Dissection of a neural circuit proposed to underlie hot flush generation

解析潮热产生背后的神经回路

基本信息

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
项目类别：
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

项目摘要

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.

抽象的体温调节是恒温动物维持稳定的核心身体的能力通过快速响应环境变化来调节温度。尽管其基本本质上，我们对温度调节背后的神经回路的理解是有限的。缺乏许多体温调节障碍的有效治疗方法，从潮热到各种药物引起的体温过高和体温过低，反映了缺乏关于如何以及在何处的知识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常常会带来压倒性的热感、出汗和潮红感，影响着数百万人个人，主要但不限于更年期妇女。在这里我提出实验旨在剖析小鼠大脑中的温度调节回路，同时测试提出的潮热产生模型。热潮红产生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。一个主要的假设表明，神经元中存在着一群神经元。下丘脑弓状核 (ARC) 共表达 Kisspeptin、Neurokinin B 和强啡肽 (KNDy) 因雌激素撤退而变得肥大，并且被认为投射到下丘脑的视前区（POA）。 POA 已十分完善作为大脑的体温调节中心，但 POA 神经元的分子身份基本的温度调节在很大程度上是未知的。这项研究计划有三个目标旨在阐明构成温度调节回路的神经元的分子身份老鼠。鉴定用于温度调节的细胞特异性神经基质将有望揭示有助于促进新疗法开发的靶标（例如受体）温度调节功能失调的研究，并进一步了解温度到底如何变化信号被转换成补偿响应。这些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，包括那些与饮食有关的。