DISCRETE FUNCTIONS OF BASAL FOREBRAIN CHOLINERGIC SIGNALING TO AMYGDALA AND ORBITOFRONTAL CORTEX IN REVERSAL LEARNING - THIS PROPOSAL DESCRIBES A FOUR-YEAR RESEARCH CAREER DEVELOPMENT PROGRAM FOR AN MD/PHD STUDYING THE CIRCUIT PHYSIOLOGY OF COGNITIVE FLEXIBILITY, WHICH HAS RELEVANCE FOR A LARGELY UNADDRESSED SYMPTOM DOMAIN SEEN IN SCHIZOPHRENIA (SCZ), AUTISM SPECTRUM DISORDER (ASD), POST-TRAUMATIC STRESS DISORDER (PTSD), AND OTHER CONDITIONS. THE PROPOSED STUDIES BUILD UPON THE CANDIDATE'S FOUNDATION IN RODENT BEHAVIOR AND ADVANCED CELL AND MOLECULAR BIOLOGY TECHNIQUES, BUT THEY WILL REQUIRE TRAINING TO DEVELOP NEW, COMPLEMENTARY SKILLS IN TWO KEY DIMENSIONS: A) COMPUTATIONAL MODELING OF COMBINED NEURAL AND BEHAVIORAL DATA SETS, AND B) USING SYNAPSE-SPECIFIC OPTOGENETIC AND PHARMACOLOGIC MANIPULATIONS TOGETHER WITH STATE-OF THE-ART MARKERLESS BEHAVIORAL TRACKING TOOLS TO PERFORM BEHAVIORAL EXPERIMENTS WITH REAL-TIME INTERVENTIONS. THESE TRAINING GOALS ARE REFLECTED IN THE EXPERTISE OF THE INVOLVED CO-MENTORS (DRS. CHRISTOPH KELLENDONK AND KIYOHITO IIGAYA), TAILORED SEMINARS AND DIDACTICS, AND THE STRONG NEUROSCIENCE TRAINING ENVIRONMENT AT NEW YORK STATE PSYCHIATRIC INSTITUTE AND COLUMBIA UNIVERSITY. COMPLETING THE PROPOSED STUDIES AND MULTI-FACETED TRAINING PLAN WILL POSITION THE CANDIDATE WITH A SOUGHT-AFTER COMBINATION OF SKILLS THAT WILL FACILITATE TRANSITIONING INTO A PRODUCTIVE, INDEPENDENT PHYSICIAN-SCIENTIST STUDYING COGNITIVE DYSFUNCTIONS IN MENTAL DISORDERS. ACETYLCHOLINE (ACH)-RELEASING NEURONS OF THE BASAL FOREBRAIN (BF) ARE IMPLICATED IN ASSOCIATIVE LEARNING AND BEHAVIORAL FLEXIBILITY, AS MEASURED VIA THE PARADIGM OF REVERSAL LEARNING. HOWEVER, THE TIMING AND BEHAVIORALLY RELEVANT EFFECTS OF ACH INPUT TO BF TARGET REGIONS INVOLVED IN REVERSAL LEARNING, INCLUDING THE BASOLATERAL AMYGDALA (BLA) AND LATERAL ORBITOFRONTAL CORTEX (LO), REMAIN LARGELY UNEXPLORED. PROBING THESE MECHANISMS HAS TRANSLATIONAL IMPORTANCE, AS REVERSAL LEARNING DEFICITS ARE MEASURABLE IN PEOPLE WITH SCZ, ASD, AND PTSD, THOUGH IT IS UNCLEAR HOW MUCH THESE FINDINGS ARE GENERALIZABLE TO DISPARATE LEARNING CONTEXTS. THE PROPOSED STUDIES INVESTIGATE THE HYPOTHESIS THAT STIMULUS-ASSOCIATED CHANGES IN BF-DERIVED ACH INPUT TO THE BLA AND LO REGULATE DISCRETE BEHAVIORAL PARAMETERS UNDERLYING REWARD-BASED REVERSAL LEARNING DEPENDING ON THE ASSOCIATIVE CONTEXT USED-WHETHER PAVLOVIAN OR OPERANT, DETERMINISTIC OR PROBABILISTIC. IN AIM 1, COMPUTATIONAL ANALYSIS WILL BE USED ON SIMULTANEOUS RECORDINGS OF ACH ACTIVITY IN THE BLA AND LO DURING REVERSAL LEARNING TASKS TO DISCERN THE SPECIFIC BEHAVIORAL PARAMETERS, SUCH AS PREDICTION ERROR OR LEARNING RATE, ENCODED THROUGH EACH TARGET AREA AND THEIR INTERACTIONS. IN AIM 2, OPTOGENETIC CONTROL OF BF PROJECTION NEURONS AND INTRAVITAL MICROINFUSIONS OF PHARMACOLOGIC INHIBITORS WILL BE EMPLOYED TO DEMONSTRATE THE NECESSITY OF ACH RELEASE IN THE BLA AND LO FOR THE DIFFERENT LEARNING CONTEXTS TESTED, AND COMPUTATIONAL MODELS WILL BE TESTED AGAINST EACH OTHER TO ASSESS THEIR INTERPRETABILITY AND PREDICTIVE POWER. THESE STUDIES AND THEIR FUTURE DIRECTIONS WILL FORM THE BASIS OF MY INDEPENDENT RESEARCH CAREER AND HELP TO IDENTIFY TARGETS FOR NOVEL THERAPIES TO ADDRESS DEFICITS IN COGNITIVE FLEXIBILITY, WHICH DRIVE DISABILITY AND POSE BARRIERS TO RECOVERY.