Central Sympathetic Regulation of Thermogenesis

这项研究的长期目标是提高我们对调节体温的神经回路的理解，以及它们的功能在发热反应期间是如何改变的。发烧是对炎症刺激的急性期反应的一个组成部分。在不受控制的条件下，它可以威胁细胞的动态平衡和生存。了解热原激活的神经通路的功能组织，以及调节其影响的神经递质，将有助于治疗发烧期间体温调节失调。拟议的研究计划将检验这样一种假设，即中缝苍白带(RPA)中的一组神经元构成交感前运动通路，该通路是激活交感神经流出到棕色脂肪组织(BAT)以响应icv所必需的。PGE2，“发烧瀑布”中的一个中介。这些数据将为进一步的研究提供基石，以确定(A)调节热稳态的下丘脑神经元在发热期间激活交感调节的生热作用的途径，以及(B)在发热期间调节RPA发热神经元活动的主要神经递质和受体。这项旨在阐明蝙蝠产热的纵向组织核心通路的功能和药理学的研究将利用从交感神经到蝙蝠的电生理记录和延髓单个神经元的电生理记录，结合显微注射技术来激活和中断神经轴受限区域的神经元活动。第一个具体目标将确定RPA神经元在ICV引起的BAT SNA和BAT产热增加中的作用。PGE2。将确定投射到脊髓以调节这些效应的交感运动前神经元，并确定它们对发热刺激的反应。第二个目标将确定强直的来源，即RPA神经元的GABA能抑制，并确定这种抑制是如何调节的，以产生与发热相关的交感流出到蝙蝠的增加。在第三个目的中，我们将检验这样的假设，即谷氨酸神经传递介导了在发热反应中看到的RPA神经元的兴奋，并且这种兴奋可以被RPA中的产热神经元的5-羟色胺能输入所调制。了解决定蝙蝠交感神经流出的通路中的药理学将是开发改变交感神经介导的热产生的策略的基础。

The long-term objective of this research is to improve our understanding of the neural circuits regulating body temperature and how their function is altered during the fever response. Fever is a component of the acute-phase response to inflammatory stimuli. In uncontrolled conditions, it can threaten cellular homeostasis and survival. Treating the dysregulation of body temperature during fever will be aided by an understanding of the functional organization of the neural pathways that are activated by pyrogens and of the neurotransmitters mediating their effects. The proposed research plan will test the hypothesis that a population of neurons in the raphe pallidus (RPa) constitutes the sympathetic premotor pathway that is necessary for the activation of the sympathetic outflow to brown adipose tissue (BAT) in response to icv. PGE2, an intermediary in the "fever cascade". These data will provide the cornerstone for further investigations to determine (a) the pathways by which hypothalamic neurons regulating thermal homeostasis activate sympathetically-regulated thermogenesis during fever and (b) the principal neurotransmitters and receptors that regulate the activity of RPa thermogenic neurons during fever. The proposed studies to elucidate the function and pharmacology of the longitudinally-organized core pathway for the regulation of thermogenesis in BAT will use electrophysiological recordings from the sympathetic nerves to BAT and from single neurons in the medulla in combination with microinjection techniques to activate and interrupt neuronal activity in restricted regions of the neuraxis. The first specific aim will determine the role of RPa neurons in the increases in BAT SNA and BAT heat production evoked by icv. PGE2. The sympathetic premotor neurons that project to the spinal cord to mediate these effects will be identified and their responses to febrile stimuli will be determined. The second aim will identify the source of the tonic, GABAergic inhibition of RPa neurons and determine how this inhibition is modulated to produce fever-related increases in the sympathetic outflow to BAT. In the third aim, we will test the hypothesis that glutamate neurotransmission mediates the excitation of RPa neurons seen during the febrile response and that this excitation can be modulated by serotonergic inputs to thermogenic neurons in RPa. Understanding the pharmacology within pathways determining BAT sympathetic outflow will be a foundation for developing strategies to alter sympathetically- mediated heat production.