Project Summary The striatum is an evolutionarily conserved structure involved in cognitive and limbic regulation of motor control. Striatal circuits are implicated in the initiation and execution of ethologically relevant motor output, ranging from exploratory actions to highly stereotyped motor patterns. Dysfunction of these circuits leads to motor control abnormalities that frequently manifest as excessive repetitive behaviors. Self-directed grooming, a highly stereotyped repetitive motor pattern, is observed in virtually all animals, serving vital functions in hygiene maintenance, thermoregulation, de-arousal, stress reduction, and social communication. Abnormally repetitive grooming is a central behavioral phenotype observed in numerous models for neurological and neuropsychiatric diseases. A better understanding of the neural control of grooming may thus yield fundamental insights into how the brain controls repetitive motor output in both normal and diseased conditions. Our preliminary work suggests that an understudied population of interneurons within the olfactory tubercle (OT; the most ventral part of the striatum), predominantly in the Islands of Calleja (IC), is involved in mediating this behavior. The striatum has a fairly uniform cellular composition, with ~95% of the neurons being spiny projection neurons (SPNs), classified as D1- or D2-type according to the dopamine receptors they express. One exception to this uniformity is the existence of evolutionarily conserved IC, clusters of densely- packed, GABAergic granule cells, which express the D3 dopamine receptor. By means of optogenetic manipulations, we have shown that activation of OT D3 neurons initiates robust grooming behavior via arrest of other alternative ongoing behaviors. In contrast, inactivation of these neurons halts ongoing grooming. These findings lead to the central hypothesis that OT D3 neurons play critical roles in controlling grooming behavior. Through an array of modern neuroscience approaches (optogenetics, ex vivo and in vivo electrophysiology, fiber photometry, neural circuit tracing, and behavior), we will pursue three specific aims to determine (1) in vivo activity patterns of OT D3 neurons and SPNs in grooming and other behaviors, (2) contributions of OT D3 neurons to grooming in relation to other brain regions, and (3) the effects of dopamine release into the OT on grooming behavior. Overall, this project will provide insights into the neural circuitry of the IC/OT D3 neurons and its role in neurobiological control of a highly important motor pattern.