Central Sympathetic Regulation of Thermogenesis in Fever

描述（由申请人提供）：发烧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。发热性体温升高是由中枢神经系统对热原介质前列腺素E2 （PGE2）在视前区（POA）（大脑中主要的体温调节整合中心）的增加产生的有模式的自主和躯体运动反应的结果。PGE2与POA神经元上的EP3抑制受体结合，通过激活四种主要热调节效应的神经通路来增加核心体温：棕色脂肪组织（BAT）产热增加，骨骼肌颤抖和明显的心动过速增加，通过皮肤血管收缩（CVC）增加热量保存。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，增加躯体运动神经元向肌肉的放电，也构成了对皮肤冷受体刺激或核心温度下降的冷防御稳态反射反应。在之前的资助期内，我们在了解调节热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PGE2的发热反应和皮肤冷却的冷防御反应。我们建议通过使用我们在过去几年中完善的卓有成效的体内电生理，解剖学和神经药理学方法来扩展这些研究，以解决三个特定目标，这些目标将为影响发烧和执行关键的体温调节稳态功能的大脑机制提供新的重要见解。第一个目的是通过确定PGE2和冷诱发的寒战反应背后的中枢神经机制，验证体细胞以及交感发热和冷防御反应是通过POA和髓质中叶之间的分层通路组织起来的假设。第二个目标将确定调节皮肤血流量的体温调节网络和驱动BAT产热的体温调节网络在性能上的根本差异的神经基础。第三个目标将集中在热调节中的关键整合神经元：POA的输出神经元，以了解热调节效应物的差异控制机制，并确定它们在介导热失调条件下涉及神经递质系统的效应反应中的作用。公共卫生相关性：了解中枢神经机制介导发烧和感冒防御，对于开发治疗方法来对抗危及生命的过度发烧（如败血症、毒血症、脑膜炎和某些癌症），以及在各种其他临床重要情况下（如脑缺血和中风、滥用安非他明类药物）发生的热失调影响的管理，具有重要意义。绝经期、前列腺手术伴发的潮热及手术麻醉时引起的体温过低。

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.