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

剖析女性活动和重复行为的激素反应处理器

基本信息

批准号：
10115716
负责人：
HOLLY A. INGRAHAM
金额：
$ 48.58万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10115716
关键词：
Address Affect Age Behavior Behavior Control Behavioral Body Weight Body Weight decreased Brain Cell physiology Clustered Regularly Interspaced Short Palindromic Repeats Cues Data Dependence Drops Electrophysiology (science)Estrogen Receptor alpha Estrogen Receptors Estrogens Estrus Female Gene Dosage Genetic Recombination Goals Health Hormonal Hormone Responsive Hormones Human Hypothalamic structure Investments Knockout Mice Life Longevity Medial Mediating Melanocortin 4 Receptor Metabolic Metabolic Control Methods Molecular Molecular Profiling Mus Neurons Non-Insulin-Dependent Diabetes Mellitus Obesity Outcome Output Pathway interactions Physical activity Physiological Population Postmenopause Process Proestrus Property Public Health Reproduction Role Signal Transduction Slice Travel Viral Woman Work age related aged alpha-Melanocyte stimulating hormone anatomical tracing designer receptors exclusively activated by designer drugs dosage experience falls improved inhibitory neuron innovation insight male metabolic fitness mind control mouse model neural circuit neurophysiology novel repetitive behavior response sex transcriptome sequencing

项目摘要

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.

项目概要/摘要修订后的 R01 的目标是确定下丘脑区域如何整合并处理激素和中枢神经系统代谢信号影响雌性小鼠的性别依赖性体力活动行为。我们先前表明，下丘脑内侧基底层（MBH）中激素反应性神经元的丧失仅减少雌性小鼠的活动。在新的工作中，我们发现一个小的、离散的集群腹内侧腹外侧区表达黑皮质素 4 受体 (Mc4r) 的神经元下丘脑（VMHvlMC4R 神经元）激活后会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 Mc4r 的剂量，增加移动距离当与对照小鼠配对喂养时，会导致体重减轻。在这里，我们将询问是否可以利用该 VMHvlMC4R 节点来缓解与年龄相关和环境相关的问题诱导代谢挑战，并定义负责的机制途径和回路调节该模块。目标1会问VMHvlMC4R节点是否依赖激素，可以改善代谢缺陷，以及沉默该节点（抑制性 DREADD）是否会导致体力活动降低行为。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 将解决生理问题黑皮质素和雌激素信号传导在调节 VMHvlMC4R 神经元活动中的后果与高实验室（耶鲁大学）进行电生理学脑切片记录，并开始绘制相互作用的输入图与 VMHvlMC4R 神经元。我们假设这个辅助 VMHvlMC4R 母模块在低状态下脱离或没有雌激素（发情期或绝经后时期），从而降低代谢健康。我们的方法定义该 VMHvl 活动节点的分子基础具有高度创新性，并且可能提供新颖的深入了解正常骑行女性或不同生命阶段的激素状态波动如何身体活动行为。