Project Grant F31DA061493

DYNAMIC CHANGES IN CHLORIDE HOMEOSTASIS COORDINATES MIDBRAIN INHIBITORY NETWORK ACTIVITY DURING REWARD LEARNING - ABSTRACT THE MECHANISMS UNDERLYING HOW REWARDS ARE LEARNED, AND HOW THEY TRANSLATE INTO BEHAVIOR HAVE BEEN A SUBJECT OF INTEREST TO RESEARCHERS AND SCIENTISTS SINCE PAVLOV'S CLASSICAL CONDITIONING EXPERIMENTS IN THE 1890S. RECENTLY, GAMMA AMINO BUTYRIC ACID (GABA) NEURONS IN THE VENTRAL TEGMENTAL AREA (VTA) HAVE EMERGED AS KEY MODULATORS OF REWARD LEARNING, AND POTENTIAL THERAPEUTIC TARGETS FOR ADDRESSING ADDICTION, DEPRESSION, AND OTHER NEUROPSYCHIATRIC DISORDERS. PREVIOUS STUDIES HAVE SHOWN THAT GABA NEURONS IN THE VTA UNDERGO A FORM OF EXPERIENCE-DEPENDENT PLASTICITY THAT INVOLVES THE DOWNREGULATION OF THE ANION TRANSPORTER, KCC2. THIS REDUCTION OF KCC2 LEVELS HAS BEEN FOUND TO INCREASE THE EXCITABILITY OF GABA NEURONS BY DECREASING THE EFFICACY OF GABAA RECEPTOR FUNCTION. IN THE CONTEXT OF DRUGS OF ABUSE AND AVERSIVE STIMULI, THIS MECHANISM HAS BEEN STUDIED IN GREAT DETAIL. FOR INSTANCE, EXPOSURE TO NICOTINE AND STRESS HAS SHOWN TO INDUCE KCC2 DOWNREGULATION IN THE VTA, WHICH IN TURN, ENHANCES THE FORMATION OF REWARD-SEEKING BEHAVIORS. THE IMPACT OF THIS MECHANISM ON SPECIFIC REWARD-RELATED PATHWAYS AND ITS CONTRIBUTION TO NATURALISTIC REWARD LEARNING, HOWEVER, REMAINS UNKNOWN. TO INVESTIGATE THIS MATTER, I PROPOSE TO CHARACTERIZE THE EXPRESSION OF KCC2 THROUGHOUT THE COURSE OF CUE-REWARD ASSOCIATIVE LEARNING, AND DETERMINE WHETHER ITS DOWNREGULATION IS LIMITED TO A SPECIFIC CIRCUIT (AIM 1). MY PRELIMINARY EVIDENCE DEMONSTRATES THAT KCC2 DOWNREGULATION SHIFTS LATERAL VTA GABA NEURONS TOWARDS EXCITABILITY AT CRITICAL TIME POINTS DURING REWARD LEARNING. MORE PRECISELY, KCC2 DOWNREGULATION TRANSIENTLY IMPACTS INHIBITORY INPUTS TO LATERAL PROJECTING VTA DA NEURONS, WHICH ARE KNOWN TO PLAY A SIGNIFICANT ROLE IN REWARD LEARNING. SUBSEQUENTLY, I SEEK TO UNDERSTAND HOW A COLLECTION OF INHIBITORY NEURONS UNDERGOING THIS FORM OF SYNAPTIC PLASTICITY CAN INFLUENCE THE LATERAL VTA AT THE NETWORK LEVEL (AIM 2). TO THIS END, I WILL COMBINE MULTI-UNIT TETRODE RECORDINGS WITH PHARMACOLOGICAL AND GENETIC APPROACHES TO EXAMINE NEURAL NETWORK ACTIVITY DURING REWARD LEARNING. MY PRELIMINARY DATA SHOWS THAT KCC2-MEDIATED PLASTICITY DRIVES INCREASED SYNCHRONIZED ACTIVITY BETWEEN VTA GABA NEURONS. THIS MULTIDISCIPLINARY PROPOSAL WILL INVESTIGATE WHETHER CIRCUIT-SPECIFIC MODIFICATIONS IN KCC2 SERVE AS AN INNATE MECHANISM DURING REWARD LEARNING THAT ALLOWS THE BRAIN TO ESTABLISH ENDURING ASSOCIATIONS BETWEEN CONTEXTUAL CUES AND APPETITIVE STIMULI. THE FINDINGS FROM THIS PROPOSAL WILL GUIDE NEW THERAPEUTIC AVENUES FOR NEUROPSYCHIATRIC DISORDERS WITH DEFICITS IN REWARD LEARNING.