Project Grant F31AA033517

INVESTIGATING CORTICO-LIMBIC ENSEMBLE DYNAMICS DURING ALCOHOL CONSUMPTION - PROJECT SUMMARY THE PROGRESSION OF ALCOHOL USE DISORDER (AUD) IS DRIVEN BY IMPAIRED CONTROL AND SUBSEQUENT ESCALATION FROM CASUAL TO CHRONIC ALCOHOL USE, AFFECTING AN ESTIMATED 28 MILLION PEOPLE IN THE UNITED STATES. WHILE SEVERAL STUDIES HAVE IDENTIFIED FUNCTIONAL AND STRUCTURAL DEFICITS IN THE MEDIAL PREFRONTAL CORTEX (MPFC) ASSOCIATED WITH CHRONIC ALCOHOL USE, THE MOLECULAR AND CIRCUIT-LEVEL MECHANISMS RESPONSIBLE FOR DISINHIBITION IN AUD REMAIN POORLY DEFINED. RESULTS FROM PHARMACOLOGICAL STUDIES SHOW THAT INACTIVATION OF DOPAMINE TYPE 1 RECEPTOR (D1R) ACTIVITY IN THE VENTRAL PORTION OF THE MPFC (E.G., INFRALIMBIC, IL) RESTORES GOAL-DIRECTED BEHAVIOR AFTER HABIT FORMATION, SUGGESTING THAT IL-D1RS ARE A LIKELY TARGET FOR MODULATING CORTICAL CONTROL OF DRINKING AFTER DEPENDENCE. ADDITIONALLY, PRIOR RESEARCH SUGGESTS THAT CONTROL OF ALCOHOL-SEEKING IS REGULATED BY SPARSE COORDINATED NEURAL ACTIVITY (I.E., NEURONAL ENSEMBLES) IN THE IL. THIS IS SUPPORTED BY THE FINDING THAT D1R EXPRESSING NEURONS (D1) IN THE IL PROJECTING TO THE POSTERIOR BASOLATERAL AMYGDALA (PBLA) ARE NECESSARY FOR ALCOHOL-SEEKING. CRUCIALLY, CHRONIC INTERMITTENT ETHANOL (CIE) MODELS OF DEPENDENCE SHOW PERSISTENT, ESCALATED DRINKING, DESPITE DEVALUATION WITH A BITTER SUBSTANCE (I.E., QUININE-RESISTANT DRINKING). SINCE THE ILD1PBLA CIRCUIT IS NECESSARY FOR ALCOHOL-SEEKING, AND DEPENDENCE SHIFTS BEHAVIOR TOWARD PERSISTENT RESPONDING, IT IS PLAUSIBLE THAT PATHOLOGICAL HYPERACTIVITY OF THIS SPECIFIC CORTICO-LIMBIC PROJECTION DRIVES BOTH EXCESSIVE AND QUININE-RESISTANT ALCOHOL CONSUMPTION. EXTENDING THESE FINDINGS TO UNCOVER HOW ALCOHOL INFLUENCES BOTH LOCAL ILD1 AND CIRCUIT ILD1PBLA ENSEMBLES IS CRITICAL FOR IDENTIFYING AND UNDERSTANDING ENSEMBLES THAT CONTROL EXCESSIVE DRINKING BEHAVIOR. MY PRELIMINARY DATA HIGHLIGHTS A POTENTIAL ROLE FOR D1S ENCODING LICK BOUTS FOR ALCOHOL, WHICH BECOME EXCITED WHEN ALCOHOL IS SPIKED WITH QUININE. THESE CURRENT DATA SUGGEST THAT CORTICAL D1S MAY SERVE AS A PROMISING NEW TARGET FOR MODULATING CONTROL OF ALCOHOL CONSUMPTION BEHAVIOR. TO DATE, NO WORK HAS EXPLORED SINGLE-CELL ACTIVITY IN ILD1 ENSEMBLES DURING FREELY MOVING ALCOHOL CONSUMPTION IN DEPENDENCE. THEREFORE, THE FOCUS OF THIS PROPOSAL IS TO MEASURE ILD1 ENSEMBLE ACTIVITY AND MANIPULATE ILD1PBLA PROJECTION POPULATION ACTIVITY BEFORE AND AFTER DEPENDENCE. MY OVERARCHING HYPOTHESIS IS THAT DEPENDENCE ENHANCES ILD1PBLA ENSEMBLE ACTIVITY TO PROMOTE EXCESSIVE AND AVERSION-RESISTANT DRINKING. AIM 1 WILL MEASURE SINGLE-CELL CALCIUM DYNAMICS OF LOCAL ILD1 AND CIRCUIT ILD1PBLA ENSEMBLES ENCODING DEVALUED AND UNALTERED ALCOHOL LICK BOUTS BEFORE AND AFTER DEPENDENCE. AIM 2 WILL CAUSALLY ASSESS THE FUNCTION OF ILD1PBLA PROJECTION NEURONS IN DEPENDENCE-INDUCED DRINKING BY OPTOGENETICALLY MANIPULATING ACTIVITY DURING QUININE-RESISTANT DRINKING. OVERALL, THIS RESEARCH WILL PROVIDE VALUABLE TRAINING IN CUTTING-EDGE IMAGING AND GENETIC APPROACHES FOR THE FELLOW IN AN EXCELLENT TRAINING AND RESEARCH ENVIRONMENT AT MUSC. NOVEL INSIGHT INTO THE ROLE OF ILD1 ENSEMBLES AND CORTICOLIMBIC PROJECTIONS WILL IMPROVE OUR UNDERSTANDING OF THE NEUROBIOLOGICAL MECHANISMS THAT UNDERLIE DISINHIBITION OF DRINKING IN AUD.