Medial amygdala ERα neurocircuits in the regulation of physical activity

 描述（由申请人提供）：本申请旨在绘制对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。我们的研究不仅将推进我们目前对身体活动控制和肥胖发展的理解，而且还将确定新的可行干预目标，以开发新的治疗方法来对抗久坐行为。因此，这项拟议中的研究与公共卫生和NIH的使命直接相关。我有四年的博士后研究经验时提交此申请（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枢调节领域的独立研究者。为了培养该领域的独立研究人员，我将利用K99资助的辅导期来（1）获得运动生理学方面的新培训，以比较小鼠模型中跑步机运动和自主轮跑行为的不同方面;（2）实施有关身体活动/代谢的最先进知识以及代谢行为中枢调节领域的前沿技术;（3）推进项目、实验室管理技能、指导、教学技能等，我将在K99阶段第一年年底开始寻找大学教师职位，以确保顺利过渡到R 00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能量平衡方面起着重要作用。虽然下丘脑弓状核（ARC）中阿黑皮素原（POMC）表达的ERα调节食物摄入，但影响运动的雌激素反应神经元仍不清楚。最近，我们证明ERα由MeA中的单一心智1（SIM 1）神经元表达，致力于促进男性和女性的运动。此外，MeA SIM 1神经元的急性激活导致运动的短期增加。这些表明，由MeA SIM 1神经元表达的ERα构成了先前未定义的运动回路的一部分，该运动回路在男性和女性中都使用。在这里，我们计划进一步定义和理解这种MeA雌激素反应神经回路如何促进运动。在目标1和2中（K99期），我们将（1）通过使用小鼠/病毒遗传功能丧失和功能获得模型特异性删除或过表达MeA中的整个ERα群体，测试MeA中的ERα是否是协调控制运动活性、体重和运动诱导的代谢益处所必需的;（2）通过一种新的被设计者药物独家激活的设计者受体（DREADD）技术进一步证明MeA ERα神经元的激活/抑制是否增加/减少运动。有了这些信息，我们将开始目标3（R 00阶段），绘制MeA ERα神经元的下游神经回路，并确定雌激素刺激运动和预防肥胖的关键MeA下游神经回路。拟议的研究代表了我们以前的工作的逻辑扩展，并提供了一个很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。

 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.