TARGETING OLFACTORY NEURAL PATHWAYS TO COMBAT OBESITY - PROJECT SUMMARY THE SENSE OF SMELL MAINLY PLAYS A PRIMING ROLE IN EATING BEHAVIOR. RECENTLY, WE OBSERVED THAT RELATIVELY LONG TIME FOOD (CHOW)-DERIVED ODOR EXPOSURE SUPPRESSES BOTH CHOW AND HIGH FAT DIET INTAKE IN MICE. FURTHER, WE FOUND THAT A SUBSET OF NEURONS IN THE VENTRAL SUBICULUM (VSUB) ARE ACTIVATED BY FOOD ODOR AND SEND MONOSYNAPTIC PROJECTIONS TO THE VENTROMEDIAL HYPOTHALAMUS (VMH). ADDITIONALLY, WE FOUND THAT INHIBITION OF THESE NEURONS ATTENUATED THE HYPOPHAGIC RESPONSE INDUCED BY FOOD-DERIVED ODOR EXPOSURE. BASED ON THIS, THE FIRST OBJECTIVE OF THIS PROPOSAL IS TO DETERMINE THE PHYSIOLOGICAL RELEVANCE OF FOOD ODOR-RESPONSIVE VSUB NEURONS IN REGULATION OF FOOD INTAKE. NOTEWORTHY, WE WILL DETERMINE THE TRANSCRIPTOMIC FEATURES OF FOOD ODOR-ACTIVATED VSUB NEURONS, WHICH COULD POTENTIALLY IDENTIFY A NOVEL NEURON POPULATION THAT GOVERN OLFACTORY SENSATION-REGULATED FEEDING BEHAVIOR. USING CHRONIC ACTIVATION AND INHIBITION MODEL, THE SECOND OBJECTIVE IS TO EXPLORE THE LONG-TERM IMPLICATIONS OF VSUB VMH CIRCUIT IN BODY WEIGHT REGULATION. WE ALSO DISCOVERED THAT VMH-PROJECTING VSUB NEURONS RECEIVE STRONG SYNAPTIC INPUTS FROM OB NEURONS. FURTHERMORE, WE OBSERVED THAT ACTIVATION OF VSUB- PROJECTING OB NEURONS SUPPRESSES FOOD INTAKE AND BODY WEIGHT GAIN. BUILDING ON THIS OBSERVATION, THE THIRD OBJECTIVE IS TO ELUCIDATE THE FUNCTIONAL SUFFICIENCY AND NECESSITY OF THE OB VSUB VMH CIRCUIT IN THE REGULATION OF SYSTEMIC ENERGY HOMEOSTASIS. THE CURRENT PROPOSAL AIMS TO DETERMINE HOW THE OLFACTORY BULB (OB)-ORIGINATED NEURAL CIRCUITS MEDIATE FOOD- DERIVED ODOR-INDUCED SATIETY. OUR STUDIES WILL ADVANCE OUR CURRENT UNDERSTANDING ABOUT THE SENSORY INPUTS IN REGULATING FEEDING BEHAVIOR. THIS MAY FACILITATE DEVELOPMENT OF NOVEL THERAPIES FOR RELATED HUMAN DISEASES, SUCH AS OBESITY AND EATING DISORDERS. THEREFORE, THIS PROPOSED RESEARCH IS DIRECTLY RELEVANT TO PUBLIC HEALTH AND THE NIH'S MISSION.