Spatiotemporal network coding of physiological mossy fiber inputs by the cerebellar granular layer

The granular layer, which mainly consists of granule and Golgi cells, is the first stage of the cerebellar cortex and processes spatiotemporal information transmitted by mossy fiber inputs with a wide variety of firing patterns. To study its dynamics at multiple time scales in response to inputs approximating real spatiotemporal patterns, we constructed a large-scale 3D network model of the granular layer. Patterned mossy fiber activity induces rhythmic Golgi cell activity that is synchronized by shared parallel fiber input and by gap junctions. This leads to long distance synchrony of Golgi cells along the transverse axis, powerfully regulating granule cell firing by imposing inhibition during a specific time window. The essential network mechanisms, including tunable Golgi cell oscillations, on-beam inhibition and NMDA receptors causing first winner keeps winning of granule cells, illustrate how fundamental properties of the granule layer operate in tandem to produce (1) well timed and spatially bound output, (2) a wide dynamic range of granule cell firing and (3) transient and coherent gating oscillations. These results substantially enrich our understanding of granule cell layer processing, which seems to promote spatial group selection of granule cell activity as a function of timing of mossy fiber input

The Critical Role of Golgi Cells in Regulating Spatio-Temporal Integration and Plasticity at the Cerebellum Input Stage

The discovery of the Golgi cell is bound to the foundation of the Neuron Doctrine. Recently, the excitable mechanisms of this inhibitory interneuron have been investigated with modern experimental and computational techniques raising renewed interest for the implications it might have for cerebellar circuit functions. Golgi cells are pacemakers with preferential response frequency and phase-reset in the theta-frequency band and can therefore impose specific temporal dynamics to granule cell responses. Moreover, through their connectivity, Golgi cells determine the spatio-temporal organization of cerebellar activity. Finally, Golgi cells, by controlling granule cell depolarization and NMDA channel unblock, regulate the induction of long-term synaptic plasticity at the mossy fiber – granule cell synapse. Thus, the Golgi cells can exert an extensive control on spatio-temporal signal organization and information storage in the granular layer playing a critical role for cerebellar computation

High frequency field potentials of the cerebellar cortex

The cerebellum plays a crucial role in motor coordination along with basal ganglia and the motor areas of the cerebral cortex. Both somatosensory and the cerebro-cerebral pathways bring in massive amounts of neural information to the cerebellum. The output of the cerebellar cortex projects to various motor cortices as well as down to the spinal cord to make its contributions to the motor function. The origin and function of the field potential oscillations in the cerebellum, especially in the high frequencies, have not been explored sufficiently. The primary objective of this study was to investigate the spatio-temporal characteristics of high frequency field potentials (150-350Hz) in the cerebellar cortex in a behavioral context. To this end, the paramedian lobule in rats was recorded using micro electro-corticogram (µ-ECoG) electrode arrays while the animal performed a lever press task using the forelimb. The phase synchrony analysis shows that the high frequency oscillations recorded at multiple points across the paramedian cortex episodically synchronize immediately before and desynchronize during the lever press. The electrode contacts were grouped according to their temporal course of phase synchrony around the time of lever press. Contact groups presented patches with slightly stronger synchrony values in the medio-lateral direction, and did not appear to form parasagittal zones. Spatiotemporal synchrony of high frequency field potentials has not been reported at such large-scales previously in the cerebellar cortex

The Critical Role of Golgi Cells in Regulating Spatio-Temporal Integration and Plasticity at the Cerebellum Input Stage

The discovery of the Golgi cell is bound to the foundation of the Neuron Doctrine. Recently, the excitable mechanisms of this inhibitory interneuron have been investigated with modern experimental and computational techniques raising renewed interest for the implications it might have for cerebellar circuit functions. Golgi cells are pacemakers with preferential response frequency and phase-reset in the theta-frequency band and can therefore impose specific temporal dynamics to granule cell responses. Moreover, through their connectivity, Golgi cells determine the spatio-temporal organization of cerebellar activity. Finally, Golgi cells, by controlling granule cell depolarization and NMDA channel unblock, regulate the induction of long-term synaptic plasticity at the mossy fiber – granule cell synapse. Thus, the Golgi cells can exert an extensive control on spatio-temporal signal organization and information storage in the granular layer playing a critical role for cerebellar computation

