Friday, March 14, 2025
3/14/2025
Dissecting basal ganglia circuits underlying motivated behaviors Project Summary The basal ganglia, in particular the dorsal striatum, play essential roles in motor control, motivational regulation and reinforcement learning. On the other hand, striatal dysfunctions have been implicated in a number of neurological and psychiatric disorders, including Parkinson's disease, Huntington’s disease, obsessive compulsive disorder, autism, depression and drug addiction. A notable feature of the dorsal striatum is its separation into two neurochemically distinct compartments, the striosome (or “patch”) compartment and the surrounding matrix compartment. It is thought that neurons in the matrix and those in the striosome have distinct functions, with the former critical for motor functions, whereas the latter important for evaluation functions during learning and for regulation of motivation. In addition, the striosome compartment has been especially implicated in the non-motor aspects of the neurological disorders, such as learning deficits, and mood and motivational aberrations. However, despite intensive study, to date the functionality of neurons in the striosome remains largely uncharacterized. Consequently, how striosome neurons contribute to reinforcement learning and regulation of motivation is unclear. Whether and how dysfunctions in these neurons occur and contribute to the diseases are also unknown. A major challenge to studying the striosome lies in the fact that it is labyrinthine in shape and has no clear anatomical boundaries, making it difficult to precisely target for in vivo recording or manipulation. To address this issue, we recently exploited mouse genetics for targeting neurons in the striosome. This strategy laid the foundation for selectively monitoring and manipulating the activities of different populations of striosome neurons. In the proposed study, we will capitalize on our approach and findings to investigate the behavioral roles of distinct striosome populations in health and disease, and to uncover the underlying circuit and cellular mechanisms. Our central hypothesis is that functionally distinct striosome populations differentially control reward seeking and punishment avoidance through different circuit mechanisms. We further hypothesize that these striosome neurons become dysfunctional after major stressful life events, thereby causing maladaptive behaviors. We will test our hypotheses in the following Aims: Aim 1. To determine the behavioral roles of distinct classes of striosome neurons. Aim 2. To determine the circuit and cellular mechanisms underlying striosome functions. Aim 3. To elucidate the striosome dysfunctions underlying stress-induced maladaptive behaviors.
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