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.

摘要 体温调节在中枢神经系统中控制，其中外周体温信息被集成并 体温调节反应被激活。核心温度调节网络包括侧向 臂旁核、视前区、下丘脑背内侧和苍白球吻侧 参与了大多数适应性体温调节和发热反应的机制。温度调节器 当核心体温(CBT)达到40.5摄氏度或 更多的，还没有完全理解。我们已经确定了只有在这种情况下才能特别激活的大脑区域 条件和我们的初步数据表明，这些神经元是温度敏感的，并投射到视前 体温调节神经元。我们的初步研究还显示，这些种群的激活 神经元会引起强烈的体温降低。这一提议的首要假设是，特定的人口 的神经元在较高的核心体温下被激活，它们刺激下游的体温调节 视前神经元触发热量损失机制。在具体目标1中，我们将使用基因工具识别 并研究其生理和神经化学特性。在……里面 具体目标2我们将利用转基因模型、病毒载体和光遗传学来研究 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温度敏感放电的离子通道 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)。正在研究的 极端高温暴露激活的体温调节神经元网络和细胞机制可能导致 更好地治疗中暑，并为低温症的发展提供中心药理靶点 探员们。