Central Sympathetic Regulation of Thermogenesis in Fever

描述（由申请方提供）：发热是一种防御性体温升高，在感染期间释放的内源性热原级联刺激的急性期反应中起重要作用。体温的发热性升高是由中枢神经系统响应于视前区（POA）（大脑中的主要体温调节整合中心）中致热介质前列腺素E2（PGE2）的产生增加而协调的模式化自主和躯体运动反应的结果。PGE2与POA中神经元上的EP3抑制性受体结合，通过激活四种主要体温调节效应物的神经通路来增加核心体温：棕色脂肪组织（BAT）产热、骨骼肌颤抖和显著心动过速的产热增加以及通过皮肤血管收缩（CVC）的热量保存增加。同样的反应组合：增强的交感神经流出到BAT、心脏和皮肤血管，以及增加的躯体运动神经元放电到肌肉，也构成了对皮肤冷受体刺激或核心温度福尔斯下降的冷防御稳态反射反应。在上一个资助期，我们在了解调节体温调节途径活动的功能组织和神经递质方面取得了重大进展，这些途径介导BAT产热，心率和CVC的增加，从而促进POA中对PGE2的发热反应和对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，解剖学和神经药理学的方法，我们已经完善了在过去几年中，以解决三个具体的目标，将提供新的和重要的见解，影响发热和执行的关键稳态功能的体温调节的大脑机制来扩展这些研究。第一个目标将测试的假设，即躯体，以及交感神经发热和寒冷的防御反应组织通过一个层次之间的途径POA和延髓中缝通过确定PGE2和冷诱发的颤抖反应的中枢神经机制。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的根本差异的神经基础。第三个目标将集中在温度调节的关键整合神经元：POA的输出神经元，了解温度调节效应器的差异控制机制，并确定其在介导效应器对热失调条件下涉及的神经递质系统的反应中的作用。公共卫生相关性：了解介导发热和感冒防御的中枢神经机制与治疗威胁生命的过度发热的治疗方法的发展有关（如在脓毒症、毒血症、脑膜炎、某些癌症期间）以及在各种其它临床显著病症（如脑缺血和中风，滥用安非他明类药物，更年期和前列腺手术引起的潮热以及手术麻醉期间引起的体温过低。

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.