Project Grant F31AA032987

DETERMINING THE ROLE OF ANTERIOR INSULAR CORTEX PARVALBUMIN-POSITIVE INTERNEURON FUNCTION IN AVERSION-RESISTANT ALCOHOL DRINKING - PROJECT SUMMARY/ABSTRACT DRINKING ALCOHOL DESPITE NEGATIVE CONSEQUENCES OR OUTCOMES IS ONE OF THE MAJOR RISK FACTORS FOR THE DEVELOPMENT OF ALCOHOL USE DISORDER (AUD) AND IS A SIGNIFICANT BARRIER TO CURRENT TREATMENT STRATEGIES. PARVALBUMIN POSITIVE INTERNEURONS (PV-IN) WITHIN THE ANTERIOR INSULAR CORTEX (AIC) ARE A PROMISING TARGET OF INVESTIGATION, AS THE AIC PLAYS A SIGNIFICANT ROLE IN AVERSION RESISTANT DRINKING AND IS VULNERABLE TO ALCOHOL EXPOSURE, INCLUDING BINGE DRINKING. FURTHER, PV-INS CAN BE MODULATED TO REVERSE DISRUPTIONS TO EXCITATORY/INHIBITORY BALANCE WITHIN THE AIC CAUSED BY BINGE ALCOHOL DRINKING AND CONTROL AVERSION-RESISTANT DRINKING IN OTHER BRAIN REGIONS. THE OVERALL OBJECTIVES OF THE STUDY ARE (1) TO DETERMINE WHETHER AIC PV-IN FUNCTION DRIVES AVERSION-RESISTANT ALCOHOL CONSUMPTION AND (2) TO CHARACTERIZE SPECIFIC MOLECULAR MECHANISMS AND PATHWAYS ASSOCIATED WITH AVERSION- RESISTANT DRINKING. THE LONG-TERM GOAL OF THE PROPOSAL IS TO IDENTIFY POTENTIAL THERAPEUTIC TARGETS AND PATHWAYS TO PREVENT AVERSION-RESISTANT ALCOHOL DRINKING. THE CENTRAL HYPOTHESIS IS THAT DISRUPTED PV-IN SIGNALING POTENTIATES EXCITATORY AIC OUTPUTS THAT DRIVE AVERSION-RESISTANT DRINKING, SUCH THAT RESTORING LOCAL INHIBITION WITHIN THE AIC WOULD DECREASE AVERSION-RESISTANT DRINKING. THIS CENTRAL HYPOTHESIS WILL BE TESTED THROUGH TWO SPECIFIC AIMS DESIGNED TO (1) EXAMINE AIC PV-IN CALCIUM ACTIVITY DURING AVERSION-RESISTANT DRINKING AND ASSESS THEIR FUNCTIONAL ROLE IN AVERSION-RESISTANT DRINKING, AS WELL AS (2) PROFILE GENETIC SIGNATURES OF PV-INS THAT ARE ASSOCIATED WITH AVERSION-RESISTANT DRINKING. THE PROPOSED STUDY IS INNOVATIVE AS IT WILL BE THE FIRST DIRECT ASSESSMENT OF THE ROLE OF AIC PV-INS IN AVERSION-RESISTANT ALCOHOL DRINKING AND THE FIRST TO USE CELL-TYPE SPECIFIC TRANSCRIPTOMICS TO PROFILE THE GENETIC SIGNATURES OF AVERSION-RESISTANT DRINKING IN AIC PV-INS. FURTHERMORE, WE WILL EMPLOY TRANSLATING RIBOSOME AFFINITY PURIFICATION (TRAP), A NOVEL METHOD WHICH WILL EXAMINE ACTIVELY TRANSLATING MRNA SPECIFIC TO PV-INS. THIS WILL IDENTIFY TRANSCRIPTS THAT ARE MORE CLOSELY RELATED TO PROTEIN EXPRESSION, ALLOWING FOR THE IDENTIFICATION OF MORE FUNCTIONALLY RELEVANT TARGETS THAN TRADITIONAL TRANSCRIPTOMIC METHODS. THE PROPOSED STUDY IS SIGNIFICANT, AS IT WILL PROVIDE FOUNDATIONAL INFORMATION AS TO THE NEURAL MECHANISMS UNDERLYING AVERSION- RESISTANT DRINKING AND IDENTIFY NOVEL MOLECULAR TARGETS FOR THE DEVELOPMENT OF THERAPEUTICS TO BROADEN THE EFFICACY OF AUD TREATMENT STRATEGIES. THE PROPOSED RESEARCH ALONGSIDE THE TRAINING PLAN WILL ALLOW FOR THE TRAINEE TO MEET THE TRAINING GOALS OF DEVELOPING TECHNICAL SKILLS IN MOLECULAR BIOLOGY, CELL-TYPE SPECIFIC MANIPULATIONS AND BIOINFORMATICS AS WELL AS DEVELOPING PROFESSIONAL SKILLS TO SUPPORT A FUTURE CAREER AS AN INDEPENDENT RESEARCHER AT A RESEARCH-INTENSIVE ACADEMIC INSTITUTION.