The compartmentalization of the cerebellum into modules is often used to discuss its function. What, exactly, can be considered a module, how do they operate, can they be subdivided and do they act individually or in concert are only some of the key questions discussed in this consensus paper. Experts studying cerebellar compartmentalization give their insights on the structure and function of cerebellar modules, with the aim of providing an up-to-date review of the extensive literature on this subject. Starting with an historical perspective indicating that the basis of the modular organization is formed by matching olivocorticonuclear connectivity, this is followed by consideration of anatomical and chemical modular boundaries, revealing a relation between anatomical, chemical, and physiological borders. In addition, the question is asked what the smallest operational unit of the cerebellum might be. Furthermore, it has become clear that chemical diversity of Purkinje cells also results in diversity of information processing between cerebellar modules. An additional important consideration is the relation between modular compartmentalization and the organization of the mossy fiber system, resulting in the concept of modular plasticity. Finally, examination of cerebellar output patterns suggesting cooperation between modules and recent work on modular aspects of emotional behavior are discussed. Despite the general consensus that the cerebellum has a modular organization, many questions remain. The authors hope that this joint review will inspire future cerebellar research so that we are better able to understand how this brain structure makes its vital contribution to behavior in its most general form.

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The cerebellar cortex encodes sensorimotor adaptation during skilled locomotor behaviors, however the precise relationship between synaptic connectivity and behavior is unclear. We studied synaptic connectivity between granule cells (GCs) and Purkinje cells (PCs) in murine acute cerebellar slices using photostimulation of caged glutamate combined with patch-clamp in developing or after mice adapted to different locomotor contexts. By translating individual maps into graph network entities, we found that synaptic maps in juvenile animals undergo critical period characterized by dissolution of their structure followed by the re-establishment of a patchy functional organization in adults. Although, in adapted mice, subdivisions in anatomical microzones do not fully account for the observed spatial map organization in relation to behavior, we can discriminate locomotor contexts with high accuracy. We also demonstrate that the variability observed in connectivity maps directly accounts for motor behavior traits at the individual level. Our findings suggest that, beyond general motor contexts, GC-PC networks also encode internal models underlying individual-specific motor adaptation.

The cerebellar cortex computes sensorimotor information from many brain areas through a feedforward inhibitory (FFI) microcircuit between the input stage, the granule cell layer, and the output stage, the Purkinje cells (PC). While in other brain areas FFI underlies a precise excitation vs. inhibition temporal correlation, recent findings in the cerebellum highlighted more complex behaviors at the granule cell (GC) – molecular layer interneuron (MLI) – PC pathway. To dissect the temporal organization of this cerebellar FFI pathway, we combined exvivo patch clamp recordings of PCs in male mice with a viral-based strategy to express Channelrhodopsin2 in a subset of mossy fibers (MFs), the major excitatory inputs to GCs. We show that while light-mediated MF activation elicited pairs of excitatory and inhibitory postsynaptic currents in PCs, excitation (E) from GCs and inhibition (I) from MLIs reached PCs with a wide range of different temporal delays. However, when GCs were directly stimulated, a low variability in E/I delays was observed. Our results demonstrate that in many recordings MF stimulation recruited different groups of GCs that trigger E and/or I, and expanded PCs temporal synaptic integration. Finally, using a computational model of the FFI pathway, we showed that this temporal expansion could strongly influence how PCs integrate GC inputs. Our findings show that specific E/I delays may help PCs encoding specific MF inputs.Significance statementSensorimotor information is conveyed to the cerebellar cortex by mossy fibers. Mossy fiber inputs activate granule cells that excite molecular interneurons and Purkinje cells, the sole output of the cerebellar cortex, leading to a sequence of synaptic excitation and inhibition in Purkinje cells, thus defining a feedforward inhibitory pathway. Using electrophysiological recordings, optogenetic stimulation, and mathematical modeling, we demonstrated that different groups of granule cells can elicit synaptic excitation and inhibition with various latencies onto Purkinje cells. This temporal variability control how granule cells influence Purkinje cell discharge and may support temporal coding in the cerebellar cortex.

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The cerebellar cortex computes sensorimotor information from many brain areas through a feedforward inhibitory (FFI) microcircuit between the input stage, the granule cell layer, and the output stage, the Purkinje cells. While in other brain areas FFI underlies a precise excitation vs inhibition temporal correlation, recent findings in the cerebellum highlighted more complex behaviors at the granule cell (GC)-molecular layer interneuron (MLI)-Purkinje cell (PC) FFI pathway. To dissect the temporal organization of the cerebellar FFI pathway, we combined ex vivo patch clamp recordings of PCs with a viral-based strategy to express Channelrhodopsin2 in a subset of mossy fibers (MFs), a major excitatory input to GCs. We show that light-mediated MF activation elicits excitatory and inhibitory currents in PCs with a wide range of temporal delays. Furthermore, in many recordings, excitation and inhibition were initiated by different groups of GCs, expanding PCs synaptic temporal integration. Using a computational model of the FFI pathway we demonstrated that this temporal expansion could strongly influence how PCs integrate MF inputs. Our findings suggest that MF inputs are also encoded by specific delays between excitation and inhibition in PCs.

From planification to execution, cerebellar microcircuits encode different features of skilled movements. However, it is unknown whether cerebellar synaptic connectivity maps encode movement features in a motor context specific manner. Here we investigated the spatial organization of excitatory synaptic connectivity in mice cerebellar cortex in different locomotor contexts: during development and in normal, trained or altered locomotor conditions. We combined optical, electrophysiological and graph modelling approaches to describe synaptic connectivity between granule cells (GCs) and Purkinje cells (PCs). Synaptic map maturation during development revealed a critical period in juvenile animals before the establishment of a stereotyped functional organization in adults. However, different locomotor conditions lead to specific GC-PC connectivity maps in PCs. Ultimately, we demonstrated that the variability in connectivity maps directly accounts for individual specific behavioral features of mice locomotion, suggesting that GC-PC networks encode a general motor context as well as individual specific internal models underlying motor adaptation.

The telencephalon and eye in mammals are originated from adjacent fields at the anterior neural plate. Morphogenesis of these fields generates telencephalon, optic-stalk, optic-disc, and neuroretina along an axis. How these telencephalic and ocular tissues are specified coordinately to ensure directional retinal ganglion cell (RGC) axon growth is unclear. Here, we report the self-formation of human telencephalon-eye organoids comprising concentric zones of telencephalic, optic-stalk, optic-disc, and neuroretinal tissues along the center-periphery axis. Initially-differentiated RGCs grew axons towards and then along a path defined by adjacent PAX2+ optic-disc cells. Single-cell RNA sequencing identified expression signatures of two PAX2+ cell populations that mimic optic-disc and optic-stalk, respectively, mechanisms of early RGC differentiation and axon growth, and RGC-specific cell-surface protein CNTN2, leading to one-step purification of electrophysiologically-excitable RGCs. Our findings provide insight into the coordinated specification of early telencephalic and ocular tissues in humans and establish resources for studying RGC-related diseases such as glaucoma.