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：
8133184
负责人：
SHAUN F MORRISON
金额：
$ 7.7万
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 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8133184
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

项目摘要

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）：发烧是体温的防御升高，在感染过程中释放的内源性热菌刺激的急性相反应中起着重要作用。体温的发热升高是中枢神经系统策划的图案化自主神经和体细胞运动反应的结果，这是对自上型介质E2（PGE2）的增加的产生，该介体前区域（POA）（POA）是大脑中主要的热仪整合中心。 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).相同的反应星座：增强对蝙蝠，心脏和皮肤血管的交感神经外流，并增加了向肌肉的体细胞动物神经元排出，这也构成了冷防御稳态反射对皮肤冷受体刺激或核心温度下降的反射反应。在上一个资金期间，我们在理解功能组织和神经递质方面取得了重大进展，该功能组织调节了温度调节途径的活性，从而介导了蝙蝠的热生成，心率和CVC的增加，从而导致POA中PGE2的发热反应以及对皮肤冷却的冷防御反应。我们建议通过使用富有成果的体内电生理学，解剖学和神经药物方法来扩展这些研究，我们在过去几年中已经完善了，以解决三个特定的目标，这些目标将提供有关影响发烧的大脑机制并执行热心调节的关键体内稳态功能的新的重要见解。第一个目的将检验以下假设，即通过在POA和髓质raphe之间的层次结构途径来组织体，以及交感神经和冷的防御反应，通过确定PGE2和冷诱发的颤抖反应的中心神经机制，通过确定中心神经机制。第二个目标将决定调节皮肤血流和驱动蝙蝠热发生的热调节网络之间性能的基本差异的神经基础。第三个目的将重点放在热调节中的关键整合神经元：POA的输出神经元中，以了解热调节效应子的差异控制机制，并确定它们在介导效应子对神经递质系统中的作用，这些响应涉及在热失调条件下涉及的神经递质系统。公共卫生相关性：了解介导热和冷防御的中心神经机制与治疗方法的发展有关，以抗击生命的过度发烧（如脓毒症，毒血症，脑膜炎，某些癌症，某些癌症），以及在其他临床上遭受较大症状的疾病中发生的热量疾病的影响，例如，在其他临床上遭受了脑部疾病的影响，并且是脑部的脑部疾病，并且是脑部的脑部和脑中均具有较大范围的疾病。伴随于更年期和前列腺手术以及手术麻醉期间诱发的体温过低的潮热。