Central Sympathetic Regulation of Thermogenesis in Fever

发热时交感神经中枢对产热的调节

• 批准号: 7911967
• 负责人: SHAUN F MORRISON
• 金额: $ 2.79万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-15 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7911967
• 关键词: Acute-Phase Reaction; Address; Amphetamine Abuse; Anesthesia procedures; Area; Automobile Driving; Binding; Blood Vessels; Blood flow; Body Temperature; Brain; Brown Fat; Cerebral Ischemia; Coupled; Cutaneous; Dinoprostone; Environment; Fever; Figs - dietary; Funding; Goals; Heart; Heart Rate; Heat Losses; Heating; Homeostasis; Host Defense; Hot flushes; Human; Hypothalamic structure; Infection; Invaded; Investigation; Knowledge; Life; Malignant Neoplasms; Mediating; Mediator of activation protein; Meningitis; Menopause; Metabolic; Modeling; Motor; Muscle; Neural Pathways; Neuraxis; Neurons; Neurotransmitters; Operative Surgical Procedures; Output; Pathway interactions; Pattern; Performance; Pharmaceutical Preparations; Physiologic Thermoregulation; Play; Population; Preoptic Areas; Process; Production; Reflex action; Regulation; Research; Rodent; Role; Saliva; Sepsis; Septic Toxemia; Shivering; Skeletal Muscle; Skin; Spinal; Stroke; Sweat; Sweating; System; Tachycardia; Temperature; Testing; Therapeutic; Thermogenesis; Work; base; clinically significant; combat; defense response; endogenous pyrogen; expectation; falls; in vivo; induced hypothermia; insight; neural circuit; neuromechanism; novel; pathogen; prostaglandin EP3 receptor; prostate surgery; public health relevance; receptor; relating to nervous system; response; therapeutic development; vasoconstriction

Description (provided by applicant): Fever is a defended elevation in body temperature that plays a significant role in the acute phase reaction stimulated by a cascade of endogenous pyrogens released during infection. The febrile increase in body temperature is the result of a patterned autonomic and somatic motor response orchestrated by the central nervous system in response to an increased production of the pyrogenic mediator, prostaglandin E2 (PGE2), in the preoptic area (POA), a principal thermoregulatory integration center in the brain. PGE2 binding to EP3 inhibitory receptors on neurons in the POA increases core body temperature by activating neural pathways to four principal thermoregulatory effectors: increased heat production from brown adipose tissue (BAT) thermogenesis, from shivering in skeletal muscle and from a marked tachycardia and increased heat conservation through cutaneous vasoconstriction (CVC). This same constellation of responses: augmented sympathetic outflows to BAT, to the heart and to skin blood vessels and increased somatic motorneuron discharge to muscle, also constitutes the cold defense homeostatic reflex response to stimulation of cutaneous cold receptors or falls in core temperature. In the previous funding period, we have made significant progress in understanding the functional organization and neurotransmitters regulating the activity in the thermoregulatory pathways mediating the increases in BAT thermogenesis, heart rate and CVC contributing to the febrile response to PGE2 in the POA and to cold defense responses to skin cooling. We propose to extend these studies by using the fruitful in vivo electrophysiological, anatomical and neuropharmacological approaches we have perfected over the past several years to address three specific aims that will provide new and important insights into the brain mechanisms effecting fever and performing the critical homeostatic function of thermoregulation. The first aim will test the hypothesis that somatic, as well as sympathetic febrile and cold defense responses are organized through a hierarchical pathway between the POA and the medullary raphe by determining the central neural mechanism underlying the PGE2- and cold-evoked shivering response. The second aim will determine the neural basis for the fundamental differences in performance between the thermoregulatory network regulating skin blood flow and that driving BAT thermogenesis. The third aim will focus on the key integrative neurons in thermoregulation: the output neurons of the POA, to understand the mechanism for the differential control of thermoregulatory effectors and to determine their role in mediating effector responses to neurotransmitter systems implicated in conditions of thermal dysregulation. PUBLIC HEALTH RELEVANCE: Understanding the central neural mechanisms mediating fever and cold defense is relevant to the development of therapeutic approaches to combat life-threatening excessive fevers (as during sepsis, toxemia, meningitis, some cancers) and to the management of the effects of thermal dysregulation that occurs during a variety of other clinically significant conditions such as cerebral ischemia and stroke, the abuse of amphetamine-based drugs, the hot flashes accompanying menopause and prostate surgery and the hypothermia induced during surgical anesthesia.

描述（由申请人提供）：发烧是一种防御性体温升高，在感染过程中释放的一系列内源性热原刺激的急性期反应中起着重要作用。发热性体温升高是中枢神经系统协调的自主神经和躯体运动反应模式的结果，该反应是对视前区 (POA) 中致热介质前列腺素 E2 (PGE2) 产量增加的反应，POA 是主要的致热介质。大脑中的体温调节整合中心。 PGE2 与 POA 神经元上的 EP3 抑制性受体结合，通过激活四个主要温度调节效应器的神经通路来增加核心体温：棕色脂肪组织 (BAT) 产热、骨骼肌颤抖、明显心动过速和热量增加产生的热量增加通过皮肤血管收缩（CVC）进行保护。同样的一系列反应：增加交感神经向 BAT、心脏和皮肤血管的流出，以及增加体细胞运动神经元向肌肉的放电，也构成了对刺激皮肤冷感受器或核心温度下降的冷防御稳态反射反应。在之前的资助期间，我们在了解调节体温调节通路活动的功能组织和神经递质方面取得了重大进展，这些调节通路介导 BAT 产热、心率和 CVC 的增加，从而促进 POA 中 PGE2 的发热反应和冷防御对皮肤冷却的反应。我们建议通过使用我们在过去几年中完善的富有成效的体内电生理学、解剖学和神经药理学方法来扩展这些研究，以实现三个具体目标，这将为影响发烧和执行关键稳态功能的大脑机制提供新的重要见解的体温调节。第一个目标将通过确定 PGE2 和寒冷诱发的寒战反应背后的中枢神经机制来检验以下假设：躯体以及交感神经的发热和寒冷防御反应是通过 POA 和中缝髓之间的分层途径组织的。第二个目标将确定调节皮肤血流的温度调节网络和驱动 BAT 产热的温度调节网络之间性能根本差异的神经基础。第三个目标将重点关注温度调节中的关键整合神经元：POA 的输出神经元，以了解温度调节效应器的差异控制机制，并确定它们在介导与热失调条件有关的神经递质系统的效应器反应中的作用。公共健康相关性：了解介导发烧和寒冷防御的中枢神经机制与开发治疗危及生命的过度发烧（如败血症、毒血症、脑膜炎和某些癌症期间）的治疗方法以及管理热效应有关。在各种其他具有临床意义的情况下发生的调节失调，例如脑缺血和中风、滥用苯丙胺类药物、绝经期和前列腺手术引起的潮热以及引起的体温过低手术麻醉期间。