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Introduction: Inducible nitric oxide synthase (iNOS) is a critical regulator of brain and systemic inflammatory responses in many neurological disorders. Intriguingly, iNOS null mice have produced equivocal outcomes in mouse models of ischemic stroke, a result that may be due, in part, to species-specific differences between the mouse and human iNOS genes. Due to numerous differences at the gene regulatory level, mouse iNOS naturally produces much higher levels of nitric oxide (NO) than the human gene. To resolve the functional differences between mouse and human iNOS in ischemic stroke, we employed a novel mouse that expresses human iNOS on a mouse iNOS null genetic background, termed the HN mouse. Our study objective was to compare functional and behavioral outcomes following ischemic stroke between wildtype (WT) and HN mice.Hypothesis: We hypothesized that post-stroke functional outcomes would be more severe in HN male mice than in WT mice.Methods: Male C57BL/6J (WT) and HN mice (4-6 months) were subjected to 60 minutes of transient middle cerebral artery occlusion (tMCAO) followed by reperfusion and behavioral assessments at seven-day intervals for 30 days. Laser-Doppler flowmetry pre- and post-tMCAO was used to assess the effect of iNOS on blood flow. A comprehensive neurological battery was used to assess sensorimotor ability, reflexes, and balance, followed by open field, wire hang, and rotarod testing to evaluate locomotor activity, limb strength, and coordination.Results and Conclusion: Blood flow was significantly decreased in the ipsilateral hemisphere of both WT and HN mice following acute ischemic stroke; however, HN mice exhibited a sustained global decrease in blood flow following reperfusion. HN mice also demonstrated decreased locomotor activity and coordination, as well as greater neurological deficits compared to WT mice. Overall, these results suggest that the HN mouse model recapitulates more neurological deficits associated with human ischemic stroke than WT mice. Thus, the HN mouse may represent a more “humanized” model of ischemic stroke than more commonly used mouse models that express the mouse iNOS gene.