Identifying the source of feed-forward appetite regulation

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Project Summary Hunger is regulated by a group of neurons located in a distinct area of the hypothalamus, the arcuate nucleus (ARC). Agouti-related peptide (AgRP) neurons within the ARC become active in a calorically deficient state and become less active when animals are calorically replete. Hunger has traditionally been viewed to be controlled by feedback mechanisms from peripheral systems in the body such as circulating hormones that signal caloric deficiency. It is now known that in addition to ARCAgRP neurons being regulated by feedback mechanisms, ARCAgRP neurons are also rapidly regulated by feedforward mechanisms such as environmental cues that anticipate ingestion. One of these feedforward mechanisms is driven by a presynaptic inhibitory neuron present in the ventral dorsal medial hypothalamus (vDMH) that rapidly inhibits ARCAgRP activity upon food-cue presentations. However, it is unknown how sensory detection of food-cues converge on to the hypothalamus. I hypothesize that presynaptic afferents to the vDMH are the source of feedforward control and is the basis of appetite regulation. In this proposal, I will identify the higher-order inputs to the hypothalamus that are required for the feedforward regulation of the vDMH, and ultimately, ARCAgRP neurons. I will use retrograde monosynaptic tracing techniques to identify the presynaptic sources to the vDMH. I will then confirm that these inputs are functional by characterizing the nature of their synaptic input with ChR2-assisted circuit mapping. Finally, I will use a combinatorial approach of selective inhibition studies and in vivo calcium recordings to study if the candidate input is required for the rapid regulation of vDMH neuronal food-cue responses. During the tenure of this proposal, I will receive training in optogenetics, microscopy, virology, computer programming, fiber-photometry, and in vivo electrophysiological techniques from experts in the field. These techniques and skills will allow me to successfully complete the proposed experimental aims and prepare me for a career as an independent investigator.