Mapping Hypothalamic Neurocircuits Controlling Physical Activity

描述(由申请人提供)：食物摄入量和体力活动与女性生殖周期相协调并分阶段进行。雌激素受体α(ER？在调节食物摄取的下丘脑弓状核(ARC)中，影响女性运动的激素反应神经元仍未确定。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。在功能丧失研究中，我们发现，与Sf1Cre一起删除发育转录因子Nkx2-1会导致腹外侧侧VMH神经元表达ER？的亚群减少，并导致明显的肥胖和运动减少，仅在这些Nkx2-1Sf1Cre突变的雌性动物中。相反，使用功能增益方法，我们表明，直接激活完整的Nkx2-1腹外侧VMH神经元会引起女性特有的和激素依赖的身体活动爆发。性腺激素的丢失会严重削弱这种反应。我们的发现表明，专门的Nkx2-1+VMH神经元构成了以前未定义的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保持新陈代谢健康。在这里，我们计划定义和理解这种荷尔蒙反应神经回路是如何促进女性的身体活动的。在三个目标中，我们将1)评估在不同环境中对激活DREADD的反应，2)确定VMHvl神经元中的雌激素和其他潜在的神经调节剂是否影响DREADD诱导的活动，以及3)开始识别VMHv1标记和映射在Nkx2-1Sf1Cre突变雌性中缺失/改变的投影。Nkx2-1Sf1Cre雌性小鼠提供了一个很好的机会来了解性别和激素调节能量消耗的神经基础。我们的最终目标是将这一基础研究转化为可用于恢复女性新陈代谢健康的药理和/或移植疗法的开发。

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.