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.

项目概要 调节进食和焦虑的神经回路必须相互沟通以维持体内平衡。 未能对某些压力源做出适当反应可能会促进适应不良喂养的发展 观察到肥胖和饮食失调的行为。尽管饮食和饮食越来越普遍 对于焦虑症，我们对连接这些行为状态的关键输入的理解仍然很初级。 Melanocortin-3 受体 (MC3R) 在解剖学和功能上均处于理想位置，可介导直接 进食和焦虑回路之间的沟通。 MC3R 是中枢黑皮质素系统的一部分， 参与对稳态挑战的双向控制，提供变阻控制 能量储存。重要的是，MC3R 神经元双向调节进食和焦虑，以及缺失 MC3R 会产生多种形式的性二态性饮食失调，包括与焦虑相关的吞咽功能减退。 虽然 MC3R 明显影响雄性和雌性小鼠的进食和焦虑回路，但性行为 驱动这些行为的二态位点仍然未知。终纹床核 (BST) 是 高度分化的核复合体，整合自主神经、情绪和神经内分泌信号 随后传递至下丘脑和脑干区域以调节动机的表达 行为，包括进食和防御行为。 BST 主要参与与压力相关的 精神病理学，例如病理性和适应性焦虑，还可以调节食物摄入量和能量 与厌食症和暴饮暴食症的效果保持平衡。 BST 也是性别二态性最强的之一 大脑中的区域，因此可能调节在许多饮食和压力相关中观察到的性别差异 临床疾病。 MC3R 神经元和末梢在 BST 中大量表达，因此 BSTMC3R 电路可以充当信息驱动进食和焦虑样行为的集成中心。这 该应用的总体假设是 BST 中的 MC3R 神经元提供介导的神经学底物 喂养和焦虑回路之间的沟通，并且男性和女性的沟通可能有所不同。作为第一个 为了检验这一假设，我们将追求以下两个具体目标：1）定义分子 表型并绘制 BSTMC3R 神经元的神经输入和输出的组织图，2) 表征 BSTMC3R 神经元在进食和焦虑范式中的活动，并确定活动是否具有性别二态性。 完成这些目标将加深我们对 MC3R 在协调进食中的作用的理解 和焦虑，识别男性和女性之间的重要差异，并作为解决这一问题的关键一步 辨别与肥胖和饮食失调相关的复杂喂养行为。