Circuit and Molecular Anaylses of Cerebellar Output Neurons

Johns Hopkins University, Baltimore MD

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Abstract

? DESCRIPTION (provided by applicant): The goal of this project is to generate cellular and molecular information critical for improving clinical treatments of cerebellar disorders and for fundamental understanding of the mechanisms responsible for cerebellar control of oculomotor, skeletomotor, autonomic, and cerebral cortical circuits. Although much is known about cerebellar physiology, anatomy, and vulnerability to damage and disease, clinical treatments of cerebellar disorders are limited by the paucity of cellular and molecular information on cerebellar output neurons required to identify specific drug targets. The specific objectives of the project are to elucidate molecular and synaptic information in functionally distinct types of cerebellar output neurons. To achieve these objectives, quantitative, single-cell gene expression analyses of specific classes of cerebellar output neurons will be performed. Complementary anatomical circuit analyses will identify differential synaptic connectivity, and in vitro physiological experiments will probe the impact of cerebellar cortical computations on spike timing and rate in distinct classes of cerebellar output neurons. These experiments will provide a critical foundation for rational pharmacological therapies for postural instability and autonomic dysfunction and other debilitating sequelae of cerebellar disorders. Revealing the expression of neurotransmitter receptors, ion channels and other drug targets on physiologically and anatomically-defined subsets of cerebellar output neurons will enable enhanced specificity and efficacy in restoring postural and oculomotor stability, autonomic regulation, and cognitive functions while minimizing side effects