Dissecting a hormone-responsive processor for female activity and repetitive behavior

项目总结/摘要 这个修订的R 01的目标是确定下丘脑区域如何整合，然后处理 激素和中枢神经系统代谢线索影响雌性小鼠性别依赖性体力活动行为。我们 先前的研究表明，在内侧基底下丘脑（MBH）中， 仅在雌性小鼠中减少活动。在新的工作中，我们发现一个小的，离散的集群， 黑素皮质素4受体（Mc 4 r）表达神经元在腹内侧的腹外侧区 下丘脑（VMHvlMC 4 R神经元）在激活时增加女性活动并促进体重减轻。 通过CRISPRa增加野生型雌性小鼠VMHvl中Mc 4 r的剂量增加了行进的距离 当与对照小鼠配对喂养时导致体重减轻。 在这里，我们将询问是否可以利用该VMHvlMC 4 R节点来减轻与年龄相关的和环境的影响- 诱导的代谢挑战，也定义了机制途径和电路负责 控制这个模块。目的1会问VMHvlMC 4 R节点是否依赖于激素，可以改善代谢 缺陷，以及是否沉默这个节点（抑制性DREADD）导致身体活动降低 行为。目标2将确认Mc 4 r是该节点的组成部分，并定义其他信令 参与VMHvlMC 4 R活动节点的组件。目标3将解决生理问题 黑皮质素和雌激素信号传导在通过调节VMHvlMC 4 R神经元活性中的结果 与高实验室（耶鲁大学）的电生理学大脑切片记录和开始映射输入， VMHvlMC 4 R神经元。我们认为，该辅助VMHvlMC 4 R母模块在低电压状态下脱离。 或没有雌激素（发情期或绝经后时期），从而降低代谢适应性。我们的方法 定义这种VMHvl活性节点的分子基础是高度创新的，并可能提供新的 洞察如何波动的地位，在一个正常的骑自行车的女性或在不同的生命阶段驱动器 身体活动行为。

Project Summary/Abstract The goal of this revised R01 is to determine how a hypothalamic region integrates and then processes hormone and CNS metabolic cues to affect sex-dependent physical activity behavior in female mice. We showed previously that loss of hormone-responsive neurons in the medial basal hypothalamus (MBH) diminishes activity only in female mice. In new work, we discovered that a small, discrete cluster of melanocortin 4 receptor (Mc4r)-expressing neurons in the ventrolateral region of the ventromedial hypothalamus (VMHvlMC4R neurons) increases female activity and promotes weight loss when activated. Increasing dosage of Mc4r in the VMHvl of wild type female mice by CRISPRa increases distance traveled leading to weight loss when pair-fed with control mice. Here, we will ask if this VMHvlMC4R node can be exploited to mitigate age-related and environmental- induced metabolic challenges and also define the mechanistic pathway and circuits responsible for regulating this module. Aim 1 will ask if the VMHvlMC4R node depends on hormones, can improve metabolic deficits, and whether silencing this node (inhibitory DREADDs) results in lowered physical activity behaviors. Aim 2 will confirm that Mc4r is an integral part of this node and define other signaling components that participate in the VMHvlMC4R activity node. Aim 3 will address the physiological consequences of melanocortin and estrogen signaling in modulating VMHvlMC4R neuron activity by electrophysiology brain slice recordings with the Gao lab (Yale) and begin mapping inputs that interact with VMHvlMC4R neurons. We posit that this ancillary VMHvlMC4R female-module disengages in states of low or no estrogen (estrus or post-menopause period) thereby reducing metabolic fitness. Our approaches to define the molecular basis of this VMHvl activity node are highly innovative and likely to provide novel insights into how fluctuating hormone-status in a normal cycling female or during different life-stages drives physical activity behaviors.