Genetic Dissection of Catecholaminergic Innervation of the Cognitive Cerebellum

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Studies in humans and non-human primates have identified a region of the dentate nucleus of the cerebellum (DCN), or lateral nucleus in rodents (LCN), which is activated during performance of cognitive tasks involving complex spatial and sequential planning. We have previously shown that the dopamine D1 receptor marks a population of neurons in the LCN with similar spatial distribution and regulates cognitive performance on several tasks related to attention and working memory, and has connections with other parts of the brain that are classically involved in these functions. The DCN is implicated in cognitive function in humans with psychiatric illnesses, but virtually nothing is known about its basic anatomical and functional organization. Unraveling this will set the stage for precision therapeutics in the cognitive domain, an area where we have few options to offer patients. We hypothesized that the locus ceruleus is the principal source of both dopamine and norepinephrine release in LCN, catecholamines are required for cerebellar enhancement of attention and working memory tasks, and locus ceruleus neurons release catecholamines in a phasic manner. We have mapped projections of the LC to DCN, and have found that when we electrically stimulate the LC, we can observe catecholamine release in the LCN with fast scan cyclic voltammetry in anesthetized animals. We have also found that when we turn off tyrosine hydroxylase expression in the LCN, we get abnormal performance on sensory discrimination, working memory, and impulsive behaviors. Here we propose to establish the basic electrophysiological, anatomical, and behavioral function of these pathways using Cre driver mouse lines in combination with advanced techniques in viral-based circuit dissection. Successful completion of our proposed aims will provide novel insight into the basic organization of the LCN and establish a framework for novel, precision therapeutics to assist patients with cognitive dysfunction.