Cortico-cerebellar interactions underlying motor planning and movement

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Abstract A central goal in neuroscience is to understand how neural circuits give rise to behavior. Persistent and ramping preparatory activity in frontal cortex anticipates specific future movements. Preparatory activity is the neural correlate of motor planning that gives rise to volitional movements. Preparatory activity has been postulated to emerge from processes distributed across multiple brain regions, but it is unclear how this activity is mediated by multi-regional interactions and which brain areas are involved. In previous work, we have determined a discrete part of the mouse frontal cortex (anterior lateral motor cortex, ALM) is a hub for motor planning. A large fraction of ALM neurons display preparatory activity selective for specific future movements. Our recent data show that preparatory activity in ALM is dependent on the cerebellum. Neurons in both ALM and cerebellum respond robustly during motor planning and causally contribute to the behavior. Anatomical tracings reveal loop- like reciprocal connectivity between these two brain regions. This proposal aims to elucidate how movements are prepared by the cortico-cerebellar multi-regional circuits. Our central hypothesis is that the cerebellum mediates movement-selective cortical preparatory activity by controlling persistent activity in thalamocortical loops through feedback control computations that are analogous to motor control. To probe the specific roles of cortico-cerebellar interactions in motor planning, we will record preparatory activity while manipulating neural signals at various stages of the cortico-cerebellar loop. In aim 1, we will identify the cerebellar nodes of the cortico-cerebellar loop mediating motor planning by mapping preparatory activity in the cerebellar cortex and nuclei. We hypothesize that the fastigial nucleus and its input Purkinje cells are selectively engaged in planning directional licking (together with ALM). In aim 2, we will clarify neural signals propagating within the entire cortico- cerebellar loop by recording and manipulating activity in the relay brain regions, the pontine nucleus and the thalamus, as well as the inferior olive. In aim 3, we will disambiguate the specific functions of circuit nodes within the cortico-cerebellar loop by silencing activity in various stages of the cerebellar loop and determine their impacts on preparatory activity. The outcome will clarify circuit mechanisms of preparatory activity, which is an form of persistent neural activity underlying many core cognitive functions.