Accounting for uncertainty: inhibition for neural inference in the cerebellum

Sensorimotor coordination is thought to rely on cerebellar-based internal models for state estimation, but the underlying neural mechanisms and specific contribution of the cerebellar components is unknown. A central aspect of any inferential process is the representation of uncertainty or conversely precision characterizing the ensuing estimates. Here, we discuss the possible contribution of inhibition to the encoding of precision of neural representations in the granular layer of the cerebellar cortex. Within this layer, Golgi cells influence excitatory granule cells, and their action is critical in shaping information transmission downstream to Purkinje cells. In this review, we equate the ensuing excitation–inhibition balance in the granular layer with the outcome of a precision-weighted inferential process, and highlight the physiological characteristics of Golgi cell inhibition that are consistent with such computations

Synchronization in Primate Cerebellar Granule Cell Layer Local Field Potentials: Basic Anisotropy and Dynamic Changes During Active Expectancy

The cerebellar cortex is remarkable for its organizational regularity, out of which task-related neural networks should emerge. In Purkinje cells, both complex and simple spike network patterns are evident in sensorimotor behavior. However, task-related patterns of activity in the granule cell layer (GCL) have been less studied. We recorded local field potential (LFP) activity simultaneously in pairs of GCL sites in monkeys performing an active expectancy (lever-press) task, in passive expectancy, and at rest. LFP sites were selected when they showed strong 10–25 Hz oscillations; pair orientation was in stereotaxic sagittal and coronal (mainly), and diagonal. As shown previously, LFP oscillations at each site were modulated during the lever-press task. Synchronization across LFP pairs showed an evident basic anisotropy at rest: sagittal pairs of LFPs were better synchronized (more than double the cross-correlation coefficients) than coronal pairs, and more than diagonal pairs. On the other hand, this basic anisotropy was modifiable: during the active expectancy condition, where sagittal and coronal orientations were tested, synchronization of LFP pairs would increase just preceding movement, most notably for the coronal pairs. This lateral extension of synchronization was not observed in passive expectancy. The basic pattern of synchronization at rest, favoring sagittal synchrony, thus seemed to adapt in a dynamic fashion, potentially extending laterally to include more cerebellar cortex elements. This dynamic anisotropy in LFP synchronization could underlie GCL network organization in the context of sensorimotor tasks

Neurones glycinergiques et transmission inhibitrice dans les noyaux cérébelleux

The cerebellum is composed of a three-layered cortex and of nuclei and is responsible for the learned fine control of posture and movements. I combined a genetic approach (based on the use of transgenic mouse lines) with anatomical tracings, immunohistochemical stainings, electrophysiological recordings and optogenetic stimulations to establish the distinctive characteristics of the inhibitory neurons of the cerebellar nuclei and to detail their connectivity and their role in the cerebellar circuitry.We showed that the glycinergic inhibitory neurons of the cerebellar nuclei constitute a distinct neuronal population and are characterized by their mixed inhibitory GABAergic/glycinergic phenotype. Those inhibitory neurons are also distinguished by their axonal plexus which includes a local arborization with the cerebellar nuclei where they contact principal output neurons and a projection to the granular layer of the cerebellar cortex where they end onto Golgi cells dendrites. Finally, the inhibitory neurons of the cerebellar nuclei receive inhibitory afferents from Purkinje cells and may be contacted by mossy fibers or climbing fibers.We provided the first evidence of functional mixed transmission in the cerebellar nuclei and the first demonstration of a mixed inhibitory nucleo-cortical projection. Overall, our data establish the inhibitory neurons as the third cellular component of the cerebellar nuclei. Their importance in the modular organization of the cerebellum and their impact on sensory-motor integration need to be confirmed by optogenetic experiments in vivo.Le cervelet, composé d'un cortex et de noyaux, est responsable du contrôle moteur fin des mouvements et de la posture. En combinant une approche génétique (basée sur l'utilisation de lignées de souris transgéniques) avec des traçages anatomiques, des marquages immunohistochimiques et des expériences d'électrophysiologie et d'optogénétique, nous établissons les caractères distinctifs des neurones inhibiteurs des noyaux cérébelleux et en détaillons la connectivité ainsi que les fonctions dans le circuit cérébelleux. Les neurones inhibiteurs glycinergiques des noyaux profonds constituent une population de neurones distincts des autres types cellulaires identifiables par leur phénotype inhibiteur mixte GABAergique/glycinergique. Ces neurones se distinguent également par leur plexus axonal qui comporte une arborisation locale dans les noyaux cérébelleux où ils contactent les neurones principaux et une projection vers le cortex cérébelleux où ils contactent les cellules de Golgi. Ces neurones inhibiteurs reçoivent également des afférences inhibitrices des cellules de Purkinje et pourraient être contactés par les fibres moussues ou les fibres grimpantes.Nous apportons ainsi la première étude d'une transmission mixte fonctionnelle par les neurones inhibiteurs des noyaux cérébelleux, projetant à la fois dans les noyaux et le cortex cérébelleux. L'ensemble de nos données établissent les neurones inhibiteurs mixtes des noyaux cérébelleux comme la troisième composante cellulaire des noyaux profonds. Leur importance dans l'organisation modulaire du cervelet, ainsi que leur impact sur l'intégration sensori-motrice, devront être confirmés par des études optogénétiques in vivo

