The overall goals of this Program are to determine the structure- function relationships underlying the functional alterations in dopaminergic (DA) neurons in disorders of CNS function and determine if environmental factors that compromise the activity of the DA system can contribute to the etiology of movement disorders and cognitive deficits in Parkinson's disease. To achieve this goal, 4 Projects and 3 Cores will utilize an integrative and interactive approach in parallel experiments to evaluate the role of DA neurons in 1) regulation of motor behavior, 2) maintenance of basal ganglia output and cortical activity, 3) cognition, and 4) behavioral reactivity to aversive and rewarding stimuli. The projects will use common electrophysiological, biochemical and molecular methodologies. Project #1 (Dr. Hutton) uses a well-characterized transgenic mouse model of PD based on intra-nigral expression of a highly potent viral gene that causes selective toxicity in DA neurons. Project #2 (Dr. Le Moal) will determine if activation of VTA DA neurons causes a non-compulsive motor activity, as in amphetamine- induced motor activation. Project #3 (Dr. Wichmann) will determine how DA signaling influences the ability of hippocampal neurons to integrate complex patterns of presynaptic firing. Project #4 (Dr. Cepeda) will evaluate DA/glutamate interactions in the acquisition, performance and maintenance of spatial and object recognition memory in mice and rats. These projects and cores are supported by a well-established behavioral facility at UVM that is uniquely suited for this interdisciplinary program. This program is designed to provide new insight into the mechanisms of DA dysfunction and the functional consequences of DA denervation in neurologic disorders. [unreadable] [unreadable] [unreadable] [unreadable]