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核心身体的能力。 通过对环境的变化做出快速反应来使温度升高。尽管它的基本原理 自然，我们对体温调节背后的神经回路的了解是有限的。匮乏 对许多体温调节障碍的有效治疗，从潮热到各种药物- 诱发性高体温和低体温，反映了对如何以及在哪里缺乏知识 来自环境的温度信号被转换为补偿反应。也许吧 体温调节最常见的障碍是潮热，或周期性潮热。 以及经常压倒一切的炎热、出汗和潮红的感觉，影响着数百万人 个人，主要但不完全是更年期妇女。在这里我提议做一些实验 旨在解剖小鼠大脑中的体温调节电路，同时测试 提出了潮热产生的模型。 产生热刷新的确切机制目前尚不清楚，尽管它与 随着雌激素水平的下降。一项领先的假说表明，大脑中的一群神经元 下丘脑弓状核(ARC)共同表达Kispeptin、神经激肽B和 强啡肽(KNDy)，因雌激素停用而变得肥大 被认为投射到下丘脑的视前区(POA)。《小伙伴关系协定》已经确立。 作为大脑的体温调节中心，但POA神经元的分子同一性 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 旨在阐明由体温调节电路组成的神经元的分子身份 老鼠。体温调节细胞特异性神经底物的鉴定有望揭开 有助于促进治疗疾病的新疗法的开发的靶点(例如，受体) 体温调节失调，并进一步了解温度究竟是如何 信号被转换为补偿反应。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的障碍中，包括 那些与饮食有关的。

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.