Deconstructing the Neural Control of Food Seeking

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Summary. The dramatic increase in obesity and associated comorbidities in the United States is a major public health concern. While weight loss improves these conditions, widespread difficulty in implementing successful diets and high recidivism are major barriers to effective obesity treatments. The objective of this proposal is to identify neuron subpopulations and define neural mechanisms that impede weight loss. Agouti-related protein (AgRP)-expressing neurons in the arcuate nucleus of the hypothalamus are activated by energy deficit and motivate food seeking and consumption. We have demonstrated that AgRP neurons transmit a negative valence signal that may underlie the negative affect often associated with hunger and weight loss. Thus, there is a critical need to identify how AgRP neurons communicate with other brain regions to drive negative valence, food seeking, and consumption. AgRP neurons can be divided into distinct subpopulations that project to one of several target brain regions, but our understanding of the distinct AgRP projection subpopulations that mediate the physiological and affective consequences of AgRP neural activity remains incomplete. To this end, the complementary aims in this proposal use state-of-the-art techniques to characterize, with unprecedented levels of detail, the AgRP neuron projection subpopulations and circuit mechanisms that drive food intake. Specifically, our experiments will (1) identify the distinct AgRP projection subpopulation(s) that mediate the negative valence associated with hunger, (2) determine the endogenous activity patterns of AgRP subpopulations during the transition between replete and deprived physiological states, (3) examine how AgRP subpopulation activity changes with obesity, and (4) determine the AgRP projection subpopulations that contribute to the motivation to work for food. Overall, results from these experiments will identify brain regions that are physiologically and functionally recruited by AgRP neuron activity, providing novel neural substrate targets that can be leveraged to develop potent therapies for obesity.