Anterior Cingulate Cortex to Dorsal Striatal Circuits in Compulsive-like Binge Alcohol Drinking

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Project Summary/Abstract This project proposes to investigate the underlying neural mechanisms within the dorsal striatum driving the development and maintenance of compulsive-like binge-drinking, or consumption of alcohol despite known negative consequences, using chemogenetics and awake-and-behaving electrophysiology in male and female C57BL/6J mice. Despite the established functional relationship of the prefrontal cortex inputs into the dorsomedial striatum (DMS) for goal directed behaviorally flexible alcohol drinking and the dorsolateral striatum (DLS) in compulsive behaviorally inflexible alcohol drinking, the circuit level shift in control of modulating the development of compulsive-like alcohol drinking has not been defined, which limits prevention and treatment of alcohol use disorder (AUD). The major hypotheses of this project are 1) the development and maintenance of compulsive-like alcohol drinking relies on DLS mechanisms of potentiation from anterior cingulate cortex (ACC) excitatory inputs which are facilitated by reduced ACC-DMS input and 2) that neuronal activity in the DMS and DLS will differ based on alcohol drinking history, bull all mice will increase activity in the DLS and compulsive- like mice will have greater DLS activity than DMS activity. The proposed project will assess the neural mechanisms underlying home cage compulsive-like binge-drinking using drinking-in-the-dark during chemogenetic inhibition from the ACC-DMS and ACC-DLS and through awake-and-behaving electrophysiology recordings in the DS during compulsive-like alcohol drinking. The training plan for this project is curated in an ideal research environment, engaging collaboration between both Indiana University – Purdue University Indianapolis and the Indiana Alcohol Research Center to provide training in cutting edge neuroscience techniques, professional development, and research ethics that will facilitate my career as an independent scientist. The specific research hypotheses are 1) ablation of the excitatory projections from the ACC to the DMS will cause alcohol naïve mice to develop and alcohol history mice to increase compulsive-like alcohol drinking across drinking sessions. 2) Ablation of the excitatory projections from the ACC to the DLS will cause alcohol naïve mice to prevent development and alcohol history mice to attenuate compulsive-like alcohol drinking across drinking sessions. 3) Alcohol naïve and alcohol history mice will differ in their pattern of neuronal activity, with relatively increased activity in the DLS and relatively decreased activity in the DMS across drinking sessions in association with a compulsive-like alcohol drinking phenotype. Completion of the proposed work will elucidate understanding of the mechanisms and neural circuits underlying the development and maintenance of compulsive-like alcohol drinking and will serve to inform researchers in the field of addiction neuroscience, leading to increased understanding and ultimately improved prevention and treatment of AUD.