Viral infections that activate immune responses in the central nervous system can produce neuroinflammatory responses that may induce neural injury in addition to the virally mediated neuropathy. Among humans, West Nile virus (WNV) infection varies in its severity: from no overt symptoms, to a general malaise with flu-like symptoms, to severe, potentially fatal meningoencephalitis. The physical, cognitive and functional long-term outcomes of human WNV infection have only recently been accounted. Persistent symptoms include fatigue, memory disturbance, altered mental states, irritability, myalgia, acute flaccid paralysis, limb weakness, difficulty walking, and headache. In rodent models of flavivirus encephalitis, similar neurologic symptoms were observed in terms of abnormalities in gait, loss of balance, tremors, and limb paralysis in some survivors of acute infection, but these studies did not focus on the relationship of functional, behavioral, or cognitive impairments to persistently affected neural substrates. The goal of this proposal is to further develop a hamster model of WNV infection to examine long-term functional behavior and cognitive outcomes in those that resist/recover from acute infection in order to associate specific behavioral deficits with neuroanatomical substrates for neural-immune interactions. This investigation has the following research objectives: 1) determine whether WNV-induced acute encephalitis causes any long term neurobehavioral impairments as revealed by disruption of circadian rhythms (wheel running activity, general locomotor activity) or altered responses in behavioral tasks (i.e. memory, Morris water maze, exploratory behavior), and 2) utilize immunohistochemistry to identify discrete regions of the nervous system that exhibit signs of neuroinflammation (recruitment of activated immune cells, increased expression of cytokines), viral infection, and/or neuropathy that may mediate the apparent behavioral deficits observed. PUBLIC HEALTH RELEVANCE: The results of this proposal will serve as a platform for examining specific effects of neuroinflammation and neural-immune interactions and the functional outcome in neural circuitry that underlie affected behaviors or activities. A fundamental understanding of the neural-immune interactions related to long-term neurobehavioral impairments that occur following acute encephalitis induced by WNV or other pathogens, will clarify clinical manifestations of this condition and hence direct medical treatments and neurorehabilitation in man.