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

• 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
• 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

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.

项目摘要/摘要 该修订后的R01的目的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的代谢线索影响雌性小鼠性别依赖性的身体活动行为。我们 以前表明，内侧下丘脑（MBH）中激素反应性神经元的丧失 仅在雌性小鼠中减少活动。在新作品中，我们发现了一个小的离散集群 黑色皮质素4受体（MC4R）表达腹侧腹侧区域的神经元 下丘脑（VMHVLMC4R神经元）会增加女性的活性，并在激活时促进体重减轻。 CRISPRA的野生型雌性小鼠VMHVL中MC4R的剂量增加增加了旅行的距离 与对照小鼠配对时会导致体重减轻。 在这里，我们将询问是否可以利用此VMHVLMC4R节点来减轻与年龄有关的环境 - 引起的代谢挑战，还定义了机械途径和电路 调节此模块。 AIM 1会询问VMHVLMC4R节点是否取决于激素，可以改善代谢 缺陷以及沉默该节点（抑制无知）是否导致体育锻炼降低 行为。 AIM 2将确认MC4R是该节点不可或缺的一部分，并定义其他信号传导 参与VMHVLMC4R活性节点的组件。 AIM 3将解决生理问题 黑素皮质素和雌激素信号传导在调节VMHVLMC4R神经元活性中的后果 使用GAO LAB（YALE）的电生理学脑切片记录，并开始映射相互作用的输入 与VMHVLMC4R神经元。我们认为，这种辅助VMHVLMC4R女性模块在低处脱离 或没有雌激素（雌激素或培育后期），从而降低了代谢适应性。我们的方法 定义该VMHVL活性节点的分子基础是高度创新的，并且可能提供新颖 深入了解正常骑自行车女性或在不同的生命阶段中如何波动的激素状态 身体活动行为。