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Although influenza virus infection of humans has been associated with a wide spectrum of clinical neurological syndromes, the pathogenesis of influenza virus associated central nervous system (CNS) disease in humans remains controversial. To better study influenza virus neuropathogenesis, an animal model of influenza-associated CNS disease using human virus isolates without adaptation to an animal host was developed. This neonatal rat model of influenza virus CNS infection was developed using low-passage human isolates and shows outcomes in specific brain regions, cell types infected, and neuropathological outcomes that parallel the available literature on cases of human CNS infection. The degree of virus replication and spread in the rat brain correlated with the strains' neurotoxicity potential for humans. In addition, using sensitive neurobehavioral test paradigms, changes in brain function were found to be associated with areas of virus replication in neurons. These data suggest that further evaluation of this pathogenesis model may provide important information regarding influenza virus neuropathogenesis, and that this model may have possible utility as a preclinical assay for evaluating the neurological safety of new live attenuated influenza virus vaccine strains.