Melanocortin-3 receptor in feeding and anxiety neural circuits

进食和焦虑神经回路中的 Melanocortin-3 受体

• 批准号: 10662026
• 负责人: Michelle Bedenbaugh
• 金额: $ 9.15万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662026
• 关键词: Anatomy; Anorexia; Anxiety; Anxiety Disorders; Area; Automobile Driving; Axon; Behavior; Behavioral; Behavioral Paradigm; Binge Eating; Brain; Brain Stem; Cell Nucleus; Cells; Clinical; Communication; Complex; Confocal Microscopy; Cues; Development; Disease; Eating; Eating Disorders; Emotional; Experimental Genetics; Failure; Fasting; Feeding behaviors; Female; Food Energy; Future; Heterogeneity; Homeostasis; Hormones; Hypothalamic structure; Image Analysis; Immunohistochemistry; Individual; Label; Link; Maps; Mediating; Melanocortin 3 Receptor; Metabolic; Methods; Mus; Neurologic; Neurons; Neurosecretory Systems; Nuclear; Obesity; Output; Pathologic; Pathological anxiety; Phenotype; Physiological Processes; Population; Positioning Attribute; Predisposition; Prevalence; Process; Psychopathology; Regulation; Role; Sex Differences; Signal Transduction; Site; Social isolation; Stress; Structure of terminal stria nuclei of preoptic region; System; Testing; Three-Dimensional Image; Time; Tissues; Viral; Work; anorexic; anxiety-like behavior; driving behavior; energy balance; experimental study; feeding; food avoidance; food consumption; in vivo calcium imaging; male; microendoscopy; molecular phenotype; motivated behavior; neural; neural circuit; novel; novel therapeutic intervention; novel therapeutics; receptor expression; response; restraint stress; sex; sexual dimorphism; stressor

PROJECT SUMMARY Neural circuits modulating feeding and anxiety must communicate with each other to maintain homeostasis. Failure to appropriately respond to certain stressors can promote the development of maladaptive feeding behaviors observed with obesity and eating disorders. Despite an increasing prevalence of both eating and anxiety disorders, our understanding of the key inputs linking these behavioral states remains rudimentary. Melanocortin-3 receptor (MC3R) is ideally positioned, both anatomically and functionally, to mediate direct communication between feeding and anxiety circuits. MC3R is a part of the central melanocortin system and is implicated in the bidirectional control of responses to homeostatic challenges, providing rheostatic control on energy storage. Importantly, MC3R neurons bidirectionally regulate both feeding and anxiety, and deletion of MC3R produces multiple forms of sexually dimorphic disordered eating, including anxiety-related hypophagia. While it is evident MC3R impacts feeding and anxiety circuitry in both male and female mice, the sexually dimorphic sites driving these behaviors remain unknown. The bed nucleus of the stria terminalis (BST) is a highly differentiated nuclear complex whereby autonomic, emotional and neuroendocrine signals are integrated and subsequently relayed to hypothalamic and brainstem regions to regulate the expression of motivated behaviors, including feeding and defensive actions. The BST is centrally involved in stress-related psychopathologies, such as pathological and adaptive anxiety and also modulates food intake and energy balance with both anorexic and binge-like eating effects. The BST is also one of the most sexually dimorphic areas in the brain and thus may regulate sex differences observed in numerous eating and stress-related clinical disorders. MC3R neurons and terminals are abundantly expressed in the BST, and therefore BSTMC3R circuitry may function as an integration hub for information driving feeding and anxiety-like behaviors. The overall hypothesis of this application is MC3R neurons in the BST provide a neurological substrate mediating communication between feeding and anxiety circuits and may do so differently in males and females. As a first step in testing this hypothesis, the following two specific aims will be pursued: 1) Define the molecular phenotype and map the organization of neural inputs and outputs of BSTMC3R neurons and 2) Characterize the activity of BSTMC3R neurons in feeding and anxiety paradigms and determine if activity is sexually dimorphic. Completion of these aims will advance our understanding of the role of MC3R in the coordination of feeding and anxiety, identify important differences between males and females and serve as a crucial step in discerning the complex feeding behavior associated with obesity and eating disorders.

项目摘要 调节喂养和焦虑的神经回路必须相互交流以维持体内平衡。 未能适当响应某些压力源可以促进适应不良的喂养的发展 肥胖和饮食失调观察到的行为。尽管饮食和 焦虑症，我们对关键的行为状态关键输入的理解仍然是基本的。 黑素皮质素-3受体（MC3R）在解剖学和功能上都是理想位置的，以介导直接 喂养和焦虑症之间的沟通。 MC3R是中央黑色皮质素系统的一部分，是 与对稳态挑战的反应的双向控制有关 储能。重要的是，MC3R神经元双向调节喂养和焦虑，以及缺失 MC3R产生多种形式的性二态性饮食，包括与焦虑相关的垂直饮食。 虽然明显的MC3R会影响男性和女性小鼠的喂养和焦虑回路 驱动这些行为的双态部位仍然未知。 Stria末端（BST）的床核是一个 高度差异化的核复合体，从而整合了自主，情感和神经内分泌信号 随后转到下丘脑和脑干区域，以调节动机的表达 行为，包括进食和防御行动。 BST集中参与与压力有关的 心理病理学，例如病理和适应性焦虑，还调节食物摄入和能量 与厌食和暴饮暴食效果保持平衡。 BST也是最性别的二态之一 大脑中的区域，因此可能调节在众多饮食和压力有关的性别差异 临床疾病。 MC3R神经元和终端在BST中大量表达，因此BSTMC3R 电路可能充当集成枢纽，用于驱动进食和焦虑般的行为。这 该应用的总体假设是BST中的MC3R神经元提供了介导的神经系统底物 喂养和焦虑症之间的沟通在男性和女性中可能会有所不同。首先 在检验该假设的一步中，将追求以下两个具体目标：1）定义分子 表型和绘制BSTMC3R神经元的神经输入和输出的组织，2）表征 BSTMC3R神经元在进食和焦虑范式中的活性，并确定活动是否具有性二态性。 这些目标的完成将提高我们对MC3R在喂养协调中的作用的理解 和焦虑，确定男性和女性之间的重要差异，并作为关键步骤 辨别与肥胖和饮食失调相关的复杂喂养行为。