Dissection of a neural circuit proposed to underlie hot flush generation

摘要 体温调节是恒温动物维持稳定的核心体的能力 通过快速响应环境的变化来控制温度。尽管其基本 自然界中，我们对体温调节背后的神经回路的了解是有限的。缺乏 对许多体温调节紊乱的有效治疗，从潮热到各种药物， 诱发的高血压和低血压，反映了缺乏知识，如何和在哪里 来自环境的温度信号被转换成补偿响应。也许 最常见的体温调节障碍是潮热或周期性潮热的发展。 而且经常会有压倒性的热、出汗和潮红的感觉，影响着数百万人， 个体，主要是但不完全是绝经期妇女。在这里，我提出实验， 旨在解剖小鼠大脑中的体温调节回路，同时测试 提出了一种潮热生成模型。 潮热产生的确切机制目前尚不清楚，尽管它与 雌激素水平下降一个主要的假设暗示了在大脑中的神经元群体， 下丘脑弓状核（ARC）共表达Kisspeptin、神经激肽B和 强啡肽（KNDy）在雌激素戒断反应中变得肥大， 被认为投射到下丘脑的视前区（POA）。《行动纲领》已确立 作为大脑的温度调节中心，但是POA神经元的分子特性 潜在的温度调节在很大程度上是未知的。这项研究计划有三个目的 旨在阐明神经元的分子身份，包括体温调节回路， 小鼠确定细胞特异性神经底物的体温调节将有望揭示 目标（例如，受体），这有助于促进新的治疗方法的发展， 以及进一步了解温度 信号被转换成补偿响应。这种知识具有广泛的影响 不仅在体温调节障碍中，而且在一般能量平衡障碍中， 与饮食有关的。

Abstract Thermoregulation is the ability of homeothermic animals to maintain a steady core body temperature by rapidly responding to changes in the environment. Despite its fundamental nature, our understanding of the neural circuitry underlying thermoregulation is limited. The lack of effective treatments for many disorders of thermoregulation, from hot flushes to various drug- induced hyper- and hypothermias, reflects a lack of knowledge about how and where temperature signals from the environment are converted into compensatory responses. Perhaps the most common disorder of thermoregulation is the development of hot flushes, or periodic and often overwhelming sensations of heat, sweating, and flushing affecting millions of individuals, primarily but not exclusively menopausal women. Here I propose experiments designed to dissect thermoregulatory circuits in the mouse brain while simultaneously testing a proposed model of hot flush generation. The exact mechanism of hot flush generation is currently unknown, though it is associated with a drop in estrogen levels. A leading hypothesis implicates a population of neurons in the arcuate nucleus of the hypothalamus (ARC) co-expressing Kisspeptin, Neurokinin B, and Dynorphin (KNDy) that become hypertrophic in response to estrogen withdrawal and that are thought to project to the preoptic area of the hypothalamus (POA). The POA is well established as the thermoregulatory center of the brain, but the molecular identity of POA neurons underlying temperature regulation is largely unknown. This research proposal has three aims designed to elucidate the molecular identity of neurons comprising a thermoregulatory circuit in mice. Identification of cell-specific neural substrates for thermoregulation will hopefully uncover targets (e.g., receptors) that help to foster the development of novel therapeutics for conditions of dysfunctional thermoregulation and to further our understanding of exactly how temperature signals are converted into compensatory responses. Such knowledge has broad implications not only in thermoregulatory disorders, but also in disorders of general energy balance including those associated with diet.