Hypothalamic gating of the anorexic effects of estradiol

项目总结 这项建议的总体目标是了解摄食神经调节中的性别差异， 具体地说，雌二醇的厌氧效应是如何被新的下丘脑摄食结节调制的 巡回赛。以前的研究发现，产生生长抑素(SST)的神经元是神经回路的一部分， 控制喂养，但没有研究性别差异。我们发现，激活该区域的SST神经元 横跨下丘脑的结节和腹内侧核增加了雄性和雌性小鼠的摄食量。 然而，消融这些神经元只会减少雌性动物的摄食，只有在雌性大鼠高雌激素阶段才会减少 发情周期，只有当它们的身体质量相对较低时。这些发现与以前的研究结果一致 但研究进一步揭示了SST神经元在调节摄食中的上下文依赖作用。我们 假设结节核的SST神经元是脑内的性别特异性调节节点 在能量储备低的情况下，可以掩盖雌二醇的厌食作用。该提案概述了对小鼠的研究 以确定SST神经元功能是如何受到生殖和代谢信号的调节的。在目标1中，我们 使用细胞特异性操作结合性腺激素操作来揭示SST神经元如何 功能受生殖状态的调节。在目标2中，我们使用特定于细胞的操作与 控制体重和肥胖，以揭示SST神经元功能是如何受代谢状态调节的。 在目标3中，我们使用荧光标记和流式细胞术以及随后的RNA测序(Flow-Seq)来评估 SST神经元可能对生殖和代谢条件有反应，以及这种反应是否因性别而不同。 总之，这些研究将帮助我们理解神经电路是如何整合多个外周信号的 调整动态状态下的行为和生理。

PROJECT SUMMARY The overall goal of this proposal is to understand sex differences in the neural regulation of feeding, specifically how the anorexogenic effects of estradiol are modulated by a new hypothalamic node of the feeding circuit. Previous research identified somatostatin (SST)-producing neurons as part of the neural circuit that controls feeding, but sex differences were not explored. We find that activating SST neurons in the region that spans the tuberal and ventromedial nuclei of the hypothalamus increases feeding in male and female mice. However, ablating these neurons decreases feeding only in females, only during the high-estrogen phase of the estrous cycle, and only when their body mass is relatively low. These findings are consistent with previous studies but go further to reveal a context-dependent role for SST neurons in the regulation of feeding. We hypothesize that SST neurons of the tuberal nucleus are a sex-specific, modulatory node within the brain that can mask the anorexic effects of estradiol when energy reserves are low. The proposal outlines studies in mice to determine how SST neuronal function is modulated by both reproductive and metabolic cues. In Aim 1, we use cell-specific manipulations combined with gonadal hormone manipulations to reveal how SST neuron function is modulated by reproductive state. In Aim 2, we use cell-specific manipulations combined with manipulations of body mass and adiposity to reveal how SST neuron function is modulated by metabolic state. In Aim 3, we use fluorescent labeling and flow cytometry followed by RNA-sequencing (flow-Seq) to assess how SST neurons may be responsive to reproductive and metabolic conditions and whether this differs by sex. Together, these studies will help us understand how neural circuits integrate multiple peripheral signals to fine tune behavior and physiology across dynamic states.