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

项目摘要/摘要 修订后的R01的目标是确定下丘脑区是如何整合和处理的 激素和中枢神经系统代谢线索影响雌性小鼠的性别依赖性体力活动行为。我们 以往的研究表明，下丘脑内侧基底核(MBH)激素反应神经元的丢失 仅降低雌性小鼠的活动。在新的工作中，我们发现一个小的，离散的星系团 黑素皮质素4受体(Mc4r)在腹内侧腹外侧区的表达 下丘脑(VMHvlMC4R神经元)在激活时增加女性的活动并促进体重减轻。 CRISPRA增加野生型雌性小鼠VMHvl中Mc4r的剂量可增加行走距离 当与对照组小鼠配对喂养时，会导致体重减轻。 在这里，我们将询问是否可以利用此VMHvlMC4R节点来缓解与年龄和环境相关的- 诱导代谢挑战，还定义了负责 调节这个模块。目的1会问VMHvlMC4R节点是否依赖激素，能否改善新陈代谢 缺陷，以及沉默这个节点(抑制性DREADD)是否会导致体力活动减少 行为。目标2将确认Mc4r是该节点的组成部分，并定义其他信令 参与VMHvlMC4R活动节点的组件。目标3将解决生理学问题 黑素皮质素和雌激素信号在调节VMHvlMC4R神经元活性中的作用 电生理学大脑切片记录与高实验室(耶鲁大学)，并开始映射相互作用的输入 有VMHvlMC4R神经元。我们假设这个辅助的VMHvlMC4R母模块在Low状态下脱离 或者没有雌激素(动情期或绝经期)，从而降低新陈代谢的适合度。我们的方法是 定义这种VMHv1活性节点分子基础具有很高的创新性，并可能提供新的 对正常周期女性或不同生命阶段荷尔蒙状态波动的洞察 体力活动行为。

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.