Neuron- and Circuit-Specific Mechanisms and Adaptations Regulating Striatal Funct

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DESCRIPTION (provided by applicant): The ability to control one's movements is essential to life. Neural circuits involving the basal ganglia are a key component of the extrapyramidal motor system, which is required for adaptive motor control and procedural learning. Disruption of these circuits leads to profound movement disorders, such as Parkinson's disease and Huntington's disease. The striatum, which is the input nucleus of the basal ganglia, is a major site of activity- dependent plasticity and neuromodulation, particularly by dopamine. Because the striatum lies upstream of other basal ganglia nuclei, cellular and synaptic plasticity within this region alters the transfer of information throughout basal ganglia circuits. However, studies of the striatal function and dysfunction have been hampered by significant heterogeneity in both principal and interneuron populations. I propose to utilize recently developed transgenic mouse lines to identify cell-type-specific properties and plasticity that regulate striatal output and basal ganglia circuit function. I will also examine how these properties are altered in dopamine-depleted mice in order to gain insight into the mechanisms underlying basal ganglia dysfunction in Parkinson's disease. Finally, I will seek to identify pharmacological targets that enable in vivo manipulation of striatal output, with the goal of normalizing basal ganglia circuit activity and restoring proper locomotor function in Parkinsonian mice. The ultimate goal of these studies is to uncover novel therapeutic strategies for treating striatal-based brain disorders. PUBLIC HEALTH RELEVANCE The control of movement is among the most fundamental of all nervous system functions. Movement disorders such as Parkinson's disease and Huntington's disease are debilitating neurological disorders that result from altered neural activity in the striatum, a core region of the brain involved in motor control. We propose to characterize how different cells interact in the striatum to produce output that controls motor activity. The long- term goal is to develop a framework for the development of novel therapies for treating movement disorders involving the striatum.