Estrogenic modulation of neural circuits that control temperature

项目摘要 绝经期雌激素戒断与一系列代谢、血管和神经内分泌 影响健康和生活质量的变化。与更年期相关的最具体的症状是 血管痉挛症状，包括潮热和盗汗。一般认为血管扩张症状是 由绝经过渡期雌激素水平波动引起。然而，目前还不清楚如何 这些变化影响大脑的温度调节。我们的初步数据确定了体温调节的作用 对于表达雌激素受体α（ER α）的神经元，在内侧视前区（MPO）， 下丘脑是一个有效的温度传感器和调节器。我们假设MPO中的ER α信号 调节体温调节神经回路的活动。为了验证这一假设，我们提出以下建议： 具体目标：1）确定ER α +神经元和ER α信号在MPO中的温度调节作用，2）解剖 介导雌激素诱导的热耗散和产生变化的神经回路，以及3） 确定雌激素信号在体温调节ER α +神经元中的转录作用。综合这些 研究将剖析雌激素对温度调节的影响，在电路，神经元， 基因表达。这种机制的方法是必不可少的了解如何雌激素改变身体 这是确定新的潮热非激素疗法的必要的第一步， 其他血管炎症状。

PROJECT SUMMARY Estrogen withdrawal at menopause is associated with a suite of metabolic, vascular, and neuroendocrine changes that impact health and quality of life. The most specific symptoms associated with menopause are vasomotor symptoms, which include hot flashes and night sweats. It is thought that vasomotor symptoms are caused by fluctuating estrogen levels at the time of the menopausal transition. However, it is unclear how these changes affect temperature regulation in the brain. Our preliminary data identify a thermoregulatory role for neurons that express estrogen receptor alpha (ERalpha) in the medial preoptic area (MPO) of the hypothalamus, a potent temperature sensor and regulator. We hypothesize that ERalpha signaling in the MPO modulates the activity of thermoregulatory neural circuits. To test this hypothesis, we propose the following specific aims: 1) Define the thermoregulatory role of ERalpha+ neurons and ERalpha signaling in the MPO, 2) Dissect the neural circuitry that mediates estrogen-induced changes in heat dissipation and generation, and 3) determine the transcriptional effects of estrogen signaling in thermoregulatory ERalpha+ neurons. Together these studies will dissect the effects of estrogens on temperature regulation at the level of circuits, neurons, and gene expression. This mechanistic approach is essential for understanding how estrogens alter body temperature and is a necessary first step toward identifying new non-hormonal therapies for hot flashes and other vasomotor symptoms.