THE INHIBITORY MECHANISM UNDERLYING PSYCHEDELIC DISRUPTION OF VISUAL PROCESSING - PROJECT SUMMARY SEROTONERGIC PSYCHEDELICS, SUCH AS PSILOCYBIN, ARE KNOWN FOR PROFOUNDLY ALTERING VISUAL PERCEPTION, EXPERIENCED THROUGH BOTH ELEMENTARY AND COMPLEX HALLUCINATIONS. BUT THE MECHANISM BY WHICH PSYCHEDELICS ALTER VISUAL INFORMATION PROCESSING REMAINS UNCLEAR. I HYPOTHESIZE THAT PSYCHEDELIC-DRIVEN CHANGES IN MICROCIRCUIT ACTIVITY IN THE PRIMARY VISUAL CORTEX MAY UNDERLIE THE VISUAL STATE THAT ACCOMPANIES A PSYCHEDELIC EXPERIENCE. THIS PROPOSAL AIMS TO DETERMINE PSILOCYBIN'S CELLULAR AND MICROCIRCUIT MECHANISMS OF ACTION ON PARVALBUMIN INTERNEURONS IN THE MOUSE PRIMARY VISUAL CORTEX. IN AIM 1, I WILL MEASURE THE EFFECTS OF PSILOCYBIN ON SPONTANEOUS AND EVOKED ACTIVITY OF BOTH PARVALBUMIN INTERNEURONS AND EXCITATORY CELLS. I WILL USE LARGE-SCALE IN VIVO NEUROPIXEL RECORDINGS AND OPTOGENETIC CELL-TYPE TAGGING TO MEASURE THEIR FIRING RATES BEFORE AND AFTER PSILOCYBIN TREATMENT. IN PRELIMINARY RESULTS, I FOUND PSILOCYBIN-INDUCED INCREASES IN SPONTANEOUS FIRING ACTIVITY OF PARVALBUMIN INTERNEURONS. EVOKED ACTIVITY WILL BE MEASURED WITH STIMULI OF VARYING CONTRASTS AND ORIENTATIONS TO CHARACTERIZE EFFECTS ON ELEMENTARY VISUAL PROCESSING. IN AIM 2, I WILL EXAMINE WHETHER 5-HT2AR SEROTONIN RECEPTORS, EXPRESSED IN THE PARVALBUMIN INTERNEURONS IN THE PRIMARY VISUAL CORTEX, MEDIATE THE PARVALBUMIN CELL RESPONSIVENESS TO PSILOCYBIN. TO ACCOMPLISH THIS, I WILL CREATE AND RECORD FROM PV-SPECIFIC 5-HT2AR KNOCKOUTS, GENERATED VIA AN INDUCIBLE CRE STRATEGY. THE PROPOSED EXPERIMENTS ARE DESIGNED TO ELUCIDATE HOW PSILOCYBIN DISRUPTS EARLY VISUAL PROCESSING AND THUS PERCEPTION. IN DOING SO, I HOPE TO ADVANCE OUR KNOWLEDGE OF PSYCHEDELIC ACTION ON VISION AND OPEN THE WAY FOR GREATER INSIGHT INTO HALLUCINATIONS. IN THE FUTURE, BY IDENTIFYING THE MICROCIRCUITRY RESPONSES TO PSILOCYBIN TREATMENT, TARGETED DRUGS MAY BE DESIGNED TO REDUCE OR ELIMINATE VISUAL SIDE EFFECTS WHILE MAINTAINING LONG- LASTING ANTIDEPRESSANT EFFECTS.