Physiological changes that affect hippocampal function in the adult are accompanied by parallel alterations in neurogenesis and it is thought that learning and memory may depend on continued neurogenesis. Cranial radiation therapy for the treatment of cancer is 1 of the most striking examples of injury that causes impaired neurogenesis and progressively severe deficits in hippocampal function. In modeling this process in rodents, we observed that chronic inflammation accompanies radiation injury, suggesting that inflammatory processes may contribute to neural stem cell dysfunction. Subsequent work has shown that neuroinflammation alone is a potent inhibitor of neurogenesis and that inflammatory blockade with indomethacin, a common non-steroidal anti-inflammatory drug, restores neurogenesis following endotoxin-induced inflammation and augments neurogenesis following cranial irradiation. In addition, animals with deficits in the chemokine MCP-1 are resistant to the long-term effects of radiation and neurogenesis returns to normal levels 1 month after irradiation. Although inflammatory blockade reverses the inhibition of neurogenesis, it is not known how inflammation influences neurogenesis or whether these perturbations in stem cell activity influence learning and memory function. This application proposes that the pro-inflammatory phase of inflammation influences neural stem cells in the hippocampus by 1) the direct action of inflammatory cells, cytokines and chemokines on stem cells and their progeny, 2) by the indirect effects of inflammatory cells, cytokines on the stem cell microenvironment and 3) by the inflammatory modulation of the hypothalamic-pituitary-adrenal axis and subsequent elevation of glucocorticoids. The use of primary neural stem cell cultures as well as animals that are genetically or surgically deficient in key inflammatory mediators will allow us to test these hypotheses with regards to neural stem cell activity, adult hippocampal neurogenesis, and hippocampal learning and memory function.
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