Sympathetic-Immune Interface: Central Sites & Function

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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.