Project Grant F31MH143586

CHARACTERIZING ACCUMBENS-PALLIDUM CIRCUITS IN APPROACH/AVOIDANCE CONFLICT - PROJECT SUMMARY BALANCING APPROACH AND AVOIDANCE IS CRUCIAL FOR DECISION-MAKING, AND DISRUPTIONS IN THESE PROCESSES ARE A HALLMARK OF NEUROPSYCHIATRIC DISORDERS SUCH AS ADDICTION, ANXIETY AND DEPRESSION. TRADITIONALLY, NUCLEUS ACCUMBENS DOPAMINE RECEPTOR 1-EXPRESSING (NACDRD1) NEURONS HAVE BEEN PROPOSED TO DRIVE REWARD-SEEKING BEHAVIORS, WHILE DOPAMINE RECEPTOR 2-EXPRESSING (NACDRD2) NEURONS MEDIATE THREAT AVOIDANCE. HOWEVER, EMERGING EVIDENCE SUGGESTS THAT NACDRD1 NEURONS MAY ALSO DRIVE AVERSIVE BEHAVIORS THROUGH THEIR PROJECTIONS TO THE VENTRAL PALLIDUM (VP), WHILE NACDRD2 PROJECTIONS TO THE VP MAY PROMOTE APPROACH BEHAVIORS, REVEALING A MORE NUANCED ROLE OF NAC NEURONAL SUBTYPES. INTERESTINGLY, THE VP IS THE MAIN TARGET OF THE NAC AND MEDIATES BOTH APPROACH AND AVOIDANCE BEHAVIORS VIA GABAERGIC AND GLUTAMATERGIC PROJECTIONS, RESPECTIVELY. HOWEVER, HOW NAC CELL-TYPE-SPECIFIC PROJECTIONS TO THE VP BALANCE APPROACH/AVOIDANCE BEHAVIORS DURING MOTIVATIONAL CONFLICT REMAINS UNKNOWN. TO EXPLORE THIS, I WILL USE THE NOVEL PLATFORM-MEDIATED AVOIDANCE (PMA) CONFLICT TASK, IN WHICH ANIMALS ARE CO-PRESENTED WITH REWARD AND THREAT-PREDICTING CUES. IN PMA CONFLICT, ANIMALS MUST BALANCE BETWEEN REWARD-APPROACH, RISKING A FOOT-SHOCK OR MOUNTING A SAFETY PLATFORM (THREAT AVOIDANCE) FAR FROM THE REWARD PORT, MISSING OUT ON THE REWARD. THIS PROJECT WILL CHARACTERIZE NACDRD1 AND NACDRD2 PROJECTIONS TO VP IN APPROACH/AVOIDANCE CONFLICT BY USING CALCIUM FIBER PHOTOMETRY AND OPTOGENETIC MANIPULATIONS DURING THE PMA CONFLICT TASK, WITH DRD1-CRE AND A2A-CRE MICE FOR CELL-TYPE SPECIFICITY. FOR AIM 1, I WILL MEASURE THE ACTIVITY OF NACDRD1 AND NACDRD2 PROJECTIONS TO THE VP DURING APPROACH/AVOIDANCE CONFLICT. FIBER PHOTOMETRY RECORDINGS WILL PROVIDE REAL-TIME NEURAL ACTIVITY IN RESPONSE TO BOTH APPETITIVE AND AVERSIVE EVENTS, AS WELL AS DURING APPROACH OR AVOIDANCE BEHAVIORS. FOR AIMS 2 AND 3, I WILL OPTOGENETICALLY MANIPULATE NACDRD1 AND NACDRD2 PROJECTIONS TO VP IN APPROACH/AVOIDANCE CONFLICT. BY SELECTIVELY ACTIVATING OR SILENCING THESE PROJECTIONS DURING THE PMA CONFLICT TASK, I WILL ASSESS WHETHER THEY ARE SUFFICIENT OR NECESSARY TO DRIVE APPROACH OR AVOIDANCE BEHAVIORS DURING CONFLICT. THIS RESEARCH AIMS TO CHARACTERIZE NEURAL CIRCUITS UNDERLYING MOTIVATION AND THEIR POTENTIAL ROLE IN THE PATHOPHYSIOLOGY OF MALADAPTIVE BEHAVIORS. THESE STUDIES WILL BE INSTRUMENTAL IN MY TRAINING TOWARDS RESEARCH INDEPENDENCE AND INVESTIGATING THE NEURAL CIRCUITS UNDERLYING MOTIVATION AND DECISION-MAKING.