A HYPOTHALAMIC CIRCUIT LINKING FOOD ODOR PERCEPTION TO AGRP NEURON SUPPRESSION

Pioneering studies have shown that agouti-related peptide (AgRP)-expressing hypothalamic “hunger neurons” are inhibited not only by post-ingestive signals, but already during food sensory detection. However, the sensory modalities, neural circuits, and behavioral consequences underlying this early inhibition remain poorly defined. Here, we demonstrate that ethologically relevant food odors produce concentration- and experience-dependent inhibition of AgRP neurons, and we identify lateral hypothalamic glutamatergic neurons as selective mediators of this odor-driven suppression independently of the post-ingestive inhibition after refeeding. Additionally, using monosynaptic tracing, photometry, and circuit manipulations, we map olfactory cortical and hypothalamic populations that are rapidly recruited by food odors and form a multi-nodal pathway culminating in food-odor-specific inhibition of AgRP neuron activity. Together, our findings uncovered a specialized olfactory-hypothalamic pathway that conveys food-odor information to hunger-driving neurons prior to and independent of food consumption, revealing a distinct mechanism by which sensory food perception regulates AgRP neuronal dynamics and feeding behavior.