Defining locus coeruleus-norepinephrine (LC-NE) circuits in feeding

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PROJECT SUMMARY Overeating is a major contributor to excessive weight gain, involving the hypothalamus and innervating brain systems that control reward, motivation, learning and emotion. Accumulating clinical data indicate that disruptions to the norepinephrine (NE) signaling system underlie key aspects of obesity. NE stimulants are currently the most effective therapies for weight loss, but the precise neural circuits that underlie this regulation of feeding remain largely unresolved. The goal of this proposed K99-R00 research is to dissect the role of the locus coeruleus (LC) to lateral hypothalamus (LHA) noradrenergic circuit in feeding and dietary obesity. The central hypothesis is that increased LC-NE activity will suppress feeding through inhibition of LHA hunger- promoting neurons. The basis for this hypothesis comes from the candidate’s preliminary data, together with published findings. To test the central hypothesis, the candidate will carry out three Specific Aims: (1) Identify the natural population activity patterns of LC-NE neurons during feeding behaviors; (2) Identify the hypothalamic cell types involved in LC-NE suppression of feeding; and (3) Determine the involvement of the LC-LHA noradrenergic circuit in the physiology and treatment of obesity. These aims will be accomplished using state- of-the-art technologies developed and used by the candidate’s mentoring team, including wireless fiber photometry to visualize neuronal activity, optogenetics tools to manipulate neural activity, and devices for high- resolution measurements of feeding behavior. This career development award will build on the candidate’s skills in behavioral pharmacology and systems neuroscience, and will facilitate the candidate’s long-term career goal of developing an independent research program focused on the NE circuits underlying feeding. The ultimate goal of this research is to inform the development of novel treatment strategies that activate specific LC-NE circuits to suppress feeding without incurring the off-target side effects observed using strategies that affect the entire noradrenergic system.