Dopaminergic modulation of nucleus accumbens during prospective and retrospective neuroeconomic decision making

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PROJECT SUMMARY In 2017, it was estimated that nearly 20% of the adult population in the U.S. live with a mental illness, yet much remains unknown about the pathophysiology of psychiatric disease and the specific behavioral symptomatology. Aberrations in decision making and information processing have been implicated in neuropsychiatric diseases like schizophrenia, obsessive-compulsive disorders, and depression. Importantly, dysregulations in nucleus accumbens core (NAc core) dopamine signaling onto medium spiny neurons (MSNs) constitute a key neural mechanism underlying these aberrant processes. Currently, NAc core research disproportionately focuses on the motivation and reward-learning aspects of decision making. There is, however, strong evidence that decision making involves more complex information-processing: making a decision requires evaluation of actual outcomes but also requires prospection and retrospection on imagined alternate outcomes. Therefore, it is important to investigate the role of dopamine release and MSN activity in information processing when agents prospectively imagine potential outcomes before making a decision through deliberation and when agents retrospectively imagine what could have been in the “path untraveled” (counterfactual reasoning) or imagine poor time investments (sunk cost processing) after making a decision through reevaluation. Our understanding of how NAc core dopamine encodes these imagined outcomes during prospective deliberation and retrospective reevaluation is lacking greatly because there have not been behavioral tools with the complexity to probe the mechanisms contributing to this type of information-processing in rodents. Innovative work in the Redish lab has led to the development of a rodent behavioral task, called Restaurant Row, whose intricacy allows for in-depth behavioral analysis of neuroeconomic behaviors. This proposal aims to elucidate how NAc core dopamine dynamics reflect deliberation, counterfactual reasoning and sunk cost evaluation by 1) simultaneous monitoring of in vivo dopamine release and MSN activity using fiber photometry 2) manipulating endogenous dopamine signaling at specific points in decision making. Restaurant Row has tremendous translational potential and has been adapted for non-human primates and humans. Thus, the work proposed here will contribute to a larger translational collaboration in the future to investigate these questions across species through collaboration with my clinical mentors in the Department of Psychiatry. My advisors Dr. David Redish and Dr. Patrick Rothwell are equipped to mentor me both technically and professionally and together we have curated a training plan that perfectly aligns with my career goals. By incorporating pioneering techniques into a translational project in such an interdisciplinary environment will provide the training I need to develop become a successful physician-scientist contributing to the field of computational psychiatry.