The investigators' objective is to identify the neural substrates and mechanisms that mediate the neural control of the immune system. Based on the model that the immune system can signal the brain, and that the CNS can subsequently modify peripheral immune function, the investigators showed that an immune challenge (endotoxin) activates central autonomic regulatory regions and increases sympathetic output to the spleen and found that splenic macrophages are regulated by the splenic nerve. They propose that immune signals modify CNS activity via a specific signal transduction cascade and activation of this cascade alters autonomic and endocrine regulatory circuits which then signal the immune system via definable pathways and chemical mediators. HIV-1 may disrupt this neural-immune regulatory circuit and they hypothesize it produces autonomic dysregulation and disarms the neural regulation of the immune system. The investigators' aim is to identify the neuroanatomical and neurochemical mechanisms mediating the effects of endotoxin and the HIV-1 viral coat protein gp120 on splenic macrophage function. Central induction of pCREB and c-fos proteins and multiunit recordings in the brain will index activation of the central circuit, nerve recordings will measure sympathetic output to the spleen, in vitro and in vivo splenic macrophage cytokine production will measure immune function, and ACTH/corticosterone levels will index endocrine activation. Intracranial injections of specific antagonists to prostaglandin, glutamate, nitric oxide synthase, peptides, Ca2+/Calmodulin-dependent kinase and cytokines will be combined with an immune challenge to establish the organization of the signaling cascade and determine if it is a target for gp120. Intrathecal injections of receptor antagonist will identify the chemical specificity of descending projections from the central regulatory circuit onto sympathetic preganglionic neurons in the cord. Simultaneous brain and splenic nerve recordings will monitor the activation and output of the regulatory system and provide a direct link between the central activation of the neural-immune axis and alterations in splenic macrophage function. Changes in splenic macrophage cytokine mRNA, protein, and secretion following splenic nerve sections and intracranial and intrathecal injections, will link the activation of pCREB and c-fos proteins in the brain via the signaling cascade with changes in splenic macrophage cytokine production that are mediated by the sympathetic nervous system. These experiments will characterize the functional pathways from the brain to the splenic macrophage and determine the effects of gp120 on this regulatory system.
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