Elucidating MCH neural circuitry underlying consummatory behavior

项目摘要/摘要 饮食失调和肥胖在美国变得越来越严重，造成了广泛的 对于那些受影响的人来说，健康和经济成本。目前的治疗方法主要集中在改变饮食和锻炼上， 几乎没有针对这些疾病背后的神经回路的干预措施。过去几十年 虽然仍有许多尚不清楚之处，但许多研究已经提高了我们对体内平衡喂养回路的理解。 此外，动态平衡需求并不是决定消费食物的唯一因素。人类通常 体验非动态平衡的进食动机，例如即使吃饱了也想吃含糖或脂肪的食物(即， “总是有吃甜点的空间”)。食物可获得性和可取性的神经表征在我们的 围绕消费的决策。负责激励和奖励的神经回路可以促进 在没有营养不足或动态平衡需要的情况下进食，会导致肥胖或其他饮食失调。 这项工作的目标是了解驱动摄食行为的神经回路，包括体内平衡 和非内环境平衡的驱动力来进食。 黑色素浓缩激素(MCH)神经元是动态平衡和非稳态的相关靶点 动态平衡的进食动力。MCH神经元起源于下丘脑外侧区和未定带，投射 到大脑的许多区域，包括伏隔核(NAcc)和 弓状核(ARC)，以及像蓝斑(LC)这样的兴奋区。有趣的是，MCH神经元 牵涉到包括进食、睡眠和学习在内的一系列行为。我们假设 离散的妇幼保健亚群通过投射到不同的下游地区促进特定的行为。 具体地说，我们假设向NAcc或ARC投射的MCH将促进进食而不是睡眠，而 妇幼保健素投射到LC将促进睡眠而不是进食。 这一建议旨在通过光遗传学分离特定妇幼保健亚群的行为功能 在离散的下游区域(NAcc、Arc、Lc)激活MCH神经元终末。使用光致发电 刺激结合严格的行为模式，观察进食和睡眠行为，这 这项工作将揭示在不影响唤醒状态的情况下，妇幼保健系统是如何促进喂养的。此外， 这一建议旨在阐明MCH神经元活动的动机价，以及它参与了 稳态和非稳态喂养，通过允许小鼠自愿自我刺激离散的MCH 有或没有配对送餐的预测。通过使用尖端方法和行为分析 确定MCH回路在进食行为中的作用，我们将增加对神经回路的理解 不适应喂养的背后，并有助于确定治疗进食障碍的新治疗靶点 还有肥胖症。

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.