Dissection of a neural circuit proposed to underlie hot flush generation

解析潮热产生背后的神经回路

• 批准号: 9754740
• 负责人: Christopher Johnson
• 金额: $ 4.01万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2020-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754740
• 关键词: Affect; Animals; Body Temperature; Brain; Cells; Development; Diet; Disease; Dissection; Drops; Dynorphins; Enterobacteria phage P1 Cre recombinase; Environment; Esthesia; Estrogens; Flushing; Fostering; Generations; Genes; Genetic Identity; Heat Losses; Hot flushes; Hypothalamic structure; Individual; KISS1 gene; Knowledge; Menopause; Messenger RNA; Modeling; Molecular; Mus; Names; Nature; Neurokinin B; Neuromedin K Receptor; Neurons; Participant; Periodicity; Pharmaceutical Preparations; Physiologic Thermoregulation; Population; Preoptic Areas; Rattus; Regulation; Research Proposals; Role; Signal Transduction; Structure of nucleus infundibularis hypothalami; Sweat; Sweating; Temperature; Testing; Transcript; Vasodilation; Viral Vector; Withdrawal; Woman; design; effective therapy; energy balance; experimental study; natural hypothermia; neural circuit; novel therapeutics; optogenetics; receptor; recruit; relating to nervous system; response

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.

抽象的 温度调节是主流动物保持稳定核心身体的能力 温度通过快速响应环境变化。尽管它的基本 性质，我们对基础温度调节的神经回路的理解是有限的。缺乏 从热潮到各种药物的许多温度调节疾病的有效治疗方法 诱发的高温和体温过低，反映了关于如何和何处的知识 来自环境的温度信号转化为补偿性响应。也许 最常见的温度调节疾病是潮热的发展或周期性的 而且通常会产生压倒性的热，出汗和冲洗感，影响数百万 个人，主要是但不仅是绝经的妇女。我在这里提出实验 设计用于剖析小鼠大脑中的温度调节电路，同时测试 提议的热潮生成模型。 当前尚不清楚热潮生成的确切机制，尽管它是关联的 雌激素水平下降。主要的假设暗示着神经元中的人群 下丘脑（ARC）共表达亲吻肽，神经蛋白B和 响应于雌激素的响应肥厚的dynorphin（kndy）， 被认为可以投射到下丘脑（POA）的前视区域。 POA已经建立了 作为大脑的温度调节中心，但POA神经元的分子身份 基本的温度调节在很大程度上未知。该研究建议有三个目标 旨在阐明神经元的分子身份，包括在 老鼠。鉴定细胞特异性神经底物进行温度调节，希望可以发现 靶（例如受体）有助于促进新的治疗剂的发展 功能失调的热量调节，并进一步了解我们对温度的准确理解 信号转换为补偿性响应。这样的知识具有广泛的含义 不仅在体温调节障碍中，而且还处于一般能量平衡的障碍中 与饮食相关的人。