Role of preoptic NK3R neurons in the estrogen modulation of body temperature

摘要 潮热发生在大多数更年期妇女和停用雌激素后的年轻妇女。他们 其特征是激活散热效应器，包括皮肤血管扩张、出汗和 求冷行为。尽管数以百万计的人经历了这些症状，但原因仍然是 这是一个谜，人们对雌激素调节体温的神经回路知之甚少。 我们的实验室长期以来一直假设Kispeptin/Neurokinin B/Dynorphin(KNDy)神经元参与 潮红的产生，是因为绝经后妇女的下丘脑发生了戏剧性的变化。在……里面 支持这一假设，我们最近表明，消融大鼠KNDy神经元减少皮肤 扩张血管，改变雌激素对体温调节的作用。这笔赠款的目标是 阐明雌激素反应的KNDy神经元所使用的下游(视前)通路 体温调节性血管扩张。KNDy神经元投射到调节热量的关键体温调节结构- 消散效应：正中视前核(MnPO)和内侧视前区(MPO)。此外，两者 这些区域表达初级NKB受体(NK3R)，而NK3R在MnPO体内的激活会降低机体 温度。我们推测，MnPO和MPO中的NK3R神经元整合了来自 雌激素反应的KNDy神经元具有温热信号，触发散热效应器。 本研究的主要目的如下：1)探讨NK3R神经元在大鼠脑内MnPO和MPO中的作用 Tacr3-EGFP小鼠被来自环境的温热信号激活，受雌激素和 接受来自KNDy神经元的输入；2)对NK3R神经元进行电生理记录 Tacr3-EGFP小鼠的视前区，以确定它们是否对热敏感，接受来自KNDy的输入 以及它们的热敏感性是否被雌激素或NK3R信号改变；3)确定NK3R是否 MnPO和MPO中的神经元是雌激素调节体温所必需的；4)确定 如果人类存在从KNDy神经元到视前NK3R神经元的同源投射通路。这些 研究将阐明生殖和体温调节系统的整合，并提供线索 潮热的病因。了解潮热的机制对于设计有针对性的潮红是必不可少的 治疗。

ABSTRACT Hot flushes occur in the majority of menopausal women and in young women after estrogen withdrawal. They are characterized by the activation of heat dissipation effectors, including skin vasodilatation, sweating, and cold-seeking behavior. Despite the millions of individuals who experience these symptoms, the cause remains an enigma, and there is little understanding of the neural circuits for estrogen modulation of body temperature. Our laboratory has long hypothesized that kisspeptin/neurokinin B/dynorphin (KNDy) neurons contribute to the generation of flushes, because of their dramatic changes in the hypothalamus of postmenopausal women. In support of this hypothesis, we recently showed that ablation of KNDy neurons in the rat decreases cutaneous vasodilatation and alters the effects of estrogen on thermoregulation. The goal of the present grant is to elucidate the downstream (preoptic) pathways used by estrogen-responsive KNDy neurons to mediate thermoregulatory vasodilatation. KNDy neurons project to key thermoregulatory structures that regulate heat- dissipation effectors: the median preoptic nucleus (MnPO) and medial preoptic area (MPO). Moreover, both these areas express the primary NKB receptor (NK3R) and activation of NK3R in the MnPO reduces body temperature. We hypothesize that NK3R neurons in the MnPO and MPO integrate information from estrogen-responsive KNDy neurons with warm thermal- signals that trigger heat dissipation effectors. The following specific aims are proposed: 1) To evaluate whether NK3R neurons in the MnPO and MPO of Tacr3-EGFP mice are activated by warm-thermal signals from the environment, are modulated by estrogen and receive inputs from KNDy neurons; 2) To perform electrophysiological recordings of NK3R neurons in the preoptic area of the Tacr3-EGFP mouse to determine if they are warm-sensitive, receive inputs from KNDy neurons and if their thermal sensitivity is altered by estrogen or NK3R signaling; 3) To determine if NK3R neurons in the MnPO and MPO are essential for the estrogen modulation of body temperature; 4) To determine if a homologous projection pathway from KNDy neurons to preoptic NK3R neurons exists in the human. These studies will shed light on the integration of reproductive and thermoregulatory systems and provide clues into the etiology of hot flushes. Understanding the mechanisms of hot flushes is essential for designing targeted therapies.