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以及它们的功能在发热反应期间如何改变的理解。 发热是对炎症刺激的急性期反应的一个组成部分。 在不受控制的情况下，它会威胁细胞的稳态和生存。 治疗发热期间体温失调将有助于了解由热原激活的神经通路的功能组织和介导其效应的神经递质。 拟议的研究计划将测试的假设，即在中缝苍白（RPa）的神经元的人口构成的交感神经运动前通路，这是必要的激活交感神经流出到棕色脂肪组织（BAT）在icv。PGE2，“发烧级联”中的中间体。 这些数据将为进一步研究提供基石，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神经调节的产热的途径和（B）在发热期间调节RPa产热神经元活性的主要神经递质和受体。拟开展的研究旨在阐明BAT产热调节的神经组织核心通路的功能和药理学，将使用从交感神经到BAT和从延髓中单个神经元的电生理记录，结合显微注射技术激活和中断轴突受限区域的神经元活动。 第一个具体目标将确定RPa神经元在由icv诱发的BAT SNA和BAT产热增加中的作用。前列腺素E2。 将识别投射到脊髓以介导这些效应的交感神经前运动神经元，并确定它们对发热刺激的反应。 第二个目标是确定RPa神经元的紧张性GABA能抑制的来源，并确定如何调节这种抑制以产生BAT交感神经流出的发热相关增加。 在第三个目标中，我们将测试的假设，谷氨酸神经传递介导的兴奋RPa神经元在发热反应过程中看到，这种兴奋可以调制的热能输入RPa中的产热神经元。 了解确定BAT交感神经流出的途径内的药理学将是开发改变交感神经介导的产热的策略的基础。

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.