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The olivocerebellar system, which is critical for sensorimotor performance and learning, functions through modules with feedback loops. The main feedback to the inferior olive comes from the cerebellar nuclei (CN), which are predominantly GABAergic and contralateral. However, for the d subnucleus of the caudomedial accessory olive (cdMAO), a crucial region for oculomotor and upper-body movements, the source of GABAergic input has yet to be identified. Here, we demonstrate the existence of a disynaptic inhibitory projection from the medial CN (MCN) to the cdMAO via the superior colliculus (SC) by exploiting retrograde, anterograde and transsynaptic viral tracing at the light microscopic level as well as anterograde classical and viral tracing combined with immunocytochemistry at the electron microscopic level. Retrograde tracing in Gad2-Cre mice reveals that the cdMAO receives GABAergic input from the contralateral SC. Anterograde transsynaptic tracing uncovered that the SC neurons receiving input from the contralateral MCN provide predominantly inhibitory projections to contralateral cdMAO, ipsilateral to the MCN. Following ultrastructural analysis of the monosynaptic projection about half of the SC terminals within the contralateral cdMAO are GABAergic. The disynaptic GABAergic projection from the MCN to the ipsilateral cdMAO mirrors that of the monosynaptic excitatory projection from the MCN to the contralateral cdMAO. Thus, while completing the map of inhibitory inputs to the olivary subnuclei, we established that the MCN inhibits the cdMAO via the contralateral SC, highlighting a potential push-pull mechanism in directional gaze control that appears unique in terms of laterality and polarity among olivocerebellar modules.Significance Statement All dendritic spines of the inferior olive receive a combined inhibitory and excitatory input, which is critical for regulation of temporal control during sensorimotor coordination. Yet, some sources of GABAergic input

Despite its uniform appearance, the cerebellar cortex is highly heterogeneous in terms of structure, genetics and physiology. Purkinje cells (PCs), the principal and sole output neurons of the cerebellar cortex, can be categorized into multiple populations that differentially express molecular markers and display distinctive physiological features. Such features include action potential rate, but also their propensity for synaptic and intrinsic plasticity. However, the precise molecular and genetic factors that correlate with the differential physiological properties of PCs remain elusive. In this article, we provide a detailed overview of the cellular mechanisms that regulate PC activity and plasticity. We further perform a pathway analysis to highlight how molecular characteristics of specific PC populations may influence their physiology and plasticity mechanisms.

The olivocerebellar system, which is critical for sensorimotor performance and learning, functions through modules with feedback loops. The main feedback to the inferior olive comes from the cer-ebellar nuclei (CN), which are predominantly GABAergic and contralateral. However, for the subnu-cleus d of the caudomedial accessory olive (cdMAO), a crucial region for oculomotor and upper body movements, the source of GABAergic input has yet to be identified. Here, we demonstrate the ex-istence of a disynaptic inhibitory projection from the medial CN (MCN) to the cdMAO via the superior colliculus (SC) by exploiting retrograde, anterograde, and transsynaptic viral tracing at the light microscopic level as well as anterograde classical and viral tracing combined with immunocytochem-istry at the electron microscopic level. Retrograde tracing in Gad2-Cre mice reveals that the cdMAO receives GABAergic input from the contralateral SC. Anterograde transsynaptic tracing uncovered that the SC neurons receiving input from the contralateral MCN provide predominantly inhibitory projections to contralateral cdMAO, ipsilateral to the MCN. Following ultrastructural analysis of the monosynaptic projection about half of the SC terminals within the contralateral cdMAO are GABAergic. The disynaptic GABAergic projection from the MCN to the ipsilateral cdMAO mirrors that of the monosynaptic excitatory projection from the MCN to the contralateral cdMAO. Thus, while completing the map of inhibitory inputs to the olivary subnuclei, we established that the MCN inhibits the cdMAO via the contralateral SC, highlighting a potential push–pull mechanism in directional gaze control that appears unique in terms of laterality and polarity among olivocere-bellar modules.

Cerebellar output neurons integrate strong inhibitory input and weaker excitatory input during the control of spontaneous and learned movements. A new study sheds light on how those inputs are integrated during associative swimming in zebrafish larvae.

The posterior parietal cortex (PPC) in rodents is reciprocally connected to primary somatosensory and vibrissal motor cortices. The PPC neuronal circuitry could thus encode and potentially integrate incoming somatosensory information and whisker motor output. However, the information encoded across PPC layers during refined sensorimotor behavior remains largely unknown. To uncover the sensorimotor features represented in PPC during voluntary whisking and object touch, we performed loose-patch single-unit recordings and extracellular recordings of ensemble activity, covering all layers of PPC in anesthetized and awake, behaving male rats. First, using single-cell receptive field mapping, we revealed the presence of coarse somatotopy along the mediolateral axis in PPC. Second, we found that spiking activity was modulated during exploratory whisking in layers 2-4 and layer 6, but not in layer 5 of awake, behaving rats. Population spiking activity preceded actual movement, and whisker trajectory endpoints could be decoded by population spiking, suggesting that PPC is involved in movement planning. Finally, population spiking activity further increased in response to active whisker touch but only in PPC layers 2-4. Thus, we find layer-specific processing, which emphasizes the computational role of PPC during whisker sensorimotor behavior.SIGNIFICANCE STATEMENT The posterior parietal cortex (PPC) is thought to merge information on motor output and sensory input to orchestrate interaction with the environment, but the function of different PPC microcircuit components is poorly understood. We recorded neuronal activity in rat PPC during sensorimotor behavior involving motor and sensory pathways. We uncovered that PPC layers have dedicated function: motor and sensory information is merged in layers 2-4; layer 6 predominantly represents motor information. Collectively, PPC activity predicts future motor output, thus entailing a motor plan. Our results are important for und

Our cerebellum has been proposed to generate prediction signals that may help us plan and execute our motor programmes. However, to what extent our cerebellum is also actively involved in perceiving the action of others remains to be elucidated. Using functional MRI, we show here that observing goal-directed hand actions of others bilaterally recruits lobules VI, VIIb and VIIIa in the cerebellar hemispheres. Moreover, whereas healthy subjects (n = 31) were found to be able to discriminate subtle differences in the kinematics of observed limb movements of others, patients suffering from spinocerebellar ataxia type 6 (SCA6; n = 21) were severely impaired in performing such tasks. Our data suggest that the human cerebellum is actively involved in perceiving the kinematics of the hand actions of others and that SCA6 patients' deficits include a difficulty in perceiving the actions of other individuals. This finding alerts us to the fact that cerebellar disorders can alter social cognition.

