Medial amygdala ERα neurocircuits in the regulation of physical activity

内侧杏仁核 ERα 神经回路在身体活动调节中的作用

基本信息

批准号：
9109788
负责人：
Pingwen Xu
金额：
$ 9万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9109788
关键词：
Acute Agonist American Amygdaloid structure Animals Anterior Hypothalamus Area Behavior Body Weight Brain region Canine Adenoviruses Cardiovascular Diseases Comorbidity Developed Countries Development Eating Educational process of instructing Energy Intake Energy Metabolism Ensure Epidemic Estrogen Receptor alpha Estrogens Exercise Exercise Physiology Faculty Female Food Food Intake Regulation Funding Goals Hand Homeostasis Hormones Human Hypothalamic structure Intervention Knowledge Laboratories Locomotion Maps Medial Mediating Mentors Metabolic Metabolism Mind Mission Modeling Motor Activity Mus Neural Pathways Neurons Non-Insulin-Dependent Diabetes Mellitus Obesity Output Ovarian hormone Ovary Overweight Phase Phenotype Physical activity Play Population Positioning Attribute Pro-Opiomelanocortin Public Health Regulation Research Research Personnel Role Running Signal Transduction Site Staging Structure of nucleus infundibularis hypothalami Synapses System Techniques Technology Testing Tracer Training Universities Virus Weight Gain Weight maintenance regimen Work base combat designer receptors exclusively activated by designer drugs estrogenic experience gain of function loss of function male mouse model neural circuit new technology novel novel therapeutic intervention overexpression paraventricular nucleus prevent public health relevance relating to nervous system sedentary lifestyle skills treadmill virus genetics

项目摘要

DESCRIPTION (provided by applicant): The current application aims to map the medial amygdala (MeA) estrogen receptor alpha (ERα) neurocircuits that are essential for physical activity and body weight control. Our studies will not only advance our current understanding about the physical activity control and the development of obesity in general but also identify new feasible intervention targets for the development of novel therapeutic approaches to combat sedentary behaviors. Therefore, this proposed research is directly relevant to public health and the NIH's mission. I have four years of postdoctoral research experience when submitting this application (07/2011-07/2015). My long- term goal is to establish myself as an independent investigator in the area of central regulation of physical activity and metabolism. In order to develop an independent researcher in this field, I will use my K99-funded mentored period to (1) gain new training in exercise physiology to compare different aspects of treadmill exercise and voluntary wheel running behavior in mouse model; (2) implement the most advanced knowledge about physical activity/metabolism and cutting-edge techniques in the field of central regulation of metabolic behavior; (3) advance grantsmanship, project and laboratory management skills, mentoring, teaching skills, etc. I will start looking for university faculty positions towards the end of the first year of the K99 stage to ensure the smooth transition to the R00 phase. The ovary hormone, estrogen, plays an important role in maintaining normal energy homeostasis by regulating food intake and physical activity. While ERα expressed by pro-opiomelanocortin (POMC) in the hypothalamic arcuate nucleus (ARC) modulates food intake, estrogen- responsive neurons influencing locomotion remain undefined. Recently, we demonstrated that ERα expressed by the Single Minded 1 (SIM1) neurons in the MeA dedicated to promoting locomotion in both males and females. Additionally, acute activation of MeA SIM1 neurons led to short term increase of locomotion. These suggest that ERα expressed by MeA SIM1 neurons constitute part of a previously undefined locomotor circuit that is used in both males and females. Here, we plan to further define and understand how this MeA estrogen- responsive neural circuit promotes locomotion. In the aim 1 and 2 (K99 phase), we will (1) test if ERα in the MeA is required for the coordinated control of locomotor activity, body weight and exercise-induced metabolic benefits by using mouse/virus genetic loss-of-function and gain-of-function models to specifically delete or overexpress whole ERα population in the MeA; (2) further demonstrate if activation/inhibition of MeA ERα neurons increases/decreases locomotion by using a novel technology termed Designer Receptors Exclusively Activated by Designer Drugs (DREADD). With this information in hand, we will then start aim 3 (R00 phase) to map the downstream neural circuits of MeA ERα neurons and identify the critical MeA downstream neural circuits where estrogen acts to stimulate locomotion and prevent obesity. The proposed studies represent logical extensions to our previous work and offer an excellent opportunity to understand the neural basis of estrogenic regulation of locomotion, not only in females but also in males.

描述（由申请人提供）：本申请旨在绘制对于身体活动和体重控制至关重要的内侧杏仁核（MeA）雌激素受体α（ERα）神经回路，我们的研究不仅将增进我们目前对身体活动的理解。总体上控制肥胖的发展，同时也确定新的可行的干预目标，以开发新的治疗方法来对抗久坐行为。因此，这项拟议的研究与公共健康和 NIH 的使命直接相关。提交此申请时的博士后研究经验（07/2011-07/2015）我的长期目标是使自己成为身体活动和新陈代谢的中央调节领域的独立研究者。作为该领域的独立研究员，我将利用 K99 资助的指导时间来 (1) 获得新的生理学训练，以比较小鼠模型中跑步机运动和自愿轮跑行为的不同方面；(2) 运用最先进的物理学知识；代谢行为中央调节领域的活动/代谢和尖端技术；（3）推进资助、项目和实验室管理技能、指导、教学等。我将开始寻找大学教职职位。 K99 阶段的第一年，确保顺利过渡到 R00 阶段卵巢激素雌激素通过调节食物摄入和身体活动在维持正常的能量稳态中发挥着重要作用，而 ERα 由阿片黑皮质素原表达。下丘脑弓状核（ARC）中的 POMC（POMC）调节食物摄入，但影响运动的雌激素反应性神经元仍不清楚。最近，我们证明了 MeA 中的单心 1（SIM1）神经元表达的 ERα 致力于促进雄性的运动。此外，MeA SIM1 神经元的急性激活导致短期运动增加，这表明 MeA SIM1 神经元表达的 ERα 构成了先前未定义的运动回路的一部分。在这里，我们计划进一步定义和了解这种 MeA 雌激素反应神经回路如何促进运动。在目标 1 和 2（K99 阶段）中，我们将 (1) 测试 ERα 是否在通过使用小鼠/病毒遗传特异性功能丧失和功能获得模型来删除或过度表达 MeA 中的整个 ERα 群体，MeA 是协调控制运动活动、体重和运动引起的代谢益处所必需的； (2) 通过使用一种名为设计药物独家激活的设计受体 (DREADD) 的新技术，进一步证明 MeA ERα 神经元的激活/抑制是否会增加/减少运动。有了这些信息，我们将开始目标 3（R00 阶段）。绘制 MeA ERα 神经元的下游神经回路，并确定雌激素在其中发挥刺激运动和预防肥胖作用的关键 MeA 下游神经回路。拟议的研究代表了我们的逻辑延伸。以前的工作，并提供了一个极好的机会来了解雌激素调节运动的神经基础，不仅在女性，而且在男性。