gait performance. The precise definition of the cerebellar role to gait functional recovery in people with PD may be crucial to create patient-tailored rehabilitative approaches.
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Trends in Neurosciences

ReviewTiming and plasticity in the cerebellum: focus on the granular layer

Section snippets

The cerebellum and timing of movements

Principles of granular layer processing: highlights and problems

The impact of inhibition on timing in the granular layer

The impact of neuronal electroresponsiveness on timing in the granular layer

The impact of plasticity on temporal processing in the granular layer: the ‘window-matching’ hypothesis

Transferring temporal codes to Purkinje cells and molecular layer interneurons

Temporal patterns in Purkinje cells and behavioural relevance

Timing and the modular organization of cerebellar motor output

Granular layer dynamics with tonic mossy fiber discharge

A summary of concepts and conclusions

Acknowledgements

Trends Neurosci.

Neuron

Trends Neurosci.

Biol. Psychiatry

Trends Neurosci.

Trends Neurosci.

Brain Res. Brain Res. Rev

Neuron

Curr. Opin. Neurobiol.

Neuron

Math. Biosci.

Prog. Neurobiol.

Neuron

Neuron

Neuron

Neuron

Neuron

Neuron

Neuron

Trends Neurosci.

Neuron

Neuron

Neuroscience

Neuron

Neuron

Neuroimage

Il cervelletto: Nuovi studi di fisiologia normale e patologica

Disorders of the cerebellum: ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome

J. Neuropsychiatry Clin. Neurosci.

Cognition, emotion and the cerebellum

Brain

The Cerebellum as a Neuronal Machine

The Cerebellum and Neural Control

Cerebellar Cortex

Central cancellation of self-produced tickle sensation

Nat. Neurosci.

R. Dissociating timing and coordination as functions of the cerebellum

J. Neurosci

The cerebellar interpositus nucleus and the dynamic control of learned motor responses

J. Neurosci.

Phase relations of Purkinje cells in the rabbit flocculus during compensatory eye movements

J. Neurophysiol.

Gain and phase control of compensatory eye movements by the vestibulo-cerebellar system

Role of cerebellar interpositus nucleus in the genesis and control of reflex and conditioned eyelid responses

J. Neurosci.

The learning of novel finger movement sequences

J. Neurophysiol.

Anticipatory and sequential motor control in piano playing

Exp. Brain Res.

The effect of tapping finger and mode differences on cortical and subcortical activities: a PET study

Exp. Brain Res.

Failure of cerebellar patients to time finger opening precisely causes ball high-low inaccuracy in overarm throws

J. Neurophysiol.

Contribution of somatosensory cortex to responses in the rat cerebellar granule cell layer following peripheral tactile stimulation

Exp. Brain Res.

Cerebellar Golgi cells in the rat: receptive fields and timing of responses to facial stimulation

Eur. J. Neurosci

On climbing fiber signals and their consequences

Behav. Brain Sci.

Signal processing in the C2-module of the flocculus and its role in head movement control

Prog. Brain Res.

The critical role of Golgi cells in regulating spatio-temporal integration and plasticity at the cerebellum input stage

Front. Neurosci.

A theory of the cerebellar cortex

J. Physiol.

Recurrent cerebellar loops simplify adaptive control of redundant and nonlinear motor systems

Review
Timing and plasticity in the cerebellum: focus on the granular layer