Studies Of Central Nervous System Functional Anatomy

National Institute Of Mental Health

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Abstract

Our approach is to clarify the normal and pathophysiological roles of immune system molecules in the brain, to identify cellular and molecular components induced by immunological challenges, seizures, and behavioral manipulations, and to further characterize the responses at molecular, anatomical, and functional levels. A recent focus is on the role of a transcription factor called NF-kappaB (NF-kB) in neuronal function. NF-kB is found in all cells but is normally associated with immune cell function, regulating inflammation, apoptosis, or survival. However its presence in neurons suggests other roles, possibly related to cell survival or neuronal plasticity. Tools are being designed to measure NF-kB exclusively in neurons in vivo and to show genes regulated by it in models of neuronal excitation and excitotoxicity. Key anatomical pathways and relevant neurotransmitter/receptor systems are mapped using histochemical techniques. In situ hybridization histochemistry is used to localize and quantify mRNA expression of neurotransmitters, cytokines, enzymes, receptors, transcription factors, and immediate-early genes in studies of adaptive changes to immunological, pharmacological, physiological, behavioral, or surgical manipulations. 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) shown that the p50 subunit of the NF-kB transcription factor is involved in normal expression of emotional behavior in mice, 2) that one function of p50 in controlling gene expression is to modify the chromatin state 3) found a phosphorylation and acetylation states of the p65 subunit of NF-kB that can serve as a reliable index of neuronal NF-kappa activity. Current work examines role that the NF-kB transcription factor plays in anxiety-like behavior, fear learning, environmental enrichment, and response to psychosocial stressors. Primary cell cultures are used to examine neuronal genes regulated by the NF-kB transcription factor in an activity-dependent manner.