Characterization of NAc D1 MSNs in Encoding Reward, Aversion, and Decision-Making During Conflict

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PROJECT SUMMARY Impaired reward and aversion processing underlie the symptomatology of a diverse set of psychiatric disorders. However, the precise neural basis of reward and aversive stimuli remains to be elucidated. The nucleus accumbens (NAc) is a key brain region implicated in hedonic processing, encoding reward and aversion signals via medium spiny neurons (MSNs) that express dopamine D1 receptors (D1) or dopamine D2 receptors (D2). The canonical view of NAc functioning is that D1- MSNs encode reward, and D2- MSNs encode aversion. However, recent work has challenged this view, as D1 MSNs have been found to encode aversive states or inhibit reward seeking. Our preliminary data using single unit recording with miniscope imaging, revealed that only some NAc D1 MSNs activate in response to a footshock whereas others do not. NAc D1-MSNs project to the LH, VTA, and VP, whereas D2-MSNs only project to the VP. Hence, one possibility is that there are subsets of D1 MSNs that encode both reward and aversion based depending on their output regions. To address this gap, we propose that NAc D1 MSNs encode reward or aversion based on their efferent organization and participate in adaptive decision -making during conflict between reward and aversion. This hypothesis will be tested in two specific aims: Aim 1 tests the hypothesis that different ensembles of NAc D1 MSNs encode reward or aversion depending on efferent organization. In Aim 2, we will test the hypothesis that D1 MSNs encode decision making during motivational conflict between reward and aversion, advancing our understanding of D1 MSNs independent of the outcomes obtained in Aim 1. To test the hypothesis, these experiments will combine novel methods, such as transgenic/viral approaches, single-cell Ca2+ imaging, optogenetics, and machine learning. Thus, I will gain training in in these techniques forming a strong foundation for my independent research program to answer questions in line with my interests in motivation and decision making in a technically elegant and translationally relevant manner. These results will contribute to our understanding of motivational and emotional neural circuits implicated in the pathophysiology of psychiatric disorders, such as depression and addiction.