Melanocortin 3 receptor in neural circuits linking reproductive state and metabolism

项目摘要 调节代谢状态和繁殖的神经回路必须相互沟通， 体内平衡尽管代谢和生殖疾病的患病率不断增加， 对连接能量稳态和生殖的神经回路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的定位，以介导直接的免疫应答。 生殖和代谢回路之间的交流。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是控制生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的神经元可能代表了 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 生殖状态。然而，在AVPV和ARH中表达MC3R的神经元的细胞特性具有一定的差异性。 尚未确定，也没有定义他们的神经投射的组织。最近的证据 表明MC3R也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导致的代谢挑战期间，如怀孕和 卵巢切除术、MC3R缺失分别导致小鼠体重增加过少或过多。 MC3R的缺失导致雄性和雌性的额外生殖和代谢紊乱， 包括对禁食的不良反应、进食行为的中断和循环激素的改变 浓度的此外，具有MC3R突变的女性通常表现出更异常的生殖和生殖功能。 代谢表型，与突变体男性观察到的。然而，详细了解 导致男性和女性这些不同反应的机制缺乏。因为性类固醇 在发育的关键时期，指定性二态神经回路的组织，它是 在这些时期暴露于雌激素可能会导致结构的永久性变化， MC3R调节电路，从而调节生殖和代谢生理学。总体假设 这种应用是MC3R神经元提供了一种神经学底物，用于代谢信号与 生殖状态，并且该回路在男性和女性中的配置可能不同。作为第一步 为了验证这一假设，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 2）确定MC3R回路的组织和功能是否取决于 在出生后发育过程中对雌激素受体信号传导的影响。实现这些目标将建立一个 了解MC3R如何协调代谢的神经机制的新框架 调节生殖状态。

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.