The existence of neural progenitor/stem cells in the adult central nervous system (CNS) of all mammals, including humans, raises the possibility to replace damaged or lost neurons by activation of endogenous neural progenitor/stem cells or transplantation of in vitro expanded neural stem cells and their progeny. Since most degenerative neurological diseases and injuries occur in the aged population, better understanding of how neural stem cells interact with their local environment in the aged brain will be essential to develop strategies for stem cell based therapies. Adult neurogenesis in the dentate gyrus of the hippocampus, a region involved in learning and memory, has been shown to decrease with increasing age. Whether this reduction reflects changes in the intrinsic properties of neural progenitor/stem cells and/or changes of the local environment during aging is unknown. While neural stem cells of young adult rodents can generate functional neurons with essential properties of mature CNS neurons both in culture and in vivo, it is not known if aged neural stem cells can generate functional neurons and whether the aged brain can support functional neurogenesis. Aging is associated with increases of brain inflammation and oxidation. CNS inflammation was recently shown to negatively regulate adult neurogenesis. We have previously shown that inflammation modifies the sphingolipid and sterol content of neural cells and disrupts the structure and function of lipid rafts, which in turn can modify neural cell function by perturbation of cellular signaling. We have isolated neural progenitors from the hippocampus of both young adult and aged rats and developed methods to investigate their proliferation, fate determination, functional and electrophysiological properties both in culture and in vivo. In this project, we propose to determine the roles of intrinsic vs. extrinsic mechanisms in regulating the sequential steps of functional adult neurogenesis in a rodent model of aging. In particular, we will use pharmacological and dietary manipulations to modify redox balance, sphingolipid and sterol metabolism and quantitatively compare the properties of neural progenitor/stem cells of young adult and aged hippocampus both in vitro and in vivo. ? ?
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