Mapping Hypothalamic Neurocircuits Controlling Physical Activity

描述（申请人提供）：食物摄入和身体活动是协调调节的，并与女性生殖周期相适应。而雌激素受体(ER？在调节食物摄入的下丘脑弓状核（ARC）中，影响女性运动的激素反应神经元尚不清楚。在这里，我们在下丘脑腹内侧（VMH）发现了一个性别二态神经元簇，专门用于促进女性的身体活动。在一项功能缺失的研究中，我们发现用Sf1Cre删除发育转录因子Nkx2-1可使表达ER？并且只在这些Nkx2- 1Sf1Cre突变的雌性中导致明显的肥胖和运动能力下降。相反，使用功能获得方法，我们发现直接激活完整的Nkx2-1腹侧VMH神经元会引发女性特异性和激素依赖性的身体活动爆发。性腺激素的缺失严重削弱了这种反应。我们的研究结果表明，专门的Nkx2-1+ VMH神经元构成了先前未定义的两性二态运动回路的一部分，该回路专门用于女性对抗久坐行为和维持代谢健康。在这里，我们计划定义和理解这种激素反应神经回路如何促进女性的身体活动。在三个目标中，我们将1)评估在不同环境下对激活dreadd的反应，2)确定雌激素和VMHvl神经元内其他潜在的神经调节剂是否影响dreadd诱导的活性，3)开始识别VMHvl标记并绘制Nkx2-1Sf1Cre突变女性中缺失/改变的投影。Nkx2-1Sf1Cre雌性小鼠为了解性别和激素调节能量消耗的神经基础提供了极好的机会。我们的最终目标是将这项基础研究转化为可用于恢复女性代谢健康的药理学和/或移植疗法的发展。

DESCRIPTION (provided by applicant): Food intake and physical activity are coordinately regulated and phased with the female reproductive cycle. While estrogen receptor alpha (ER? in the hypothalamic arcuate nucleus (ARC) modulates food intake, hormone-responsive neurons influencing female locomotion remain undefined. Here, we identify a sexually dimorphic neuronal cluster in the ventromedial hypothalamus (VMH) solely dedicated to promoting physical activity in females. In a loss-of-function study we find that deleting the developmental transcription factor Nkx2-1 with Sf1Cre ablates a subpopulation of ventrolateral VMH neurons expressing ER?and results in marked obesity and reduced locomotion only in these Nkx2- 1Sf1Cre mutant females. Conversely, using a gain-of-function approach we show that directly activating intact Nkx2-1 ventrolateral VMH neurons elicits a female-specific and hormone-dependent burst of physical activity. Loss of gonadal hormone severely blunts this response. Our findings demonstrate that specialized Nkx2-1+ VMH neurons constitute part of a previously undefined sexually dimorphic locomotor circuit that is used specifically in females to combat sedentary behavior and maintain metabolic fitness. Here, we plan to define and understand how this hormone-responsive neural circuit promotes physical activity in females. In three aims, we will 1) assess responses in a different settings to activating DREADDs, 2) determine if estrogen and other potential neuromodulators within VMHvl neurons affect DREADD-induced activity and 3) begin identifying VMHvl markers and mapping projections that are missing/altered in the Nkx2-1Sf1Cre mutant females. Nkx2-1Sf1Cre female mice offer an excellent opportunity to understand the neural basis of gender and hormonal regulation of energy expenditure. Our ultimate goal is to translate this basic research into the development of pharmacological and/or transplantation therapies that can be used to restore metabolic health in females.