Estrogenic modulation of neural circuits that control temperature

项目总结 绝经期雌激素撤退与一系列代谢、血管和神经内分泌有关 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 血管舒缩症状，包括潮热和盗汗。据认为，血管舒缩症状是 由绝经过渡时雌激素水平波动引起的。然而，目前还不清楚是如何 这些变化会影响大脑中的温度调节。我们的初步数据确定了体温调节作用 对于在视前内侧区(MPO)表达雌激素受体α(ERpha)的神经元 下丘脑，一个强大的温度传感器和调节器。我们假设MPO中的ERAlpha信号 调节体温调节神经回路的活动。为了检验这一假设，我们提出了以下建议 具体目标：1)明确ERpha神经元和ERpha信号在MPO中的体温调节作用；2)解剖 调节雌激素引起的热量消耗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ERpha神经元中的转录效应。把这些放在一起 研究将剖析雌激素对温度调节的影响，在电路、神经元和 基因表达。这种机械论方法对于理解雌激素如何改变身体是至关重要的。 体温，是确定治疗潮热和潮热的新的非激素疗法的必要的第一步 其他血管舒缩症状。

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.