Medial amygdala ERα neurocircuits in the regulation of physical activity

 描述(申请人提供)：目前的申请旨在绘制杏仁内侧核(MeA)雌激素受体α(ERα)神经回路，这对身体活动和体重控制是必不可少的。我们的研究不仅将促进我们目前对运动控制和肥胖发展的理解，而且还将为开发对抗久坐行为的新的治疗方法确定新的可行的干预靶点。因此，这项拟议的研究直接关系到公共卫生和美国国立卫生研究院的使命。提交此申请表时(2011年7月-2015年7月)，本人已有四年博士后研究经验。我的长期目标是在身体活动和新陈代谢的中央调节领域确立我自己的独立研究者的地位。为了在这个领域发展一名独立的研究人员，我将利用我的K99资助的辅导期来(1)获得新的运动生理学方面的培训，以比较不同方面的跑步机运动和自愿跑步的小鼠模型；(2)实施最先进的体力活动/新陈代谢知识和代谢行为中央调控领域的尖端技术；(3)高级资助金、项目和实验室管理技能、指导、教学技能等。卵巢激素，即雌激素，通过调节食物摄入量和身体活动，在维持正常的能量平衡方面发挥着重要作用。虽然下丘脑弓状核中前阿片黑素皮质素(POMC)表达的ERα调节摄食，但影响运动的雌激素反应神经元仍未明确。最近，我们证明了ERα表达于MeA中的单意识1(SIM1)神经元，该神经元致力于促进男性和女性的运动。此外，MEA SIM1神经元的急性激活可导致短时运动增加。这些表明，MeA SIM1神经元表达的ERα构成了先前未定义的运动回路的一部分，该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一雌激素反应神经回路如何促进运动。在目标1和2(K99阶段)，我们将(1)测试MEA中的ERα是否需要协调控制运动活动、体重和运动诱导的代谢益处，方法是使用小鼠/病毒遗传功能丧失和功能获得模型来特定地删除或过表达MEA中的整个ERα群体；(2)进一步证明通过使用一种名为设计者受体的新技术(DREADD)，MeA中的ERα神经元是否可以增加/减少运动。有了这些信息，我们将开始目标3(R00阶段)，以绘制Mea ERα神经元的下游神经回路，并确定关键的Mea下游神经回路，在这些回路中，雌激素发挥刺激运动和预防肥胖的作用。拟议的研究代表了我们之前工作的逻辑扩展，并提供了一个极好的机会来理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.