An immune or inflammatory insult has been linked to a number of mental disorders, including schizophrenia. In view of the potential importance of this association, the long-term objective is to understand the changes in gene expression that underlie the developmental and functional responses of the central nervous system (CNS) to inflammation. The hippocampus is a well-defined brain structure involved in memory and cognition, and is particularly susceptible to inflammation-induced injury; in addition, alterations in hippocampal function are likely to be involved in some of the behavioral effects of inflammation. Therefore, the response of mouse hippocampus to peripheral administration of lipopolysaccharide (LPS) will be used as a model system. Screening for inflammation-sensitive genes will be accomplished by the use of mouse gene expression microarrays, which make it possible to probe for changes in expression of 18,200 cDNAs in a single hybridization experiment.
The specific aims are as follows: 1) To confirm that the genes identified in an initial screen are up-regulated specifically in response to inflammation. This will be accomplished by (a) a comparison of LPS-treated mice with sham-injected controls by cDNA microarray analysis; (b) verification of changes in gene expression by use of quantitative RT-PCR; and (c) comparison of the response of mouse strain C57BL/6J with that of the non-responder strain C57BL/l0Cr. 2) To categorize novel inflammation-sensitive genes based on (a) homology to known genes; (b) time course of changes in expression in response to LPS, (c) specificity of the response to the CNS as compared to other tissues; and (d) expression in the CNS during development. 3) To analyze LPS-induced changes in gene expression of a characterized gene and one to two novel genes by in situ hybridization and immunohistochemistry. For each gene, the cell type specificity and time course of induction within the CNS will be determined, with the goal of better understanding the significance and pathways leading to the observed changes in expression.
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