The posterior parietal cortex (PPC) in rodents is reciprocally connected to primary somatosensory and vibrissal motor cortices. The PPC neuronal circuitry could thus encode and potentially integrate incoming somatosensory information and whisker motor output. However, the information encoded across PPC layers during refined sensorimotor behavior remains largely unknown. To uncover the sensorimotor features represented in PPC during voluntary whisking and object touch, we performed loose-patch single-unit recordings and extracellular recordings of ensemble activity, covering all layers of PPC in anesthetized and awake, behaving male rats. First, using single-cell receptive field mapping, we revealed the presence of coarse somatotopy along the mediolateral axis in PPC. Second, we found that spiking activity was modulated during exploratory whisking in layers 2-4 and layer 6, but not in layer 5 of awake, behaving rats. Population spiking activity preceded actual movement, and whisker trajectory endpoints could be decoded by population spiking, suggesting that PPC is involved in movement planning. Finally, population spiking activity further increased in response to active whisker touch but only in PPC layers 2-4. Thus, we find layer-specific processing, which emphasizes the computational role of PPC during whisker sensorimotor behavior.SIGNIFICANCE STATEMENT The posterior parietal cortex (PPC) is thought to merge information on motor output and sensory input to orchestrate interaction with the environment, but the function of different PPC microcircuit components is poorly understood. We recorded neuronal activity in rat PPC during sensorimotor behavior involving motor and sensory pathways. We uncovered that PPC layers have dedicated function: motor and sensory information is merged in layers 2-4; layer 6 predominantly represents motor information. Collectively, PPC activity predicts future motor output, thus entailing a motor plan. Our results are important for unders

Cerebellar plasticity is a critical mechanism for optimal feedback control. While Purkinje cell activity of the oculomotor vermis predicts eye movement speed and direction, more lateral areas of the cerebellum may play a role in more complex tasks, including decision-making. It is still under question how this motor-cognitive functional dichotomy between medial and lateral areas of the cerebellum plays a role in optimal feedback control. Here we show that elite athletes subjected to a trajectory prediction, go/no-go task manifest superior subsecond trajectory prediction accompanied by optimal eye movements and changes in cognitive load dynamics. Moreover, while interacting with the cerebral cortex, both the medial and lateral cerebellar networks are prominently activated during the fast feedback stage of the task, regardless of whether or not a motor response was required for the correct response. Our results show that cortico-cerebellar interactions are widespread during dynamic feedback and that experience can result in superior task-specific decision skills.

The directed differentiation of patient-derived induced pluripotent stem cells into cell-type specific neurons has inspired the development of therapeutic discovery for neurodegenerative diseases. Many forms of ataxia result from degeneration of cerebellar Purkinje cells, but thus far it has not been possible to efficiently generate Purkinje neuron (PN) progenitors from human or mouse pluripotent stem cells, let alone to develop a methodology for in vivo transplantation in the adult cerebellum. Here, we present a protocol to obtain an expandable population of cerebellar neuron progenitors from mouse embryonic stem cells. Our protocol is characterized by applying factors that promote proliferation of cerebellar progenitors. Cerebellar progenitors isolated in culture from cell aggregates contained a stable subpopulation of PN progenitors that could be expanded for up to 6 passages. When transplanted into the adult cerebellum of either wild-type mice or a strain lacking Purkinje cells (L7cre-ERCC1 knockout), GFP-labeled progenitors differentiated in vivo to establish a population of calbindin-positive cells in the molecular layer with dendritic trees typical of mature PNs. We conclude that this protocol may be useful for the generation and maturation of PNs, highlighting the potential for development of a regenerative medicine approach to the treatment of cerebellar neurodegenerative diseases.

Many daily life activities demand precise integration of spatial and temporal information of sensory inputs followed by appropriate motor actions. This type of integration is carried out in part by the cerebellum, which has been postulated to play a central role in learning and timing of movements. Cerebellar damage due to atrophy or lesions may compromise forward-model processing, in which both spatial and temporal cues are used to achieve prediction for future motor states. In the present study we sought to further investigate the cerebellar contribution to predictive and reactive motor timing, as well as to learning of sequential order and temporal intervals in these tasks. We tested patients with spinocerebellar ataxia type 6 (SCA6) and healthy controls for two related motor tasks; one requiring spatio-temporal prediction of dynamic visual stimuli and another one requiring reactive timing only. We found that healthy controls established spatio-temporal prediction in their responses with high temporal precision, which was absent in the cerebellar patients. SCA6 patients showed lower predictive motor timing, coinciding with a reduced number of correct responses during the 'anticipatory' period on the task. Moreover, on the task utilizing reactive motor timing functions, control participants showed both sequence order and temporal interval learning, whereas patients only showed sequence order learning. These results suggest that SCA6 affects predictive motor timing and temporal interval learning. Our results support and highlight cerebellar contribution to timing and argue for cerebellar engagement during spatio-temporal prediction of upcoming events.