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

• 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
• 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

 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（由应用程序提供）：当前的应用旨在绘制内侧杏仁核（MEA）雌激素受体α（ERα）神经电路，这对于体育活动和体重控制至关重要。我们的研究不仅将提高我们对体育活动控制和肥胖发展的当前理解，而且还将确定新的可行干预目标，以开发新的治疗方法来打击久坐的行为。因此，这项拟议的研究与公共卫生和NIH的使命直接相关。提交此申请时，我有四年的博士后研究经验（07/2011-07/2015）。我的长期目标是在体育锻炼和新陈代谢的中心监管领域确立自己是独立研究者。为了在这一领域发展独立的研究人员，我将使用我的K99资助的Mendored时期来（1）获得运动生理学的新培训，以比较跑步机运动的不同方面和鼠标模型中的自愿车轮跑步行为； （2）在代谢行为中心调节领域中实施有关体育活动/代谢和尖端技术的最先进的知识； （3）提高赠款，项目和实验室管理技能，心理，教学技能等。我将在K99阶段第一年结束时开始寻找大学教师职位，以确保平稳过渡到R00阶段。卵巢激素（雌激素）在控制食物摄入和体育活动中维持正常能量稳态方面起着重要作用。虽然下丘脑弧菌（ARC）中促蛋白酶素（POMC）表达的ERα调节食物摄入量，但雌激素反应性神经元会影响运动。最近，我们证明了ERα表明，通过单一智力1（SIM1）神经元，致力于促进男性和女性的运动。另外，MEA SIM1神经元的急性激活导致运动的短期增加。这些表明，MEA SIM1神经元表达的ERα构成了先前未定义的运动电路的一部分，该电路都用于男性和女性。在这里，我们计划进一步定义和了解这种MEA雌激素反应性神经回路如何促进运动。在AIM 1和2（K99期）中，我们将（1）测试是否需要通过使用小鼠/病毒遗传功能丧失和功能障碍模型来对MEA中的ERα进行协调控制运动，体重和运动诱导的代谢益处。 （2）进一步证明，通过使用新型技术称为设计器的受体受到设计器药物（DREADD）激活的新技术称为设计器受体（DREADD），MEAERα神经元的激活/抑制是否会增加/减少运动。借助此信息，我们将开始启动AIM 3（R00相），以绘制MEAERα神经元的下游神经元，并确定雌激素起作用以刺激运动和防止肥胖的关键MEA下游神经元。拟议的研究代表了我们以前的工作的逻辑扩展，并提供了一个绝佳的机会来了解运动的雌激素调节的神经基础，不仅在女性中，而且在男性中。