Project Grant F31AA031397

INPUT SPECIFIC ADAPTATIONS TO GLUTAMATERGIC STRENGTH AND PLASTICITY ON PFC PV-INS FOLLOWING ETHANOL DRINKING - PROJECT SUMMARY/ABSTRACT: ALTHOUGH BOTH MEN AND WOMEN ARE AFFECTED BY ALCOHOL USE DISORDER (AUD), WOMEN OFTEN PROGRESS THROUGH AUD DISEASE MILESTONES FASTER AND EXPERIENCE MORE SEVERE HEALTH CONSEQUENCES THAN MEN. ONE KEY BRAIN REGION ASSOCIATED WITH AUD IS THE PREFRONTAL CORTEX (PFC), A STRUCTURE ASSOCIATED WITH DEFICITS IN MODERATING DRINKING BEHAVIORS. PREVIOUS FINDINGS FROM OUR LAB DEMONSTRATE THAT PARVALBUMIN-EXPRESSING INHIBITORY INTERNEURONS (PV-INS), A KEY SUBPOPULATION OF GABAERGIC CELLS WITHIN PFC, DISPLAY BASAL SEX DIFFERENCES IN MEMBRANE PHYSIOLOGY AND UNDERGO SEX-DEPENDENT ADAPTATIONS IN SYNAPTIC STRENGTH FOLLOWING CHRONIC DRINKING. IN RECENT YEARS, THE METABOTROPIC GLUTAMATE (MGLU) RECEPTOR SUBTYPE 5 HAS EMERGED AS A PROMISING THERAPEUTIC TARGET FOR THE TREATMENT OF AUD. THE MGLU5 RECEPTOR IS HIGHLY EXPRESSED ON PFC PV-INS AND HAS BEEN IMPLICATED IN MEDIATING ETHANOL SEEKING ACROSS SEVERAL RODENT MODELS OF AUD. HOWEVER, LIMITED CLINICAL SUCCESS OF COMPOUNDS THAT INHIBIT MGLU5 RECEPTORS NECESSITATES A MORE PRECISE UNDERSTANDING OF THE CIRCUITS AND SYNAPTIC MECHANISMS THROUGH WHICH MGLU5 RECEPTORS REGULATE DRINKING BEHAVIORS. MY PRELIMINARY DATA SUGGESTS THAT MGLU5 RECEPTORS SEX-DEPENDENTLY REGULATE SYNAPTIC TRANSMISSION AND ENDOCANNABINOID PLASTICITY ONTO PFC PV-INS. IN THIS PROPOSAL I WILL USE EX VIVO SLICE ELECTROPHYSIOLOGY, VIRAL-MEDIATED OPTOGENETIC TOOLS, AND RNASCOPE TO TEST THE HYPOTHESIS THAT DISTINCT EXCITATORY INPUTS ONTO PV-INS ARE REGULATED BY MGLU5 RECEPTOR SIGNALING, AND THAT CHRONIC DRINKING FUNCTIONALLY ALTERS THESE INPUTS AND MGLU5 RECEPTOR FUNCTION. THIS PROPOSAL WILL SPECIFICALLY ASSESS GLUTAMATERGIC AFFERENTS FROM THE BASOLATERAL AMYGDALA (BLA) AND MEDIODORSAL THALAMUS (MDT), WHICH PREFERENTIALLY TARGET PV-INS TO DRIVE ROBUST FEEDFORWARD INHIBITION IN THE PFC. IN BOTH HUMAN AND ANIMAL STUDIES, ACUTE AND CHRONIC ETHANOL EXPOSURE ALTERS GLUTAMATE TRANSMISSION IN THE BLA AND MDT. HOWEVER, DIFFERENCES IN SUBCELLULAR LOCALIZATION AND EXPRESSION OF CB1 RECEPTORS MAY SUGGEST THAT EACH OF THESE EXCITATORY INPUTS HAVE DIFFERENT FUNCTIONS AT PFC PV-INS FROM MALE AND FEMALE MICE. IN AIM 1, I WILL DETERMINE WHETHER MGLU5 RECEPTORS REGULATE EXCITATORY TRANSMISSION (1.1) AND ENDOCANNABINOID PLASTICITY (1.2) AT BLA AND MDT SYNAPSES ON PFC PV-INS IN A SEX-SPECIFIC MANNER. IN AIM 2, I WILL DETERMINE WHETHER CHRONIC DRINKING SEX-DEPENDENTLY ALTERS BLA AND MDT SYNAPTIC STRENGTH (2.1) AND MGLU5 RECEPTOR SIGNALING ON PFC PV-INS (2.2). PRELIMINARY DATA INDICATE FEMALE (BUT NOT MALE) MICE WITH A GENETIC DELETION OF MGLU5 FROM PV+ CELLS DRINK LESS WHEN PROVIDED IA ETHANOL. IN AIM 3, I WILL DETERMINE WHETHER PFC PV-INS MEDIATE BINGE-DRINKING IN PV-MGLU5-/- MICE. THE RESULTS OF THESE EXPERIMENTS WILL IMPROVE OUR UNDERSTANDING OF THE MOLECULAR COMPONENTS UNDERLYING ETHANOL-INDUCED ADAPTATIONS IN SYNAPTIC PLASTICITY AT SPECIFIC PFC INPUTS AND MAY DIRECT THERAPEUTIC INTERVENTIONS FOR THE TREATMENT OF AUD. BY COMPLETING THIS PROPOSAL, I WILL HAVE STRENGTHENED MY TECHNICAL SKILLS, ENHANCED MY KNOWLEDGE, AND RECEIVED PROFESSIONAL DEVELOPMENT NECESSARY FOR MY SUCCESS AS AN INDEPENDENT INVESTIGATOR IN THE FIELD OF ALCOHOL RESEARCH.