Studies Of Central Nervous System Functional Anatomy

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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 explore the interaction between the central nervous system (CNS) and the immune system in animals that are subjected to stress, inflammatory stimuli, or infections. Our approach is to identify cellular and molecular components in the brain induced by immunological challenges and to further characterize the responses at molecular, anatomical, and functional levels. Key anatomical pathways and relevant neurotransmitter/receptor systems are mapped using histochemical techniques. In situ hybridization histochemistry (ISHH) is used to localize and quantify mRNA expression of neurotransmitters, cytokines, receptors, transcription factors, and immediate-early genes in studies of adaptive changes to immunological, pharmacological, physiological, or surgical interventions. Immunohistochemistry and double-label techniques are used to characterize the phenotypes of the cells that show induced mRNA expression of immune signaling molecules. We have 1) mapped in the brain the immune response to acute administration of lipopolysaccharide, a bacterial endotoxin, 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 stimulus (lipopolysaccharide) behaves once inside the blood-brain barrier, 4) developed a model of chronic immune system activation (trypanosome parasite infection), 5) shown activation of class I major histocompatibility complex (MHC) mRNA in both neuronal and non-neuronal cells under conditions of immune and non-immune physiological challenges, and 6) mapped the cascade of events leading to brain-wide glial activation following central administration of interleukin-1 (IL-1). Gene transcripts shown to be induced in acute and chronic challenges include IL-1, IL-6, IL-12, tumor necrosis factor-alpha (TNF-alpha), IL-1 receptor antagonist (IL-1ra), IL-1 converting enzyme (ICE), transforming growth factor beta (TGF-beta), and other immune signaling molecules such as inhibitory factor kappa B (IkappaB), inducible cyclooxygenase (COX-2), and inducible nitric oxide synthase (iNOS). The mRNAs are shown to be induced in specific cell types (endothelia, microglia, astrocytes, and meninges) and in specific patterns (high levels of expression in the blood vessels, choroid plexus and circumventricular organs). We propose that an important functional component of the innate immune response involves centrally produced cytokines. New projects underway explore interactions between the brain and the immune system during adaptive immune responses. Experimental models include the development of an antineuronal autoimmune response in Lewis rats and the initiation of work in mice using transplanted bone marrow stem cells, which are the progenitor cells of the immune system, including brain microglia.