MECHANISMS UNDERLYING OLFACTORY EFFECTS ON APPETITE

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Appetite is a basic drive that is essential to survival. The olfactory system can have potent effects on appetite in mammals, with certain odors stimulating appetite in humans, and either increasing or decreasing food intake and body weight in rodents. In the mouse, as in other mammals, olfactory sensory signals travel from olfactory sensory neurons in the nasal olfactory epithelium through the olfactory bulb to the olfactory cortex and then to other brain areas. Odorants are detected in the nose by ~1000 different odorant receptors (ORs), each expressed by a different subset of sensory neurons. Neurons with the same OR are scattered in one nasal spatial zone, but their axons converge in a few specific glomeruli in the olfactory bulb, creating a semi- stereotyped sensory map in which each glomerulus and its associated mitral and tufted relay neurons, which project to the cortex, appears dedicated to one OR. Signals from each glomerulus travel to multiple distinct areas of the olfactory cortex. How the vast array of sensory information generated by this organization might impact appetite is unexplored. To begin to investigate this question, we conducted preliminary studies on olfactory inputs to two subsets of neurons linked to appetite, both of which are located in the arcuate nucleus of the hypothalamus: AGRP (agouti related peptide) neurons, which can enhance appetite, and POMC (pro- opiomelanocortin) neurons, which can suppress appetite. We found that only some odors affect the activity of AGRP or POMC neurons and that different odors activate AGRP versus POMC neurons. Using a Pseudorabies virus (PRV) that travels retrogradely across multiple synapses, we found evidence for neurons upstream of AGRP and POMC neurons in the olfactory cortex, but only in certain olfactory cortical areas. These observations are consistent with the idea that some olfactory sensory inputs can have innate effects on appetite and that those effects involve genetically programmed neural circuits that convey signals from specific ORs in the nose through the olfactory system to hypothalamic neurons that regulate appetite. In the studies proposed in this application, we will test the hypotheses that 1) AGRP and POMC neurons can receive input from selected ORs that are similar among individuals and recognize odorants that affect the activity of the appetite neurons and appetite behaviors, 2) neurons within specific areas of the olfactory cortex can influence AGRP or POMC neuron activity and appetite-associated behaviors, and 3) odor-responsive neurons in other brain areas can relay signals from the olfactory cortex to AGRP or POMC neurons to modulate their activity and regulate behaviors associated with appetite. Together, these studies should provide significant new insights into the molecular mechanisms and neural circuits that govern the impact of olfactory sensory signals on appetite.