The basal ganglia lie at the critical interface between movement and motivation. The striatum, the largest structure of these deep-lying structures, is a hub for inputs from the overlying neocortex and is a main distributor of output to other parts of the brain via basal ganglia output nuclei. This system is implicated in a large range of neurological and neuropsychiatric disorders. It is modulated by neuromodulators, including by dopamine from the midbrain, deficient in Parkinson's disease. The dorsal striatum, the focus of this proposal, receives dopamine-containing input from the pars compacta of the substantia nigra (SNc). This nigrostriatal circuit degenerates in Parkinson's disease, and is a major controller of both motor behavior and responses to reinforcement and to motivational control. Our goal in the proposed research is to elucidate the physiology and anatomy of this system, focusing on critical questions related to these control mechanisms. First, our preliminary work suggests that the organization of the striatum into anatomically distinct compartments, the striosomes and surrounding matrix, is crucial in terms of behavior. Striosomes receive selective input from a restricted set of motivation/mood/emotion-related neocortical regions and are a main origin of the striatal projection to the SNc dopamine-containing neurons so important for mood and motor control. This evidence suggests special functions for striosomes, but what these functions are is not clear. Our preliminary and recent work suggests, however, that striosomes may be specialized for cost-benefit decision-making, in which costs and benefits presented in any situation have to be weighed in order for us to act. This kind of decision-making is critical for survival and, moreover, is disturbed in a number of neuropsychiatric conditions. We propose in Aim 1 to use state-of-the-art physiological and imaging methods in novel genetically engineered mice to test the hypothesis that striosomes underlie such decision-making. Second, our preliminary work has shown a remarkable anatomical organization of the striosome-SNc connection, suggesting that striosomes could exert powerful control over dopamine-containing SNc neurons. We propose to examine this system with novel combinations of optogenetic and physiological experiments combined with anatomy (Aim 2). Third, despite mounting evidence that striosome-matrix organization is a fundamentally important organizing property of the striatum, how this organization relates to the clinically critical division of the striatal output pathways into direct and indirect movement-control pathways is not understood. We aim to fill this gap by using specially engineered mice allowing direct testing of this relationship in physiological, imaging and behavioral experiments. Disturbances in the balance between cost and benefit in decision-making and movement control are critical in a number of neurologic and neuropsychiatric disorders ranging from P...