Elucidating MCH neural circuitry underlying consummatory behavior

阐明完成行为背后的 MCH 神经回路

• 批准号: 10600482
• 负责人: Katherine L Furman
• 金额: $ 4.02万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10600482
• 关键词: Affect; Amygdaloid structure; Anatomy; Animals; Appetite Regulation; Area; Arousal; Basic Science; Behavior; Behavioral; Behavioral Paradigm; Body Weight; Brain; Cerebral cortex; Complex; Consummatory Behavior; Consumption; Decision Making; Disease; Dissociation; Eating; Eating Disorders; Equilibrium; Feeding behaviors; Financial cost; Food; Food Intake Regulation; Fostering; Future; Goals; Health; Health Care Costs; Heterogeneity; Human; Hypothalamic structure; Infusion procedures; Intervention; Lateral; Learning; Maps; Mediating; Metabolic; Mission; Modernization; Motivation; Mus; Neurons; Nose; Nucleus Accumbens; Nutrient; Nutritional; Obesity; Pattern; Phenotype; Physiological; Population; Prevalence; Property; Public Health; REM Sleep; Research; Rewards; Role; Self Stimulation; Sleep; Societies; Structure of nucleus infundibularis hypothalami; System; Therapeutic; United States; United States National Institutes of Health; Work; craving; diet and exercise; experience; experimental study; feeding; food consumption; grasp; improved; innovation; locus ceruleus structure; melanin-concentrating hormone; neural; neural circuit; neuromechanism; new therapeutic target; optogenetics; peptide hormone; sleep behavior; zona incerta

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.

项目总结/摘要 饮食失调和肥胖在美国变得越来越严重， 对受影响者的健康和经济成本。目前的治疗主要集中在饮食和运动的改变， 很少有针对这些疾病的神经回路的干预措施。过去几十年 的研究已经推进了我们对自我平衡进食回路的理解，尽管还有很多尚不清楚。 此外，自我平衡的需要不是决定消费食物的唯一因素。人类通常 经历非稳态的进食动机，例如即使在饱足时也渴望含糖或脂肪的食物（即， “总有地方吃甜点”）。食物可用性和渴望性的神经表征在我们的生活中至关重要 围绕消费的决策。负责激励和奖励的神经回路可以促进 在没有营养缺乏或体内平衡需要的情况下进食，导致肥胖或其他饮食失调。 这项工作的目标是了解驱动进食行为的神经回路，包括自我平衡 和非自我平衡的进食欲望 黑色素浓集激素（MCH）神经元是稳态和非稳态的相关靶点。 吃东西的自我平衡动力。MCH神经元起源于外侧下丘脑和齿状回， 大脑中的许多区域，包括进食/奖励区域，如丘脑核（NAcc）和 弓状核（ARC），以及唤醒区域，如蓝斑（LC）。有趣的是，MCH神经元 与包括进食、睡眠和学习在内的各种行为有关。我们假设 离散的MCH亚群通过向不同下游区域的投射促进特定行为。 具体来说，我们假设MCH投射到NAcc或ARC将促进进食而不是睡眠， 妇幼保健预测LC将促进睡眠，而不是喂养。 该提案旨在通过光遗传学方法分离特定MCH亚群的行为功能。 在离散的下游区域（NAcc、ARC、LC）中MCH神经元末梢的激活。使用光遗传学 刺激结合严格的行为范式，观察进食和睡眠行为， 这项工作将揭示MCH系统如何在不影响唤醒状态的情况下促进进食。此外，委员会认为， 该建议旨在阐明MCH神经元活动的动机效价，以及它与 稳态和非稳态喂养，通过允许小鼠自愿自我刺激离散MCH 具有或不具有成对食物递送的投影。通过使用尖端的方法和行为分析， 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 并帮助确定治疗饮食失调的新治疗靶点 和肥胖。