BACKGROUND: Over half of pediatric stroke survivors have permanent cognitive deficits, which can emerge late after stroke. Mechanisms of cognitive decline after pediatric stroke may differ from those in adults because children's strokes occur while brain and immune development are still ongoing. We therefore aimed to develop a pediatric mouse model of infarct-induced delayed cognitive decline to define age-related differences in immune responses compared with adults. METHODS: Male and female C57BL/6J mice were randomized to stroke or sham surgery at 28 days old to model stroke in late childhood. We used permanent distal middle cerebral artery occlusion followed by 60 minutes of hypoxia to induce an ischemic cortical stroke. Juvenile mice underwent behavioral testing at 1 and 7 weeks after surgery using Barnes maze and Novel Object Recognition tests. We quantified stroke size, atrophy, and neuroinflammation at 3 days and 7 weeks after surgery in juvenile and adult mice using immunostaining. RESULTS: One week after surgery, juvenile stroke and sham mice performed comparably on cognitive testing. However, by 7 weeks after surgery, stroke mice of both sexes performed significantly worse on reversal learning with the Barnes maze. Histologically, juvenile mice had greater innate immune activation at sites of secondary neurodegeneration in the corpus callosum, corticospinal tract, and thalamus at 3 days after stroke, while adults had greater chronic innate immune activity at these sites 7 weeks after stroke. CONCLUSIONS: In a model of childhood ischemic stroke, juvenile mice of both sexes developed an emerging cognitive deficit analogous to that seen in pediatric stroke survivors. It was associated with chronic neuroinflammation in uninjured subcortical structures that undergo secondary neurodegeneration. Our results suggest that infarct-induced neurodegeneration occurs after stroke in juvenile mice, and that there are age-related divergent trajectories in the innate immune response to stroke at sites of secondary neurodegeneration.
Mayne et al. (Mon,) studied this question.