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Chronic peripheral inflammation and neuroinflammation have been linked to Gulf War Illness (GWI), but the underlying mechanisms are unknown. A Multiple-Hit Hypothesis is supported, where the synergistic interaction of several potential neurotoxicants and triggers of inflammation, such as persistent peripheral inflammation and the organophosphate pesticide chlorpyrifos (CPF) may interact to culminate in diverse symptoms. As a consequence of this biological and chemical complexity, early/accurate diagnosis and effective treatments have proven elusive. Our research over the last year has addressed these issues in GWI with a Multiple-Hit mouse model of GWI-like exposures and focused on the key molecular target NF- B p50 in CNS effects. Experiments employing a mouse model of GWI for short term and long term analysis of the brain after GWI-like exposures have been completed for AIM1 along with the collection of circulating white blood cells for AIM3. While sample analysis is ongoing, preliminary results suggest that the hippocampus in NF- B p50-/- mice is more vulnerable to chronic neuroinflammation at one week after pro-inflammatory insult. We also report that CPF impairs NF- B p50 function in microglia, suggesting that CPF may predispose the hippocampus to chronic neuroinflammation. We will directly test this hypothesis as the collected samples are further analyzed.