Functional contribution of neural stem cells in stroke

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Stroke is a major cause of death and disability in the elderly. However, in vivo experimental stroke studies, including the evaluation of neuroprotective and cell replacement strategies, have relied almost universally on models of stroke in young adult animals due to their easier availability, lower cost and fewer health problems. Compared to mature young adults, the elderly show substantial declines of baseline functions and adaptive capacities in their tissues and organs, including brain, and are thus more severely impaired by stroke than are young adults and have poorer functional recovery. The persistent failure of human trials targeted at neuroprotective agents, which are effective in animal model of stroke, further indicates that the discrepancy between animal models and human diseases could have important clinical application. Therefore, a better understanding of how age affects the response to therapeutic interventions after stroke is crucially important for rational development of effective treatment. The demonstration of neurogenesis in adult brains and of the presence of proliferating cells with the ability to give rise to neurons in the ischemic regions of brains after stroke have reinvigorated our hopes of rebuilding damaged tissues by endogenous neural cell replacement. However, critical issues that need to be addressed before clinical application of cell-based therapies for stroke include the extent to which newly generated cells become fully mature neurons and contribute functional recovery from stroke in the aged brain. We hypothesize that newly generated neurons are required for normal brain function and also contribute functional recovery of aged brains after stroke. We also hypothesize that functional outcome after stroke might be improved by pharmaceutical tools that modify the proliferation, migration or differentiation of NSCs in both young adult and aged brains, although the magnitude of this effect may vary with age. In Specific Aim 1, we will investigate the role of neurogenesis in normal brain functions in aged (24-month-old) mice. In Specific Aim 2, we will evaluate whether the inducible ablation of neurogenesis exacerbates functional outcome from experimental stroke in aged mice. In Specific Aim 3, we will determine whether pharmacologically-induced increases in the number of newborn cells will improve functional recovery from stroke in young adult and aged mice. The long-term goal of the proposed experiments is, by studying the functional contribution of stroke-induced neurogenesis in aged brain, to achieve better understanding of the fundamental principles that govern neurogenesis in normal aging and age-related neurological diseases like stroke.