Project Grant F31AA033550

THE IMPACT OF HIGH-INTENSITY DRINKING ON MOLECULAR AND ELECTROPHYSIOLOGICAL PLASTICITY IN THE NUCLEUS ACCUMBENS - PROJECT SUMMARY HIGH-INTENSITY DRINKING (HID) IS A PREVALENT PATTERN OF ALCOHOL CONSUMPTION ASSOCIATED WITH INCREASED HEALTH RISKS AND A GREATER LIKELIHOOD OF DEVELOPING AN ALCOHOL USE DISORDER (AUD). THE NUCLEUS ACCUMBENS (NAC) IS CRITICAL FOR REINFORCEMENT LEARNING AND ALCOHOL-RELATED BEHAVIORS, AND THE GABAERGIC MEDIUM SPINY NEURONS (MSNS), WHICH MAKE UP MOST NAC NEURONS, ARE CENTRAL TO UNDERSTANDING ALCOHOL-RELATED BEHAVIORS. PRIOR STUDIES HAVE EXAMINED THE EFFECTS OF ALCOHOL ON THE NAC, YET THE MOLECULAR AND ELECTROPHYSIOLOGICAL MECHANISMS UNDERLYING HID REMAIN INCOMPLETELY UNDERSTOOD. IN PARTICULAR, THE ROLE OF GSK3B AND NAV1.6 IN REGULATING MSN FUNCTION AND DRIVING EXCESSIVE DRINKING BEHAVIORS HAS NOT BEEN INVESTIGATED. TO FILL THIS GAP IN KNOWLEDGE, THIS PROPOSAL WILL INVESTIGATE HOW HID ALTERS MOLECULAR AND ELECTROPHYSIOLOGICAL PROPERTIES OF NAC MSNS, TESTING THE CENTRAL HYPOTHESIS THAT HID INCREASES GSK3B AND NAV1.6 EXPRESSION AND THAT THESE CHANGES DRIVE EXCESSIVE DRINKING. THIS PROPOSAL WILL COMBINE MOLECULAR ANALYSES OF HUMAN NAC WITH IN VIVO ELECTROPHYSIOLOGY IN MICE TO EXAMINE CHANGES IN GSK3B AND NAV 1.6 EXPRESSION AND MSN EXCITABILITY. SPECIFICALLY, THE PROPOSED AIMS WILL DETERMINE AUD- AND CELL-TYPE SPECIFIC CHANGES IN GSK3B AND NAV1.6 GENE EXPRESSION OF HUMAN NAC TISSUE (AIM 1), EXAMINE HOW HID ALTERS FIRING RATES OF NAC MSNS IN MICE (AIM 2), AND TEST WHETHER DECREASING GSK3B EXPRESSION IN THE NAC OF MICE REDUCES NAV1.6 EXPRESSION AND PROTECTS AGAINST HID (AIM 3). COLLECTIVELY, THIS PROPOSAL WILL DETERMINE THE IMPACT OF HID ON MOLECULAR AND FUNCTIONAL PROPERTIES OF NAC MSNS, FOCUSING ON THE RELATIONSHIP BETWEEN GSK3B AND NAV1.6 EXPRESSION. THE SUCCESSFUL COMPLETION OF THIS PROPOSAL WILL PROVIDE CRITICAL INFORMATION ON THE MECHANISMS BY WHICH HID ALTERS MSN FUNCTION AND DRIVES EXCESSIVE ALCOHOL CONSUMPTION. ADDITIONALLY, THIS WORK WILL PROVIDE INTENSIVE TRAINING IN SYSTEMS NEUROSCIENCE TECHNIQUES, INCLUDING AWAKE-BEHAVING HIGH-DENSITY ELECTROPHYSIOLOGY, STEREOTAXIC VIRAL INFUSIONS, AND BIOINFORMATIC AND TIME SERIES DATA ANALYSES.