Central Sympathetic Regulation of Thermogenesis in Fever

发热时交感神经中枢对产热的调节

基本信息

批准号：
8259155
负责人：
SHAUN F MORRISON
金额：
$ 35.16万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-07-15 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8259155
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 Funding Goals Heart Heart Rate Heat Losses Heating Homeostasis Host Defense Hot flushes Human Hypothalamic structure Infection Invaded Investigation 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 receptor relating to nervous system response therapeutic development vasoconstriction

项目摘要

Project Summary 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.

项目概要发烧是一种防御性体温升高，在急性发作中起着重要作用由感染期间释放的一系列内源热原刺激的相反应。发热者体温升高是自主神经和躯体运动反应模式的结果由中枢神经系统精心策划，以响应热原产生的增加介质前列腺素 E2 (PGE2)，位于视前区 (POA)，是主要的体温调节整合位于大脑的中心。 PGE2 与 POA 神经元上的 EP3 抑制性受体结合可增加核心功能通过激活四个主要温度调节效应器的神经通路来调节体温：增加棕色脂肪组织 (BAT) 产热、骨骼肌颤抖和明显的心动过速和通过皮肤血管收缩增加热量保存（CVC）。同样的一系列反应：增强交感神经流向 BAT、心脏和皮肤血管和增加躯体运动神经元对肌肉的放电，也构成了对刺激皮肤冷感受器或核心下降的冷防御稳态反射反应温度。在上一个资助期间，我们在理解调节体温调节通路活动的功能组织和神经递质介导 BAT 产热、心率和 CVC 的增加，从而促进发热反应 POA 中的 PGE2 以及皮肤冷却的冷防御反应。我们建议通过使用富有成效的体内电生理学、解剖学方法来扩展这些研究和神经药理学方法，我们在过去几年中已经完善，以解决三个问题具体目标将为影响发烧和发烧的大脑机制提供新的重要见解执行体温调节的关键稳态功能。第一个目标将检验假设躯体反应以及交感神经的发热和寒冷防御反应是通过通过确定中枢神经系统，POA 和中缝之间的分层通路 PGE2 和寒冷引起的颤抖反应的潜在机制。第二个目标将决定温度调节网络之间性能根本差异的神经基础调节皮肤血流并驱动 BAT 生热作用。第三个目标将聚焦关键温度调节中的整合神经元：POA 的输出神经元，了解其机制用于温度调节效应器的差异控制并确定它们在介导效应器中的作用对与热失调条件有关的神经递质系统的反应。