Defining functional circuits between CN molecular subpopulations and the cerebral cortex

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Recent work has provided evidence for functional connections between the cerebellum and cerebral cortex, with the hemispheres and central zone of the vermis housing the main cerebro-cerebellar circuits. Cerebellar neuropathologies have been detected in cognitive disorders including autism spectrum disorder (ASD), schizophrenia and dementias, and modulation of Purkinje neurons in one lobule in the right lateral cerebellum results in altered social and cognitive behaviors. The excitatory neurons of the cerebellar nuclei (eCN) are the output neurons of the cerebellum that interconnect with the cerebral cortex via the pons and thalamus, but their development, electrophysiology and molecular genetics are poorly understood. In particular, functional relationships between the cerebellar nuclei and cerebral cortex have not been demonstrated. In order to understand how the cerebellum functions and modulates the activity of the cerebral cortex, it is necessary to define the molecular diversity of the eCN, understand how eCN subpopulations (subP) develop, map their circuitry and relate cerebro-cerebellar functions to specific eCN subP. A major problem for such studies is a lack of genetic tools for specifically marking and modulating eCN. This project will define molecular subP of the eCN and determine how and when the subP form during normal development and in developmental mutants in which a subset of eCN are lost (En1/2 mutants) using single cell RNA sequencing (scRNA-seq). Mouse lines will then be developed to manipulate eCN subP and applied to mapping the synaptic partners of subP of eCN and to optogenetics to inhibit/activate specific eCN. Electrophysiology and cognitive/social behavior assays will be used to determine the functional interactions between specific subP of the eCN and regions of the cerebral cortex. This project represents the first definition of the molecular subP of the cerebellar nuclei and determination of their functional impact on cerebral cortex functions. RELEVANCE (See instructions): The cerebellum, in addition to the cerebral cortex, is involved in cognitive and social disorders including autism and schizophrenia, however little is know of the neural circuits that connect the two brain structures. We will map how distinct subpopulations of neurons in the cerebellum project to the cerebral cortex during development and determine how they influence cerebro-cerebellar functions. Our results will provide insights into how cerebro-cerebellar circuits function and might be therapeutically modified in diseases.