Project Grant K99DA059612

INVESTIGATION INTO THE FUNCTION OF HYPOTHALAMIC GABA AND GLUTAMATE IN MOTIVATION FOR OPIOID REWARD - PROJECT SUMMARY/ABSTRACT OPIOID USE HAS REACHED EPIDEMIC PROPORTIONS AND IS NOW THE LEADING CAUSE OF PREVENTABLE DEATH IN THE UNITED STATES. BEYOND THE RISK OF DEATH, OPIOID USE DISORDER CAUSES AN INCALCULABLE AMOUNT OF SUFFERING AS IT DEVASTATES THE LIVES OF INDIVIDUALS AND THEIR COMMUNITIES. THE HEIGHTENED MOTIVATION FOR DRUG REWARDS COMPARED TO NON- DRUG REWARDS STEMS IN PART FROM CHANGES IN THE BRAIN CIRCUITY ASSOCIATED WITH MOTIVATION. A GREATER UNDERSTANDING OF THIS CIRCUITRY MAY LEAD TO TARGETED INTERVENTIONS THAT CAN ATTENUATE DRUG MOTIVATION. DECADES OF RESEARCH DEMONSTRATE THAT THE LATERAL HYPOTHALAMUS (LHA), AND ITS MODULATION OF THE DOPAMINE SYSTEM, PLAYS A CRUCIAL ROLE MOTIVATION. MULTIPLE SPECIES OF ANIMALS WILL WORK TIRELESSLY TO OBTAIN ELECTRICAL STIMULATION OF THE LHA, AND LESIONS OF THE LHA REDUCE MOTIVATION ACROSS A BROAD SPECTRUM OF BEHAVIORS. RECENT RESEARCH HAS REVEALED COMPLEXITY IN THE FUNCTION OF THE LHA, AS SUBPOPULATIONS OF NEURONS CAN DRIVE DISCRETE OR EVEN OPPOSING BEHAVIORAL PHENOTYPES. DESPITE THE ESTABLISHED ROLE IN MOTIVATION BROADLY, THE ROLE OF THE LHA SUBPOPULATIONS IN MOTIVATION FOR OPIOIDS REMAINS LARGELY UNKNOWN. THIS PROPOSAL SEEKS TO INVESTIGATE THE BEHAVIORAL FUNCTION AND SPATIOTEMPORAL SIGNALING DYNAMICS OF MULTIPLE LHA SUBPOPULATIONS AND DOWNSTREAM DOPAMINERGIC SIGNALING DURING THE DEVELOPMENT AND EXPRESSION OF MOTIVATION FOR OPIOIDS. DURING THE K99 PERIOD, I WILL RECEIVE WORLD-CLASS TRAINING IN THE THEORY OF OPIOID PHARMACOLOGY AND SELF-ADMINISTRATION, TECHNIQUES FOR LONGITUDINAL RECORDING USING 2-PHOTON IMAGING, AND ADVANCED ANALYSIS OF THE RELATIONSHIPS BETWEEN NEURONAL SIGNALING DYNAMICS AND BEHAVIOR. IN AIM 1 (K99), I WILL DETERMINE THE CAUSAL BEHAVIORAL FUNCTION OF MULTIPLE LHA SUBPOPULATIONS DURING MOTIVATION FOR OPIOIDS USING TRANSIENT INHIBITION OR EXCITATION OF NEUROTRANSMITTER DEFINED NEURON POPULATIONS. IN AIM 2 (K99), I WILL DETERMINE THE RELATION BETWEEN BULK SIGNALING DYNAMICS IN THE LHA SUBPOPULATIONS AND DOWNSTREAM DOPAMINE SIGNALING USING FIBER-PHOTOMETRY AND THE SINGLE CELL DYNAMICS OF LHA SUBPOPULATIONS USING 2-PHOTON IMAGING THROUGHOUT THE DEVELOPMENT AND EXPRESSION MOTIVATION FOR OPIOIDS. BY RECORDING THROUGHOUT THE EXPERIMENT, I WILL HAVE THE POWER TO CHARACTERIZE BULK AND SINGLE-CELL SIGNALS BASED ON ACTIVITY ACROSS EACH STAGE OF OPIOID SELF-ADMINISTRATION. IN AIM 3 (R00), AS I TRANSITION TO DEVELOPING MY OWN RESEARCH LAB, I WILL INVESTIGATE THE CAUDAL CIRCUIT EFFECTS OF TRANSIENT STIMULATION OF LHA SUBPOPULATIONS DURING MOTIVATION FOR OPIOIDS. ALTOGETHER, THE RESULTS OF THE PROPOSED AIMS WILL DEEPEN OUR UNDERSTANDING OF THE ROLE OF THE LHA IN MEDIATING MOTIVATION FOR DRUGS OF ABUSE AND RELATED NEURONAL CIRCUITRY. THE TRAINING I WILL RECEIVE THROUGHOUT THE K99/R00 PERIOD WILL FACILITATE MY DEVELOPMENT INTO AN INDEPENDENT RESEARCHER INVESTIGATING THE BEHAVIORAL FUNCTION AND SPATIOTEMPORAL SIGNALING DYNAMICS RELATED TO SUBSTANCE USE DISORDER.