Central Sympathetic Regulation of Thermogenesis in Fever

项目摘要 发烧是一种防御性的体温升高，在急性感冒中起着重要作用。 由感染期间释放的内源性热原的级联反应所刺激的相反应。发烧 体温升高是自主神经和躯体运动反应模式化的结果 由中枢神经系统协调，以响应热原的增加 前列腺素E_2(PGE_2)在视前区(POA)是一种主要的体温调节整合因子 以大脑为中心。前列腺素E_2与POA神经元上的EP3抑制受体结合增加核仁 通过激活四个主要体温调节效应器的神经通路来提高体温： 棕色脂肪组织(BAT)产热，骨骼肌颤抖和 由于明显的心动过速和通过皮肤血管收缩增加的热量 (CVC)。这同样的反应星座：增强的交感神经流出到蝙蝠，到心脏和 皮肤血管和增加躯体运动神经元对肌肉的放电，也构成了 冷防御动态平衡反射对皮肤冷感受器刺激或核心坠落的反应 温度。在上一个资助期，我们在理解 调节体温调节通路活性的功能组织和神经递质 BAT产热、心率和CVC升高与发热反应的关系 对POA中的PGE2和对皮肤降温的寒冷防御反应。 我们建议利用在体电生理学、解剖学方面的成果来扩展这些研究。 我们在过去几年中完善了神经药理学方法，以解决三个 具体目标，将提供新的和重要的见解，对影响发烧和 执行体温调节的关键动态平衡功能。第一个目标是检验这一假设 躯体以及交感的发热和寒冷的防御反应是通过一种 确定中枢神经在POA和延髓中缝之间的分级通路 前列腺素E_2和冷诱发颤抖反应的潜在机制。第二个目标将决定 体温调节网络性能根本差异的神经基础 调节皮肤血液流动，驱使蝙蝠产热。第三个目标将聚焦于关键 体温调节中的整合神经元：POA的输出神经元，了解其机制 用于体温调节效应器的不同控制，并确定它们在调节效应器中的作用 热失调条件下对神经递质系统的反应。

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.