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.

项目摘要/摘要 在美国，饮食失调和肥胖变得越来越严重，构成了广泛的 受影响者的健康和财务成本。当前的治疗重点是饮食和运动的改变， 几乎没有针对这些疾病的神经回路的干预措施。最近几十年 研究已经提高了我们对稳态喂养电路的理解，尽管尚不清楚。 此外，稳态需求不是决定食用食物的唯一因素。人类通常 体验非瓦不固定的图案，例如即使是渴望或脂肪食物 “总是有甜点的空间”）。食物可用性和可取性的神经表示在我们的 围绕消费的决策。负责动力和奖励的神经回路可以促进 在没有营养赤字或稳态必需品的情况下进食，导致肥胖或其他饮食失调。 这项工作的目的是了解驱动喂养行为的神经回路，包括稳态包括 和非防服的驱动器要喂食。 黑色素浓缩马酮（MCH）神经元是稳态和非稳态的相关靶标 稳态的驾驶者要吃。 MCH神经元起源于下丘脑和Zona Incerta，并且Project 到整个大脑的许多区域，包括喂食/奖励区域，例如伏隔核（NACC）和 弧形核（ARC）以及诸如基因座（LC）之类的唤醒区域。有趣的是，MCH神经元有 我们假设这一点 离散的MCH亚群通过项目推向不同下游领域的特定行为。 具体而言，我们假设MCH向NACC或ARC项目将促进喂养而不是睡觉，而 LC的MCH项目将促进睡眠和不喂食。 该建议旨在通过光遗传学隔离特定MCH亚群的行为函数 离散下游区域中MCH神经元末端的激活（NACC，ARC，LC）。使用光遗传学 刺激与严格的行为范式结合，观察喂养和睡眠行为，这 工作将揭示MCH系统在没有对唤醒状态的影响的情况下如何促进进食。此外， 该建议旨在阐明MCH神经元活动的动机价，及其参与 通过允许小鼠自愿自动刺激离散MCH，稳态和非固定式喂养 有或没有配对食物的预测。通过使用尖端的方法和行为分析 确定MCH电路在进食行为中的作用，我们将增加对神经回路的理解 在适应不良的喂养后面，有助于确定治疗饮食失调的新型治疗靶标 和肥胖。