Dopamine activity patterns in the medial prefrontal cortex underlying compulsive alcohol drinking in mice

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Project Summary and Abstract Alcohol use disorder (AUD) is a chronic, relapsing disorder that is profoundly debilitating to those directly affected while placing enormous economic burden onto society. In the United States, a majority of adults consume alcohol on a monthly basis yet only a small subset of these individuals will go on to develop AUD, thus highlighting a critical need to identify risk factors underlying the transition or resilience to problematic drinking behaviors. Continued use of alcohol despite adverse consequences is a distinguishing feature of AUD that is mediated, in part, by the medial prefrontal cortex (mPFC). Activity in the mPFC is robustly modulated by the mesocortical dopamine system, a dopaminergic pathway projecting to the mPFC from the ventral tegmental area that is believed to influence a wide range of behaviors related to decision-making, response inhibition, and motivation. Clinical evidence indicates that both pre-existing and alcohol-induced alterations to the mesocortical dopamine system are critical in the development and maintenance of AUD. However, preclinical investigations of maladaptive drinking behaviors and their neural correlates involving animal models have remained predominantly focused on neuroadaptations at specific time points and as a result, often preclude assessment of pre-existing differences and how these interact with alcohol-induced changes to produce disparate behavioral outcomes. A main goal of this proposal is to longitudinally monitor real-time endogenous dopamine release dynamics within-subjects to ultimately identify dopamine release signatures in the mPFC that are associated with susceptibility to developing AUD-relevant behaviors in mice. To this end, we will use operant alcohol self-administration, punished alcohol self-administration using quinine adulteration, and free-access drinking procedures to assess the development of individual differences over multiple timepoints and drinking experience. Utilizing in vivo fiber photometry in conjunction with a novel dopamine sensor, we will measure real-time dopamine release in the mPFC throughout these behavioral tests. Further, using cell-type and projection-specific optogenetics we will directly test the impact of mPFC dopamine system activity on alcohol self-administration behaviors. Completion of this proposal will provide valuable insight into the role of mesocortical dopamine system in AUD-relevant behaviors and provide technical and conceptual training foundational to pursing my goals as an alcohol researcher.