Project Grant R21AA031415

ROLE OF PERINEURONAL NETS IN ADOLESCENT ALCOHOL-INDUCED DEFICITS - PROJECT SUMMARY/ABSTRACT ADOLESCENCE IS A DEVELOPMENTAL PERIOD MARKED BY RISK-TAKING BEHAVIOR AND EXPLORATION, AND OVER 60% OF 12TH-GRADERS IN THE US REPORTED TRYING ALCOHOL. IN FACT, 16% OF 12TH GRADERS REPORTED BINGE DRINKING, OR CONSUMING 5+ DRINKING IN A SESSION. WHILE HUMAN STUDIES SHOW THAT ADOLESCENT BINGE DRINKING IMPACTS COGNITIVE PERFORMANCE AND NEURAL SIGNALS VIA MRI, IT IS DIFFICULT TO TEASE APART ANTECEDENT FACTORS THAT MAY LEAD TO BINGE DRINKING FROM THE CONSEQUENCES OF THE RESULTING ALCOHOL EXPOSURE ON THE DEVELOPING BRAIN. WE AND OTHERS HAVE USED ANIMAL MODELS TO SHOW THAT BINGE-LEVELS OF ALCOHOL EXPOSURE IS SUFFICIENT TO REDUCE COGNITIVE AND BEHAVIORAL FLEXIBILITY IN CONDITIONING TASKS. MOREOVER, THESE BEHAVIORAL CHANGES ARE ASSOCIATED WITH A VARIETY OF NEUROCHEMICAL, PHYSIOLOGICAL, MOLECULAR AND EPIGENETIC CHANGES IN THE BRAIN. WE HAVE REPORTED THAT ADOLESCENT INTERMITTENT ETHANOL (AIE) EXPOSURE RESULTED DEFICIENT REVERSAL LEARNING, IN THAT RATS PERSEVERATED ON A PREVIOUSLY REINFORCED CHOICE INSTEAD OF SHIFTING TO A DIFFERENT CHOICE. WE ALSO FOUND THAT AIE-EXPOSED RATS EXHIBITED REDUCED FUNCTIONAL CONNECTIVITY, MEASURED WITH RESTING-STATE FMRI, AMONG REGIONS OF INTEREST THAT UNDERLIE BEHAVIORAL CHOICE. FINALLY, WE AND OTHERS HAVE REPORTED AIE-INDUCED INCREASES IN PERINEURONAL NETS (PNNS, EXTRACELLULAR MATRIX STRUCTURES THAT ENCAPSULATE PARVALBUMIN (PV)-EXPRESSING INTERNEURONS) IN FRONTAL REGIONS SUCH AS THE ORBITOFRONTAL CORTEX. THIS IS IMPORTANT AS PV+ INTERNEURONS CONTRIBUTE TO GAMMA OSCILLATIONS THAT WOULD BE REFLECTED IN FUNCTIONAL CONNECTIVITY MEASURES. HOWEVER, IT IS UNKNOWN WHETHER AIE-INDUCED INCREASES IN PNNS CONTRIBUTE TO THE AIE-INDUCED BEHAVIORAL AND FUNCTIONAL CONNECTIVITY DEFICITS. THIS PROJECT ADDRESSES THAT KNOWLEDGE GAP BY ENZYMATICALLY DEGRADING PNNS IN THE OFC OF AIE-EXPOSED RATS AND MEASURING SUBSEQUENT EFFECTS ON REVERSAL LEARNING AND FUNCTIONAL CONNECTIVITY MRI. TO OUR KNOWLEDGE, THE RESULTING DATA WILL BE THE FIRST TO LINK PNN INTEGRITY IN THE OFC TO BEHAVIORAL FLEXIBILITY AND FUNCTIONAL CONNECTIVITY. THESE DATA WILL CONTRIBUTE TO OUR UNDERSTANDING OF THE MECHANISMS BY WHICH AIE PERSISTENTLY DISRUPTS BEHAVIOR AND BRAIN CIRCUIT FUNCTION AND LAY THE FOUNDATION FOR STRATEGIES TO AMELIORATE THESE EFFECTS.