Project Grant R01DA060576

DIFFERENTIAL ROLES OF PREFRONTAL CORTICAL INTERNEURONS IN DRUG SEEKING AFTER WITHDRAWAL - PROJECT SUMMARY DRUG CRAVING DURING PROLONGED PERIODS OF ABSTINENCE IS A MAJOR FACTOR DRIVING REPEATED CYCLES OF DRUG ABUSE. GIVEN THE ESCALATING PREVALENCE OF SUBSTANCE ABUSE, IT IS IMPERATIVE TO HAVE A THOROUGH UNDERSTANDING OF THE BRAIN CIRCUIT PLASTICITY AND ASSOCIATED MOLECULAR MECHANISMS THAT SPECIFICALLY UNDERLIE DRUG SEEKING. NONETHELESS, DESPITE SEVERAL DECADES OF RESEARCH, THE NEURAL CIRCUIT MECHANISMS UNDERLYING STRONG CRAVINGS FOR DRUGS AFTER ABSTINENCE ARE NOT FULLY ELUCIDATED. THE MEDIAL PREFRONTAL CORTEX (MPFC) IS ASSOCIATED WITH VARIOUS COMPLEX BEHAVIORS INCLUDING WORKING MEMORY, IMPULSIVITY, GOAL-DIRECTED ACTION, AND DECISION-MAKING. GIVEN THE DIVERSE ROLES OF THE PFC AND ITS EFFERENT AND AFFERENT CONNECTIONS TO LIMBIC REWARD CIRCUITRY, THE PFC IS CAPABLE OF INTEGRATING AND TRANSMITTING DRUG-RELEVANT SIGNALS THROUGHOUT THE BRAIN AS THE ADDICTION PROGRESSES. IN PARTICULAR, SEVERAL REPORTS SHOW THAT VENTRAL PFC SUBREGIONS MODULATE DRUG-SEEKING AND EXTINCTION BEHAVIOR AND ARE A VIABLE TARGET FOR DEEP BRAIN STIMULATION TO REDUCE ADDICTIVE BEHAVIORS. HOWEVER, IT IS LARGELY UNKNOWN HOW PFC SUB-CIRCUITRIES CONTRIBUTE TO DRUG ADDICTION DIFFERENTIALLY AND WHETHER SPECIFIC CELL TYPES, ESPECIALLY DISTINCT TYPES OF INTERNEURONS, WITHIN THE PFC ARE DIFFERENTIALLY RESPONSIBLE FOR DRUG-SEEKING AFTER WITHDRAWAL AND EXTINCTION. IN THIS PROPOSED RESEARCH, WE WILL INVESTIGATE THE ROLE OF DIFFERENT INTERNEURONS IN THE INFRALIMBIC (VENTRAL) CORTEX FOR THE SEEKING AND THE EXTINCTION OF COCAINE AFTER WITHDRAWAL IN OUR NEWLY DEVELOPED HEAD-FIXED DRUG SELF-ADMINISTRATION PARADIGM. FIRST, WE WILL DIRECTLY MONITOR THE ACTIVITY OF DIFFERENT TYPES OF INTERNEURONS, PARVALBUMIN (PV)-, SOMATOSTATIN (SST)-, AND VASOACTIVE INTESTINAL POLYPEPTIDE (VIP)- EXPRESSING NEURONS, IN INFRALIMBIC CORTEX (IL) DURING COCAINE SELF-ADMINISTRATION AT SINGLE-NEURON RESOLUTION USING MULTIPHOTON PHOTON MICROSCOPY. SECOND, WE WILL DIRECTLY MANIPULATE THE ACTIVITY OF DISTINCT INTERNEURONS AT THE SPECIFIC TIMING OF DRUG SELF-ADMINISTRATION TO EXAMINE THE CAUSAL ROLES OF THESE NEURONS IN DRUG SELF- ADMINISTRATION. THIRD, WE WILL EXAMINE HOW CORTICAL OUTPUTS ARE REGULATED BY DISTINCT INTERNEURONS DURING DRUG SELF-ADMINISTRATION. EXCITINGLY, WE ALREADY ACQUIRED PRELIMINARY RESULTS SHOWING THE DIFFERENTIAL ROLES OF DISTINCT INTERNEURONS IN COCAINE SELF-ADMINISTRATION. OVERALL, WE BELIEVE THAT THE SUCCESSFUL COMPLETION OF THIS PROJECT WILL YIELD SIGNIFICANT BENEFITS BY ESTABLISHING A FRAMEWORK FOR THE RESEARCH OF DRUG ADDICTION IN A CIRCUIT-SPECIFIC MANNER, AS WELL AS BY FACILITATING THE DEVELOPMENT OF A TREATMENT APPROACH FOR DRUG ADDICTION.