Project Grant F30MH143351

DETERMINING BASAL FOREBRAIN CONTRIBUTIONS TO STRATEGY SHIFTS IN DECISION MAKING - PROJECT SUMMARY DURING PERCEPTUAL DECISION-MAKING, ANIMALS OFTEN SWITCH BETWEEN MULTIPLE STRATEGIES DESPITE NO CHANGE IN THE ENVIRONMENT. EXPLORING MULTIPLE STRATEGIES IS IMPORTANT FOR LEARNING AND FLEXIBILITY IN NATURAL ENVIRONMENTS. WHY AND HOW ANIMALS SWITCH STRATEGIES DURING DECISION-MAKING IS UNCLEAR. DISTRIBUTED NEUROMODULATOR RELEASING SYSTEMS HAVE BEEN PROPOSED TO HELP COORDINATE SHIFTS IN NEURAL STATE ACROSS THE BRAIN. WHILE ALL NEUROMODULATORS LIKELY CONTRIBUTE, ACETYLCHOLINE PROJECTIONS FROM THE BASAL FOREBRAIN ARE OF PARTICULAR INTEREST TO STRATEGY SHIFTS BECAUSE THEIR ACTIVITY IS LINKED WITH BOTH DISCRETE TASK EVENTS LIKE REWARDS AND ALSO SHIFTS IN INTERNAL STATES LIKE AROUSAL. FURTHERMORE, SCHIZOPHRENIA FEATURES COGNITIVE IMPAIRMENT INCLUDING DIFFICULTY SHIFTING STRATEGIES IN TASKS. THE FIRST NEW CLASS OF SCHIZOPHRENIA DRUG IN 30 YEARS, XANOMELINE TROSPIUM CHLORIDE, TARGETS ACETYLCHOLINE TO UNIQUELY IMPROVE COGNITIVE IMPAIRMENT. HOW ACETYLCHOLINE IMPACTS DECISION-MAKING IS POORLY UNDERSTOOD, SLOWING DEVELOPMENT OF MORE TARGETED THERAPIES. THE POSTERIOR PARIETAL CORTEX IS AN IDEAL CORTICAL REGION TO STUDY THE IMPACT OF NEUROMODULATION ON NEURAL ACTIVITY IN DECISION-MAKING BECAUSE IT IS NECESSARY FOR NAVIGATIONAL DECISION-MAKING, RECEIVES NEUROMODULATORY INPUTS FROM THE BASAL FOREBRAIN, AND SHOWS SHIFTS IN ITS NEURAL ACTIVITY WHEN ANIMALS SHIFT STRATEGIES. HOWEVER, NO WORK HAS YET DIRECTLY ESTABLISHED WHETHER NEUROMODULATION PLAYS A ROLE IN STATE SWITCHING IN THE PPC. I HYPOTHESIZE THAT THREE ANIMAL STRATEGIES, BIAS, RULE-FOLLOWING, AND RANDOM CHOICE, EXIST ON A SPECTRUM OF INCREASING ACETYLCHOLINE RELEASE WITH ASSOCIATED SHIFTS IN LOCAL NEURAL ACTIVITY. IN PARTICULAR, I PREDICT THAT THE LOW ACETYLCHOLINE, HIGH BIAS STATE WILL FEATURE LOW PPC FIRING RATES AND STEREOTYPED DYNAMICS WHILE THE HIGH ACETYLCHOLINE, RANDOM CHOICE STATE WILL FEATURE HIGH FIRING RATES AND MORE VARIABLE DYNAMICS. TO TEST THIS IN MY FIRST AIM, I WILL RECORD SIMULTANEOUS LOCAL NEURAL ACTIVITY AND ACETYLCHOLINE RELEASE IN THE PPC AS MICE UNDERGO STRATEGY SHIFTS WHILE COMPLETING A NAVIGATIONAL DECISION-MAKING TASK. HOWEVER, ACETYLCHOLINE IS LIKELY NOT THE ONLY BASAL FOREBRAIN OUTPUT CONTRIBUTING TO THESE BEHAVIORS SINCE THE BASAL FOREBRAIN ALSO SENDS GLUTAMATERGIC AND GABAERGIC PROJECTIONS TO THE PPC. FAR LESS IS KNOWN ABOUT THESE PROJECTIONS AND WHETHER THEY SUBSERVE SIMILAR OR DIFFERENT ROLES. RECENT WORK HAS FOUND THAT SIMILAR PROJECTIONS FROM THE RAPHE NUCLEI REGULATE THE DEGREE OF EXPLORATION. THEREFORE, I HYPOTHESIZE THAT ACETYLCHOLINE IS NECESSARY FOR RULE- FOLLOWING AND THE GLUTAMATERGIC AND GABAERGIC PROJECTIONS ARE NECESSARY TO PREVENT PERSEVERATION. TO TEST THIS, I WILL OPTOGENETICALLY INHIBIT EACH CELL TYPE IN SEPARATE MICE WHILE THEY PERFORM A NAVIGATIONAL DECISION-MAKING TASK. TOGETHER, THESE RESULTS WILL ADVANCE OUR BASIC UNDERSTANDING OF THE ROLE OF THE BASAL FOREBRAIN IN COGNITION AND ALSO IDENTIFY POTENTIAL ALTERNATIVE TARGETS FOR CELL-TYPE SPECIFIC THERAPIES TO IMPROVE COGNITIVE IMPAIRMENT IN PSYCHIATRIC ILLNESSES LIKE SCHIZOPHRENIA.