D2 receptors in cholinergic interneurons: role in striatal circuitry & motivation

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 DESCRIPTION (provided by applicant): My long-term goals are to direct and conduct original, productive, and compelling research that promotes the advancement of the field towards finding cures for brain disorders. I am interested in pursuing a research career aimed at understanding how specific neural circuits may become impaired in neuropsychiatric disorders by studying the underlying cellular mechanisms contributing to their function. With my sight set on these goals, my main objective in the near future is to obtain the necessary skillset, knowledge, and mentorship to develop a cohesive and innovative research plan aimed at elucidating the cellular mechanisms mediating motivated behavior. Through this award mechanism, I will study the functional and behavioral consequences of D2 dopamine receptor (D2R) alterations specifically in cholinergic interneurons. I will address this critical issue by learning to apply advanced tools in electrophysiology, optogenetics, in vivo pharmacogenetics, and behavioral models of motivation with the assistance of a select mentoring team. To complement my basic research training, I will also seek essential guidance in clinical and translational aspects of disorders characterized by motivational abnormalities. This new scientific knowledge will be matched by a mentored plan for professional development focused on the necessary steps towards establishing an independent and competitive research program. Several neuropsychiatric disorders, including attention-deficit hyperactivity disorder and chronic drug abuse - which display significant motivational deficits - are associated with reduced D2R function in brain regions involved in reward. However, it is poorly understood whether there is a causal relationship between D2R levels and motivation. In addition, the cell type(s) mediating this D2R effect on motivation has not been identified. Recent evidence from our group suggests that increasing D2R levels in the nucleus accumbens enhances incentive motivation, but this global approach did not distinguish between key cell populations in this region. In this proposal, I will test the intriguing possibility that D2R levels in cholinergic interneurons of the nucleus accumbens are critically involved in the regulation of striatal circuit function and motivated behaviors. To do this, I will use cell-selective strategies, in combination with electrophysiologicl and behavioral analysis. Specifically, I will test the hypothesis that D2R upregulation in cholinergic interneurons alters firing patterns linked to reinforcement learning. Further, I will determine whether increased D2R levels in these neurons not only have key consequences on the function of striatal output pathways, but are also critical regulators of incentive motivation. The information derived from this work will increase our understanding of the mechanisms underlying motivation, while shedding light on potential new treatment targets for motivational dysregulation.