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A Versatile Murine Model of Subcortical White Matter Stroke for the Study of Axonal Degeneration and White Matter Neurobiology
Published on: March 17, 2016
Juvenile Mice Develop Infarct-Induced Neurodegeneration and Emerging Cognitive Decline in a Model of Pediatric Stroke
Elizabeth W Mayne1,2,3, Kelly Vanden1, Meghan E Hefferon1
1Department of Neurology and Neurological Sciences (E.W.M., K.A.V., M.E.H., K.A.Z., M.S.B.), Stanford University School of Medicine.
Insights
Pediatric stroke survivors may experience delayed cognitive deficits. This study developed a pediatric stroke mouse model, revealing age-related differences in immune responses and neuroinflammation compared to adults.
Area of Science:
- Neuroscience
- Immunology
- Pediatric Neurology
Background:
- Pediatric stroke survivors frequently face long-term cognitive deficits, often emerging later in life.
- Unique developmental factors in children may alter stroke-induced cognitive decline mechanisms compared to adults.
Purpose of the Study:
- To establish a pediatric mouse model for studying infarct-induced delayed cognitive decline.
- To investigate age-related differences in immune responses following stroke in juveniles versus adults.
Main Methods:
- A pediatric stroke model was created in juvenile mice (28 days old) using middle cerebral artery occlusion and hypoxia.
- Cognitive function was assessed using Barnes maze and Novel Object Recognition tests at 1 and 7 weeks post-stroke.
- Histological analysis quantified stroke size, atrophy, and neuroinflammation in juvenile and adult mice.
Main Results:
- Juvenile mice showed comparable cognitive performance to controls at 1 week but significant deficits by 7 weeks post-stroke.
- Greater innate immune activation was observed in juvenile mice at 3 days post-stroke, while adults showed more chronic immune activity at 7 weeks.
- Secondary neurodegeneration in subcortical structures was associated with cognitive deficits in juvenile stroke models.
Conclusions:
- The developed pediatric stroke model replicates emerging cognitive deficits seen in human survivors.
- Age-related differences in innate immune responses to stroke exist, particularly at sites of secondary neurodegeneration.
- Infarct-induced neurodegeneration occurs in juvenile mice, with distinct immune trajectories compared to adults.
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.
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