The Section on Functional Neuroanatomy combines molecular and neuroanatomical methods to identify dynamic aspects of nervous system function that relate to issues of mental health, infectious disease, and drug abuse. The current objective of our laboratory is to determine the consequences in the central nervous system (CNS) when intact organisms are subjected to stressful and/or immunological challenges. Our approach is to identify cellular and molecular components in the brain that mediate physiological responses to these challenges, thereby delineating the neural and non-neural bases of stress and immune responses. Key anatomical pathways and relevant neurotransmitter/receptor systems are mapped using in vitro ligand binding and autoradiography, and in situ hybridization histochemistry (ISHH) is used to localize and quantify mRNA expression of neuropeptides, monoamine transporters and synthesizing enzymes, cytokines, receptors, transcription factors, and immediate-early genes in studies of adaptive changes to pharmacological, physiological, or surgical interventions. We have 1) mapped out the brain?s immune response to acute peripheral immune challenge (systemic administration of the bacterial immune stimulant lipopolysaccharide, 2) mapped the cerebrospinal and interstitial fluid flow pathways that may be involved in conveying immune signals throughout the brain, 3) shown how an immune stimulant (lipopolysaccharide) behaves once inside the blood- brain barrier, and 4) developed a model of chronic immune system activation (trypanosome parasite infection). We showed that the brain responds to a peripheral immune challenge by generating its own cytokines. Messages shown to be induced in acute and chronic challenges include interleukin-1 beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), IL-1 receptor antagonist (IL-1ra), and IL-1 converting enzyme (ICE). These mRNAs are induced in specific cell types (endothelia, microglia, astrocytes, and meninges) and in specific patterns (high levels in the blood vessels, choroid plexus and circumventricular organs). We propose that centrally produced cytokines are part of an amplification process in the immune-to-brain signaling pathways. These putative transduction processes have been examined in both acute (peripheral and central injection of lipopolysaccharide) and chronic (infection by the parasite Trypanosoma brucei) infection models. In other studies, cells expressing the nervous system cannabinoid receptor (CB1) are marked by ISHH in the brainstem, spinal cord, and dorsal root ganglia. In the dorsal root ganglia, identification of nociceptive cells of the C-fiber type is achieved by labeling for substance P mRNA. From single- and double-label experiments, we have determined that only 15 percent of the substance P mRNA expressing cells are also CB1 mRNA expressing. Cutting or tying off the peripheral nerve roots has demonstrated axonal flow of cannabinoid receptors into the dorsal horn. Several studies demonstrate the presynaptic localization of cannabinoid receptors on primary sensory afferent fibers. - neuroanatomy, neuroimmunology, infection, cytokine, blood-brain barrier, autoradiography, in situ hybridization, cannabinoid, spinal cord, pain
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