Abstract WP95: Cortical Neurogenesis in the Juvenile Brain Following Ischemic Stroke

Abstract

Introduction: Ischemic stroke is a common injury of the CNS, resulting in neuronal death and impaired brain function, likely contributing to long-term disability in adults. The lack of pharmacological interventions for patients with impairments in stroked-injured brain regions signals need for new strategies aimed at restoring function to the post-ischemic brain. Neurogenesis involves the generation of newborn neurons and occurs throughout life in the mammalian brain, making it an appealing target for potential interventions to enhance post-stroke recovery. Stroke-induced neurogenesis in adult mice has been reported to involve vigorous proliferation and migration of neural progenitors, but most cells die rapidly and fail to repopulate damaged areas. We tested the hypothesis that cortical neurogenesis is enhanced in the immature brain. Methods: We compared juvenile (P20-25) and adult (P60) mice following 45min transient middle cerebral artery occlusion (MCAo). Neurogenesis was examined with immunohistochemistry, including bromodeoxyuridine (BrdU) labeling and cell-type specific markers at 24hr, 7d, and 30d. Post-ischemic neurobehavioral outcomes were assessed at baseline, 7d, and 30d. Results and Conclusions: Despite extensive neuronal cell death in the injured cortex of both age groups at acute time points (24hr and 7d), a remarkable regenerative response was found at 30d, with substantially more mature newborn neurons found in juveniles than adults. Behavioral tests revealed reductions in affected limb use and general motor functioning in MCAo-injured adults and juveniles at 7d, with only the juveniles returning to near baseline levels on most tasks by 30d. When neurogenesis was arrested with ionizing radiation, 30d behavioral recovery was lost. Evidence of cortical neurogenesis is scarce; however, we discovered that newborn neurons in the developing brain not only survive, but post-stroke behavioral outcomes are only improved in non-irradiated juvenile mice. These results provide support for cortical neurogenesis, neuronal replacement, and enhanced functional recovery following stroke, which may have major biological significance for endogenous recovery and repair following CNS damage.