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烧反应中是如何改变的。发热是急性期对炎症刺激反应的一个组成部分。在不受控制的情况下，它可以威胁细胞的稳态和生存。治疗发烧期间的体温失调将有助于理解由热原激活的神经通路的功能组织和介导其作用的神经递质。拟议的研究计划将验证一种假设，即苍白骨中缘（RPa）中的神经元群构成交感神经运动前通路，该通路是激活交感神经流向棕色脂肪组织（BAT）以响应icv的必要条件。PGE2是“发烧级联”的中介。这些数据将为进一步研究奠定基础，以确定(a)调节热稳态的下丘脑神经元在发烧期间激活交感神经调节的产热的途径，以及(b)在发烧期间调节RPa产热神经元活动的主要神经递质和受体。为了阐明纵向组织的核心通路对BAT产热调节的功能和药理学，拟议的研究将使用交感神经到BAT和髓质单个神经元的电生理记录，结合显微注射技术激活和中断神经轴受限区域的神经元活动。第一个具体目标是确定RPa神经元在icv引起的BAT SNA和BAT产热增加中的作用。PGE2。将确定投射到脊髓介导这些效应的交感前运动神经元，并确定它们对发热刺激的反应。第二个目标将确定RPa神经元的强直性gaba能抑制的来源，并确定这种抑制是如何被调节以产生交感神经向BAT流出的发热相关增加的。在第三个目标中，我们将验证谷氨酸神经传递介导发热反应期间RPa神经元的兴奋，并且这种兴奋可以通过向RPa中产热神经元输入5 -羟色胺来调节。了解决定BAT交感神经流出的通路内的药理学将是制定改变交感神经介导的热量产生策略的基础。

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.