Central thermoregulatory mechanisms during heat stress

热应激期间的中枢体温调节机制

• 批准号: 10633227
• 负责人: Albert Chen
• 金额: $ 48万
• 依托单位: SCINTILLON INSTITUTE FOR PHOTOBIOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633227
• 关键词: Animals; Body Temperature; Brain region; Cannabinoids; Cells; Characteristics; Data; Development; Electrophysiology (science); Exposure to; FOS gene; Fever; Genetic; Glutamates; Heat Losses; Heat Stress Disorders; Heat Stroke; High temperature of physical object; Hyperthermia; Hypothalamic structure; Ion Channel; Lateral; Measures; Mus; Neurons; Neurotensin; Optics; Peripheral; Pharmaceutical Preparations; Physiologic Thermoregulation; Physiological; Play; Population; Preoptic Areas; Property; Reporting; Role; Site; Spinal Cord; Stress; Telemetry; Temperature; Testing; Therapeutic heat application; Transcript; Transgenic Model; Vasodilation; Viral Vector; experimental study; extreme heat; gamma-Aminobutyric Acid; induced hypothermia; natural hypothermia; neural network; neurochemistry; optogenetics; parabrachial nucleus; pharmacologic; pituitary adenylate cyclase activating polypeptide; postsynaptic; response; sulfated glycoprotein 2; tool; transcriptomics

ABSTRACT Thermoregulation is controlled in the CNS where peripheral thermal information is integrated and thermoregulatory responses are activated. The core thermoregulatory network comprises the lateral parabrachial nucleus, the preoptic area, the dorsomedial hypothalamus and the rostral raphe pallidus and is involved in the most mechanisms of adaptive thermoregulation and in the fever response. The thermoregulatory mechanisms activated during extreme heat exposure, when core body temperature (CBT) reaches 40.5 C or more, are not fully understood. We have identified brain regions that are specifically activated only in such conditions and our preliminary data indicate that these neurons are thermosensitive and are projecting to preoptic thermoregulatory neurons. Our preliminary studies have also revealed that activation of these population of neurons induces a potent hypothermia. The overarching hypothesis of this proposal is that a specific population of neurons are activated at high core body temperature and that they stimulate downstream thermoregulatory preoptic neurons triggering heat loss mechanisms. In Specific Aim 1 we will identify, using genetic tools, the neurons activated during heat stress and characterize their physiological and neurochemical properties. In Specific Aim 2 we will study using transgenic models, viral vectors and optogenetics the network connectivity of these neurons and their role in thermoregulation. By employing pharmacological tools, electrophysiology and transgenic models we will then study the ion channels involved in the thermosensitive firing of the neurons activated at high CBT and will determine their role in thermoregulation (Specific Aim 3). Studying the thermoregulatory neuronal networks and cellular mechanisms activated by extreme heat exposure may lead to better therapies for heat stroke and provide central pharmacological targets for the development of hypothermic agents.

抽象的 体温调节是在中枢神经系统中控制的，其中外围的热信息被集成并 体温调节反应被激活。核心体温调节网络包括侧向网络 臂旁核、视前区、下丘脑背内侧和中缝苍白肌头侧 参与大多数适应性体温调节机制和发烧反应。体温调节 当核心体温 (CBT) 达到 40.5 C 或 更多，还没有完全理解。我们已经确定了只有在这样的情况下才会被特别激活的大脑区域 条件和我们的初步数据表明这些神经元对热敏感并且投射到视前细胞 温度调节神经元。我们的初步研究还表明，这些群体的激活 神经元会引起强烈的低温。该提案的总体假设是特定人群 神经元在高核心体温下被激活，并刺激下游温度调节 视前神经元触发热损失机制。在具体目标 1 中，我们将使用遗传工具确定 神经元在热应激期间激活并表征其生理和神经化学特性。在 具体目标 2 我们将使用转基因模型、病毒载体和光遗传学研究网络连接 这些神经元及其在体温调节中的作用。通过使用药理学工具、电生理学和 转基因模型然后我们将研究参与神经元热敏放电的离子通道 在高 CBT 时被激活，并将确定它们在体温调节中的作用（具体目标 3）。正在学习 由极端高温暴露激活的温度调节神经网络和细胞机制可能会导致 更好的中暑治疗方法，并为体温过低的发展提供中心药理学靶点 代理。