Introduction: Following stroke, neurons are seriously damaged or die, impairing local brain function and contributing to long-term disability. Mounting evidence suggests that stroke recovery in children is enhanced compared to adults. Neurogenesis, a process involving the generation of functionally integrated neurons from progenitor cells, may play a role in enhanced plasticity and neuronal repair. Stroke-induced neurogenesis in adults involves massive proliferation and migration of newborn neurons, however these newborn neurons go on to die, never repopulating areas of damage. We tested the hypothesis that neurogenesis in the young brain effectively repopulates injured regions following ischemia.
Methods: Stroke was induced in adult (2-3 mo, n=21) and pediatric (P20-25, n=21) mice by 45-min right middle cerebral artery occlusion (MCAo). Bromodeoxyuridine (BrdU) was injected on days 3 and 4, and mice sacrificed at 24 hr, 7 d or 30 d after recovery from MCAo. Immunohistochemistry was performed to assess cellular proliferation and neurogenesis.
Results: The results revealed extensive neuronal cell death in the striatum of both pediatric and adult mice at 24 hr and 7 d after stroke. Remarkably, significant numbers of healthy, mature neurons (NeuN+) were observed in the striatum of pediatric mice at 30 d post-injury. Birth-dating with BrdU demonstrated robust, ischemia-induced proliferation of neural progenitor cells in both adult and pediatric brain. Consistent with previous reports, we observed very few mature NeuN+ neurons double labeled with BrdU in the injured adult brain. In contrast, significant numbers of BrdU+NeuN cells were observed in the pediatric brain 30 d after MCAo, indicative of mature neurons and most importantly, with COUP-TF1-interacting protein 2 (Ctip2) expression, a marker of medium spiny striatal neurons.
Conclusion: Our results indicate that cerebral ischemia in pediatric mice increases neurogenesis and migration to sites of damage, and supports the possibility of true neuronal replacement in the pediatric brain. These findings have exciting implications for heightened restorative processes in the pediatric brain microenvironment.