Elucidating MCH neural circuitry underlying consummatory behavior

项目总结/文摘

Project Summary/Abstract Eating disorders and obesity are becoming increasingly severe in the United States, posing extensive health and financial costs to those affected. Current treatments focus heavily on changes to diet and exercise, with few interventions available targeting the neural circuitry underlying these disorders. The last few decades of research have advanced our understanding of homeostatic feeding circuits, although much remains unclear. Furthermore, homeostatic need is not the sole factor in the decision to consume food. Humans commonly experience non-homeostatic motivators to eat, such as craving of sugary or fatty foods even when sated (i.e., “there is always room for dessert”). Neural representations of food availability and desirability are crucial in our decision-making surrounding consumption. Neural circuits responsible for motivation and reward can promote eating in the absence of nutritional deficit or homeostatic necessity, resulting in obesity or other eating disorders. The goal of this work is to understand the neural circuits that drive feeding behavior, including both homeostatic and non-homeostatic drives to feed. Melanin-concentrating hormone (MCH) neurons are a relevant target for both homeostatic and non- homeostatic motivators to eat. MCH neurons originate in the lateral hypothalamus and zona incerta, and project to many areas throughout the brain, including feeding/reward areas like the nucleus accumbens (NAcc) and the arcuate nucleus (ARC), as well as arousal areas like the locus coeruleus (LC). Interestingly, MCH neurons have been implicated in a diverse array of behaviors including feeding, sleep, and learning. We hypothesize that discrete MCH subpopulations promote specific behaviors via projections to different downstream areas. Specifically, we hypothesize that MCH projections to NAcc or ARC will promote feeding and not sleep, while MCH projections to LC will promote sleep and not feeding. This proposal aims to isolate the behavioral functions of specific MCH subpopulations by optogenetic activation of MCH neuron terminals in discrete downstream areas (NAcc, ARC, LC). Using optogenetic stimulation in combination with rigorous behavioral paradigms, observing both feeding and sleep behaviors, this work will reveal how the MCH system promotes feeding in the absence of effects on arousal state. Furthermore, this proposal aims to elucidate the motivational valence of MCH neuron activity, as well as its involvement with homeostatic and non-homeostatic feeding, by allowing mice to voluntarily self-stimulate discrete MCH projections with or without paired food delivery. By using cutting-edge approaches and behavioral analysis to identify the role of MCH circuitry in feeding behaviors, we will increase understanding of the neural circuitry behind maladaptive feeding and help to identify novel therapeutic targets for the treatment of eating disorders and obesity.