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. Drug and neurotransmitter receptors are mapped using in vitro ligand binding and autoradiography. 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. 1) We used neuroanatomical localization techniques to study the pathways by which peripheral immune signals (cytokines) transduce a signal at the blood-brain barrier and gain access to the brain to induce CNS production of immune molecules. We propose that this mechanism is part of an amplification process in the immune-to-brain signaling pathways. These putative transduction processes have been examined in both acute (lipopolysaccharide administration) and chronic (trypanosome infection) paradigms. We have used ISHH of IkappaB mRNA to track the brain's immune response. IkappaB is the controlling molecule in the NF-kappaB transcription factor signaling pathway in immune cells. We proposed that this pathway exists in brain, and we have localized and identified the cell types expressing IkappaB message following acute and chronic immune challenges. We are also showing 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 (IL-1), tumor necrosis factor-alpha, IL-1 receptor antagonist, and IL-1 converting enzyme (ICE). 2) Cells expressing the nervous system cannabinoid receptor (CB1) are marked by ISHH in the brainstem, spinal cord, and dorsal root ganglia (DRG). In the DRG, 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% of the substance P mRNA expressing cells are also CB1 mRNA expressing. Similar kinds of studies are planned for spinal cord (where enkephalin-and GABA-positive cells will be co-localized) and brainstem (where norepinephrine and serotonin will be co-localized).
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