Abstract TP293: Juvenile Mice Are Susceptible to Infarct-Induced Neurodegeneration That Causes Cognitive Decline

Abstract

Introduction: Over half of pediatric stroke survivors have permanent neurologic and cognitive deficits. Executive function and processing speed are two domains that are consistently affected on neuropsychiatric testing of pediatric stroke survivors. In adult mice, stroke triggers an immune-mediated, infarct-induced neurodegeneration that causes similar cognitive deficits. However, it is unknown whether similar pathophysiology causes children’s cognitive deficits after stroke. Hypothesis: We hypothesize that infarct-induced neurodegeneration occurs in a mouse model of pediatric arterial ischemic stroke. Methods: Male and female C57BL/6J mice were randomized to stroke or sham surgery at p28 to model stroke in late childhood and compared to adult 6-month-old mice. We used permanent distal MCAO followed by 60 minutes of hypoxia, an established model for focal ischemia that generates a purely cortical stroke. Mice underwent behavioral testing at 1- and 7-weeks post stroke with a standard Barnes Maze protocol used in adult mice, and with a protocol adapted for juveniles by increasing difficulty of the task. We performed immunostaining to quantify acute and chronic neuroinflammation, stroke size, myelination, and atrophy 3 days and 8 weeks after surgery. Results: At 7 weeks post-stroke, stroke mice performed significantly worse on Barnes Maze testing than sham mice (n = 7 stroke, 7 sham, p = 0.0265 2-way ANOVA with repeated measures) on the more difficult but not the standard protocol. Like adult mice, pediatric mice exhibited chronic B- and T- lymphocyte neuroinflammation in the stroke scar at 8 weeks after stroke and activated (CD68+) microglia in the scar and connected regions. Both groups had decreased subcortical myelin staining compared to age-equivalent sham mice. However, this decrease was more dramatic in pediatric mice at 65 ± 14% vs. 27% ± 9% in adults, p < 0.05). Conclusions: In a model of pediatric ischemic stroke, juvenile mice develop chronic neuroinflammation in the stroke and in white matter tracts that are connected to the stroke in conjunction with a delayed cognitive deficit. Our results suggest that infarct-induced neurodegeneration occurs after stroke in juvenile mice and may cause more severe dysmyelination than in adults.