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: 10341079
• 负责人: Michelle Bedenbaugh
• 金额: $ 6.98万
• 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/10341079
• 关键词: Anatomy; Androgen Receptor; Architecture; Area; Axon; Body Weight; Brain; Cell Nucleus; Communication; Cre lox recombination system; 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; relating to nervous system; reproductive; reproductive system disorder; 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.

项目概要 调节代谢状态和繁殖的神经回路必须相互通信以维持 体内平衡。尽管代谢和生殖疾病的患病率不断增加，但我们 对连接能量稳态和繁殖的神经回路的理解仍然处于初级阶段。 黑皮质素 3 受体 (MC3R) 在解剖学和功能上均处于理想位置，可介导直接作用 生殖和代谢回路之间的通讯。 MC3R 在大脑的多个区域表达， 包括前腹侧室周核（AVPV）和下丘脑弓状核 （ARH）。 AVPV 和 ARH 是控制繁殖和能量平衡的关键部位，它们相互关联 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 核心神经回路的重要组成部分，其功能是整合能量平衡的神经控制 和生殖状态。然而，AVPV 和 ARH 中表达 MC3R 的神经元的细胞身份已被证实。 尚未确定，也未定义其神经投射的组织。最近的证据 表明 MC3R 还可能在功能上介导代谢和代谢之间的信息交换。 生殖状态。在生殖状态（例如怀孕和怀孕）引起的代谢挑战期间 卵巢切除术、MC3R 缺失分别导致小鼠体重增加过少或增加过多。 MC3R 的缺失会导致男性和女性额外的生殖和代谢紊乱， 包括对禁食的不良反应、喂养行为的干扰以及循环激素的改变 浓度。此外，具有 MC3R 突变的女性通常表现出更异常的生殖和生殖能力。 与突变雄性中观察到的代谢表型相比。不过详细了解一下 导致男性和女性产生这些差异反应的机制尚不清楚。因为性类固醇 明确发育关键时期性别二态性神经回路的组织，它是 在这些时期接触雌激素可能会导致身体结构的永久性变化 MC3R 调节回路，从而调节生殖和代谢生理学。总体假设为 该应用是 MC3R 神经元为代谢信号与 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，将追求以下两个具体目标：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，并绘制了 组织他们的神经投射； 2）确定MC3R电路的组织和功能是否取决于 产后发育期间雌激素受体信号传导。完成这些目标将建立 用于理解 MC3R 如何协调代谢的神经机制的新框架 生殖状态的调节。