Melanocortin 3 receptor in neural circuits linking reproductive state and metabolism

连接生殖状态和代谢的神经回路中的黑皮质素 3 受体

• 批准号: 9907718
• 负责人: Michelle Bedenbaugh
• 金额: $ 6.12万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9907718
• 关键词: Anatomy; Androgen Receptor; Architecture; Area; Axon; Body Weight; Brain; Cell Nucleus; Communication; Data; Deterioration; Development; Diabetes Mellitus; Disease; Eating Disorders; Epidemic; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Exhibits; Exposure to; Fasting; Feeding behaviors; Female; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Health; Heterogeneity; Homeostasis; Hormones; Hypothalamic structure; Image Analysis; Immunohistochemistry; Infertility; Label; Lead; Link; Maps; Mediating; Melanocortin 3 Receptor; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Methods; Mus; Mutation; Neurologic; Neurons; Neurosecretory Systems; Nodal; Obesity; Ovariectomy; Physiological; Physiology; Play; Polycystic Ovary Syndrome; Population; Positioning Attribute; Precocious Puberty; Pregnancy; Prevalence; Process; Publishing; Receptor Cell; Receptor Signaling; Regulation; Reproduction; Reproductive Health; Role; Sensory Receptors; Sex Differences; Signal Transduction; Site; Specific qualifier value; Structure of nucleus infundibularis hypothalami; System; Testing; Three-Dimensional Image; Weight; critical period; energy balance; experimental study; male; metabolic phenotype; molecular phenotype; mutant; neural circuit; neuroregulation; novel; novel therapeutics; postnatal development; receptor expression; recombinase-mediated cassette exchange; relating to nervous system; reproductive; response; sexual dimorphism

PROJECT SUMMARY Neural circuits modulating metabolic state and reproduction must communicate with each other to maintain homeostasis. Despite an increasing prevalence of both metabolic and reproductive disorders, our understanding of neural circuitry linking energy homeostasis and reproduction remains rudimentary. Melanocortin 3 receptor (MC3R) is ideally positioned, both anatomically and functionally, to mediate direct communication between reproductive and metabolic circuits. MC3R is expressed in multiple areas of the brain, including the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus of the hypothalamus (ARH). The AVPV and ARH are critical sites controlling reproduction and energy balance, and they are linked by direct neural connections. Therefore, MC3R-expressing neurons in the AVPV and ARH may represent important components of a core neural circuit that functions to integrate the neural control of energy balance and reproductive state. However, the cellular identity of MC3R-expressing neurons in the AVPV and ARH has not been determined, nor has the organization of their neural projections been defined. Recent evidence suggests MC3R may also functionally mediate the exchange of information between metabolic and reproductive state. During metabolic challenges resulting from reproductive state, such as pregnancy and ovariectomy, deletion of MC3R results in mice gaining too little weight or too much weight, respectively. Deletion of MC3R results in additional reproductive and metabolic disturbances in males and females, including adverse responses to fasting, disruptions to feeding behavior, and altered circulating hormone concentrations. Moreover, females with MC3R mutations typically exhibit more aberrant reproductive and metabolic phenotypes, compared with those observed in mutant males. However, a detailed understanding of the mechanisms causing these differential responses in males and females is lacking. Because sex steroids specify the organization of sexually dimorphic neural circuits during critical periods of development, it is possible that exposure to estrogen during these periods may cause permanent changes in the architecture of MC3R regulated circuits, and consequently, reproductive and metabolic physiology. The overall hypothesis of this application is that MC3R neurons provide a neurological substrate for integration of metabolic signals with reproductive status, and that this circuit may be configured differently in males and females. As a first step toward testing this hypothesis, the following two specific aims will be pursued: 1) Define the molecular phenotypes of neurons that express MC3R in the AVPV and ARH of male and female mice, and map the organization of their neural projections; 2) Determine if the organization and function of MC3R circuits depends upon estrogen receptor signaling during postnatal development. Completion of these aims will establish a novel framework for understanding neurological mechanisms underlying how MC3R coordinates metabolic regulation with reproductive state.

项目摘要 调节代谢状态和繁殖的神经回路必须相互通信以维持 稳态。尽管新陈代谢和生殖疾病的患病率越来越高 对能量稳态和繁殖联系的神经回路的理解仍然是基本的。 黑色皮质素3受体（MC3R）在解剖学和功能上都是理想位置的，以介导直接 生殖和代谢回路之间的通信。 MC3R在大脑的多个区域表达， 包括前腹室核（AVPV）和下丘脑的弧形核 （arh）。 AVPV和ARH是控制繁殖和能量平衡的关键站点，它们是联系的 通过直接的神经连接。因此，AVPV和ARH中表达MC3R的神经元可能代表 核心神经电路的重要组成部分，该电路功能可以整合能量平衡的神经控制 和生殖状态。但是，AVPV和ARH中表达MC3R神经元的细胞身份具有 没有确定，也没有定义其神经预测的组织。最近的证据 建议MC3R也可能在功能上介导代谢和之间的信息交换 生殖状态。在生殖状态（例如怀孕）和 卵巢切除术，MC3R的缺失导致小鼠的体重分别减少或体重过多。 MC3R的删除会导致男性和女性的其他生殖和代谢障碍， 包括对禁食的不良反应，对喂养行为的破坏和改变的循环激素 浓度。此外，具有MC3R突变的女性通常表现出更异常的生殖和 与突变雄性中观察到的代谢表型相比。但是，对 缺乏引起男性和女性中这些差异反应的机制。因为性类固醇 在关键发展期间指定性二态神经回路的组织 在这些时期内暴露于雌激素的可能会导致建筑的永久变化 MC3R调节电路，因此是生殖和代谢生理学。总体假设 该应用是MC3R神经元为将代谢信号与与 生殖状态，并且该电路在男性和女性中的配置可能不同。作为第一步 为了检验这一假设，将追求以下两个特定目标：1）定义分子 在雄性和雌性小鼠的AVPV和ARH中表达MC3R的神经元的表型，并绘制 组织神经预测； 2）确定MC3R电路的组织和功能是否取决于 产后发育过程中雌激素受体信号传导后。这些目标的完成将建立 了解MC3R如何坐在代谢的基础上的神经机制的新框架 具有生殖状态的调节。