Mapping Hypothalamic Neurocircuits Controlling Physical Activity

描述（由申请人提供）：食物摄入和体力活动与女性生殖周期协调调节和分期。而雌激素受体α（ER？在下丘脑弓状核（ARC）调节食物摄入，影响女性运动的饮食反应神经元仍然不确定。在这里，我们确定了一个性二态神经元簇腹内侧下丘脑（VMH）专门致力于促进女性的身体活动。在功能丧失的研究中，我们发现，删除发育转录因子Nkx 2 -1与Sf 1Cre消融腹外侧VMH神经元表达ER？并且仅在这些Nkx 2 - 1 Sf 1Cre突变雌性中导致显著的肥胖和运动减少。相反，使用功能获得的方法，我们表明，直接激活完整的Nkx 2 -1腹外侧VMH神经元eldurs的女性特定的和女性依赖的突发的身体活动。性腺激素的缺失会严重减弱这种反应。我们的研究结果表明，专门的Nkx 2 -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维持代谢适应性。在这里，我们计划定义和理解这种对疼痛敏感的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）评估在不同环境中对激活DREADD的响应，2）确定VMHvl神经元内的雌激素和其他潜在神经调节剂是否影响DREADD诱导的活性，以及3）开始鉴定VMHvl标记物并绘制在Nkx 2 - 1 Sf 1Cre突变雌性中缺失/改变的投射。Nkx 2 - 1 Sf 1Cre雌性小鼠提供了一个很好的机会来了解性别的神经基础和能量消耗的激素调节。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代谢健康的药理学和/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.