PROJECT SUMMARY Acetylcholine (ACh) release in the dorsomedial striatum (DMS) is important for reversal learning, a form of cognitive flexibility impaired in schizophrenia and other psychiatric and neurologic disorders. Thalamic activity is necessary for DMS ACh release, and functional connectivity between the thalamus and the dorsal striatum is impaired in schizophrenia and other disorders, suggesting thalamostriatal regulation of ACh release may be a potential target for treatment of impaired cognition. However, it is unknown when and how thalamostriatal projections regulate striatal ACh release to update behavior and facilitate neuronal value encoding during reversal learning. To address this gap in knowledge, I will use a combination of fiber photometry, computational modeling, optogenetics, and high-density in vivo electrophysiology. To test the hypothesis that DMS ACh release accelerates learning rate, I will optogenetically inhibit DMS cholinergic interneurons during reward consumption in a reversal learning task and I will use an advanced reinforcement learning model to determine how this affects the rate at which the learning rate changes. To test the hypothesis that thalamostriatal projections are necessary for DMS acetylcholine release and reversal learning, I will use a retrograde viral strategy to determine whether projection-specific inhibition of thalamic inputs to the DMS during reward consumption decreases ACh release and impairs reversal learning. Finally, to test the hypothesis that DMS ACh release expedites value updating in medium spiny neurons I will simultaneously measure DMS ACh release with fiber photometry and striatal neuron activity with electrophysiology to determine whether DMS ACh release correlates with the rate at which striatal neurons update spike encoding of action value. This work will be performed at the New York State Psychiatric Institute and the Columbia University Irving Medical Center Department of Psychiatry. Together these institutions form a leading academic medical center and teaching hospital that has attracted a distinguished group of research scientists who provide leadership in modern psychiatry. My long-term career goal is to become an independent investigator studying the contribution of neuromodulation to behaviors and neural activity relevant to mental disorders. I have a strong background in optogenetics, behavioral neuroscience, and fiber photometry, which I will utilize in the proposed research. However, I still need additional training in advanced computational modeling of behavior and in vivo electrophysiology with high-density silicon probes. I will receive this technical training during the K01 award period, as well as professional development training to improve my grant-writing, leadership, and science communication skills. The conducted research and training during this career development award will increase my likelihood of success in becoming a leading neuroscientist and independe...