Project Grant F32AA032415

CELL-TYPE SPECIFIC CONTROL OF ALCOHOL-ASSOCIATED BEHAVIOR IN THE STRIATUM - PROJECT SUMMARY ALCOHOL USE DISORDER (AUD) IS A LEARNING DISORDER IN WHICH ALCOHOL ALTERS NEURAL CIRCUITS, CAUSING A MALADAPTIVE DESIRE TO SEEK AND TAKE ALCOHOL. AUD CAN DEVELOP FOLLOWING REPEATED EXPOSURE, INITIATING A CYCLE OF EXCESSIVE ALCOHOL CONSUMPTION, PERIODS OF ABSTINENCE, AND RELAPSE. DESPITE THE PREVALENCE AND COST OF THIS DISORDER, TREATMENT STRATEGIES ARE INEFFECTIVE, ESPECIALLY IN PREVENTING RELAPSE. IT IS WELL-KNOWN THAT CUES ASSOCIATED WITH THE AVAILABILITY OF ALCOHOL CAN TRIGGER SEEKING, INCREASE DRINKING BEHAVIOR, AND CONTRIBUTE TO RELAPSE. THUS, UNDERSTANDING THE NEURAL MECHANISMS ENCODING INFORMATION ABOUT ALCOHOL AND ASSOCIATED CUES IS CRITICAL FOR UNDERSTANDING HOW THESE ASSOCIATIONS DEVELOP AND CHANGE WITH LONG-TERM DRINKING TO CONTRIBUTE TO SEEKING BEHAVIOR. THE MAJOR GOAL OF THIS PROPOSAL IS TO ELUCIDATE THE NEURAL MECHANISMS UNDERLYING CUE-ALCOHOL ASSOCIATIONS AND HOW THEY ARE CHANGED BY CHRONIC ALCOHOL EXPOSURE AND ABSTINENCE. PREVIOUS IN VIVO WORK FROM OUR LAB HAS SHOWN THAT D2-RECEPTOR-CONTAINING MEDIUM SPINY NEURONS (MSNS) IN THE NUCLEUS ACCUMBENS (NAC) ARE CRITICAL FOR ENCODING ASSOCIATIONS BETWEEN CUES AND OUTCOMES AND CAUSALLY CONTROL CUE-ASSOCIATIONS AT THE POPULATION LEVEL. IMPORTANTLY, OUR PRELIMINARY DATA INDICATES THAT D2 MSN ACTIVITY IS DYNAMICALLY MODULATED OVER TIME WITH ALCOHOL DRINKING, SPECIFICALLY, IN RESPONSE TO ALCOHOL-ASSOCIATED CUES. HOWEVER, THE PRECISE INFORMATION ENCODED WITHIN THE TEMPORAL ACTIVITY OF THESE D2 MSNS IN VIVO HAS NOT BEEN CLEARLY DEFINED - ESPECIALLY AT THE SINGLE-CELL LEVEL. ADDITIONALLY, D2 MSNS IN THE NAC RECEIVE DIRECT PROJECTIONS FROM MULTIPLE BRAIN AREAS THAT ARE KEY TO ALCOHOL RELATED BEHAVIORAL DYSFUNCTION AND THESE GLUTAMATERGIC INPUTS HAVE BEEN SHOWN TO BE ALTERED WITH ALCOHOL EXPOSURE. HOWEVER, WHETHER THESE ALTERATIONS OCCUR GLOBALLY OR AT SPECIFIC SYNAPSES HAS YET TO BE INVESTIGATED. THIS PROPOSAL WILL UTILIZE MICROENDOSCOPES TO VISUALIZE SINGLE CELL ACTIVITY DYNAMICS OF D2 MSNS IN THE NAC DURING OPERANT ALCOHOL SELF-ADMINISTRATION TO 1) DEFINE HOW D2 MSNS ARE ENGAGED OVER THE COURSE OF OPERANT ALCOHOL DRINKING AND 2) ASSESS CHANGES IN D2 MSN ACTIVITY ASSOCIATED WITH ABSTINENCE FROM CHRONIC INTERMITTENT ETHANOL (CIE) EXPOSURE AND ALCOHOL SEEKING. NEXT, USING ELECTROPHYSIOLOGY TO MEASURE FUNCTIONAL CIRCUIT ADAPTATIONS, WE WILL 3) ASSESS THE EFFECTS OF CHRONIC ALCOHOL USE AND FORCED ABSTINENCE ON PHYSIOLOGY AND CIRCUIT CONNECTIVITY OF D2 MSNS IN THE NAC. I HYPOTHESIZE THAT D2 MSN ACTIVITY EVOKED BY ALCOHOL- ASSOCIATED CUES IS INCREASED OVER ALCOHOL EXPOSURE AND ABSTINENCE AND THAT CHRONIC ALCOHOL EXPOSURE AND ABSTINENCE ENHANCES CIRCUIT-SPECIFIC GLUTAMATERGIC DRIVE ONTO D2 MSNS, AFFECTING THEIR PHYSIOLOGICAL PROPERTIES. THIS PROPOSAL ENCOMPASSES TECHNICAL AND THEORETICAL TRAINING THAT WILL PROVIDE THE FOUNDATIONAL EXPERTISE AND CONCEPTUAL THINKING NEEDED TO ADDRESS LARGER QUESTIONS REGARDING HOW LONG-TERM EXPOSURE TO ALCOHOL CHANGES THE BRAIN AND DRIVES CONTINUED ALCOHOL USE. ADDITIONALLY, THESE FINDINGS CAN ULTIMATELY INFORM OUR UNDERSTANDING OF UNDERLYING REWARD AND LEARNING PROCESSES AND LEAD TO MORE EFFICACIOUS TREATMENT INTERVENTIONS FOR AUD.