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

摘要 潮热发生在大多数绝经期妇女和年轻妇女雌激素停药后。他们 其特征在于热耗散效应器的激活，包括皮肤血管舒张、出汗， 冷寻求行为。尽管有数百万人经历过这些症状，但原因仍然存在 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kisspeptin/神经激肽B/强啡肽（KNDy）神经元有助于 这是因为绝经后妇女的下丘脑发生了巨大的变化。在 支持这一假设，我们最近表明，消融大鼠KNDy神经元， 血管舒张，并改变雌激素对体温调节的作用。本基金的目标是 阐明雌激素反应性KNDy神经元介导的下游（视前）通路 体温调节性血管舒张KNDy神经元投射到调节热量的关键体温调节结构- 耗散效应器：正中视前核（MnPO）和内侧视前区（MPO）。而且两 这些区域表达初级NKB受体（NK 3R），并且MnPO中NK 3R的活化降低了机体 温度我们假设MnPO和MPO中的NK 3R神经元整合了来自 雌激素反应性KNDy神经元与温暖的热信号，触发散热效应。 本研究的具体目的如下：1）观察大鼠海马神经元中是否存在NK_3R神经元。 Tacr 3-EGFP小鼠被来自环境的温热信号激活，受雌激素调节， 接收来自KNDy神经元的输入; 2）在神经元中进行NK 3R神经元的电生理记录。 Tacr 3-EGFP小鼠的视前区，以确定它们是否是热敏感的，从KNDy接收输入 神经元的热敏感性是否被雌激素或NK 3R信号改变; 3）为了确定NK 3R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 是否存在从KNDy神经元到视前区NK 3R神经元的同源投射通路。这些 研究将揭示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 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.