Effects of oscillatory activity on coherence patterns in the cerebellar cortex

The cerebellum is getting more recognized as a rhythm generator, producing oscillations in different frequency bands. While the cerebellum has been associated with motor control, sensory perception, and cognition, the functional role of the granule cell layer oscillations is still elusive. Using awake, unrestrained rats, oscillations were recorded with multiple electrodes in the granule cell layer of posterior lobe of the cerebellar cortex. The purpose of this study was to investigate the effect of oscillations on pattern activity in the granule cell layer. In this study we show that cerebellar oscillations influence the synchrony of local field potential activity across the cerebellar cortex. These oscillations in the frequency range of 6-11 Hz were found to synchronize patterns of local field potentials organized along the coronal plane of the cerebellar cortex. Cerebellar oscillations of the granule cell layer synchronize local field potentials and are integral to the intrinsic circuitry of the cerebellum and playa functional role in spatially organizing cerebellar networks

Modeling the Cerebellar Microcircuit: New Strategies for a Long-Standing Issue

The cerebellar microcircuit has been the work bench for theoretical and computational modeling since the beginning of neuroscientific research. The regular neural architecture of the cerebellum inspired different solutions to the long-standing issue of how its circuitry could control motor learning and coordination. Originally, the cerebellar network was modeled using a statistical-topological approach that was later extended by considering the geometrical organization of local microcircuits. However, with the advancement in anatomical and physiological investigations, new discoveries have revealed an unexpected richness of connections, neuronal dynamics and plasticity, calling for a change in modeling strategies, so as to include the multitude of elementary aspects of the network into an integrated and easily updatable computational framework. Recently, biophysically accurate realistic models using a bottom-up strategy accounted for both detailed connectivity and neuronal non-linear membrane dynamics. In this perspective review, we will consider the state of the art and discuss how these initial efforts could be further improved. Moreover, we will consider how embodied neurorobotic models including spiking cerebellar networks could help explaining the role and interplay of distributed forms of plasticity. We envisage that realistic modeling, combined with closed-loop simulations, will help to capture the essence of cerebellar computations and could eventually be applied to neurological diseases and neurorobotic control systems

Optical Imaging as a Link Between Cellular Neurophysiology and Circuit Modeling

The relatively simple and highly modular circuitry of the cerebellum raised expectations decades ago that a realistic computational model of cerebellar circuit operations would be feasible, and prove insightful for unraveling cerebellar information processing. To this end, the biophysical properties of most cerebellar cell types and their synaptic connections have been well characterized and integrated into realistic single cell models. Furthermore, large scale models of cerebellar circuits that extrapolate from single cell properties to circuit dynamics have been constructed. While the development of single cell models have been constrained by microelectrode recordings, guidance and validation as these models are scaled up to study network interactions requires an experimental methodology capable of monitoring cerebellar dynamics at the population level. Here we review the potential of optical imaging techniques to serve this purpose