Sympathetic-Immune Interface: Central Sites & Function

描述（申请人摘要）：最近的证据表明， 白细胞衍生的激素（即，细胞因子）提供重要的信号传导 交感神经回路的通路然而，涉及的中枢通路 在介导对白细胞介素-1 β的交感神经放电（SND）反应中， 促炎细胞因子IL-1及其功能意义 β-介导的SND应答仍然不清楚。这些都很重要 遗漏是因为免疫系统的机制的阐述 改变SND对于理解免疫系统的作用至关重要。 生理调节和疾病过程中的相互作用。具体目标1： 识别参与介导对IL-1的SND反应的中枢神经位点 β的我们将测试假设，a）不同水平的脊髓上 轴突介导对IL-1 β区域选择性SND应答，B） 室旁核神经元主要参与介导 前脑依赖性SND对IL-1 β的反应，c）腹侧延髓 是介导对IL-1 β的SND应答的关键脑干位点，和d） 脑室周围器官是参与中枢神经系统的一部分， 介导对外周IL-1 β的SND应答。具体目标2：确定 IL-1 β的靶器官效应。我们假设IL-1 β的给药 在动脉血流中不产生均匀的变化， 循环和脾神经传出的激活诱导细胞因子 增强生物体免疫能力的基因表达。 电生理学，中枢神经系统显微注射，频域 分析和分子生物学技术将用于完成这些 问题研究本提案中描述的实验方法将有助于解开 免疫和交感神经系统的调节控制。 最终，这些发现可能有助于设计干预策略 在免疫调节中， 免疫和神经系统。

DESCRIPTION (Applicant's abstract): Recent evidence indicates that leukocytic-derived hormones (i.e., cytokines) provide an important signaling pathway to sympathetic neural circuits. However, the central pathways involved in mediating sympathetic nerve discharge (SND) responses to interleukin-1 beta, a proinflammatory cytokine, and the functional significance of IL-1 beta-mediated SND responses remain poorly defined. These are significant omissions because the elaboration of mechanisms by which the immune system alters SND is critical for understanding the role of autonomic-immune interactions in physiological regulation and disease processes. Specific Aim 1: To identify central neural sites involved in mediating SND responses to IL-1 beta. We will test the hypotheses that a) different levels of the supraspinal neuraxis mediate regionally-selective SND responses to IL-1 beta, b) paraventricular nucleus neurons are critically involved in mediating forebrain-dependent SND responses to IL-1 beta, c) the ventral lateral medulla is a key brainstem site mediating SND responses to IL-1 beta, and d) circum-ventricular organs are part of the central circuitry involved in mediating SND responses to peripheral IL-1 beta. Specific Aim 2: To determine target organ effects of IL-1 beta. We hypothesize that IL-1 beta administration produces no uniform changes in arterial blood flow to regionally-selective circulations and that activation of splenic nerve efferents induces cytokine gene expression which enhances the immune capability of the organism. Electrophysiological, central nervous system microinjection, frequency-domain analytical and molecular biological techniques will be used to complete these studies. The experimental approach described in this proposal will help unravel the regulatory controls of the immune and sympathetic nervous systems. Ultimately, these findings may allow for the design of intervention strategies in immune regulation fostering robust and appropriate communication between the immune and nervous systems.