Regulation of adult neurogenesis during aging

描述(申请人提供)：在包括人类在内的所有哺乳动物的成年中枢神经系统(CNS)中存在神经前体/干细胞，这增加了通过激活内源性神经前体/干细胞或移植体外扩增的神经干细胞及其后代来替代受损或丢失的神经元的可能性。由于大多数退行性神经疾病和损伤发生在老年人群中，更好地了解神经干细胞如何与其在老年大脑中的局部环境相互作用，将是开发基于干细胞的治疗策略的关键。海马齿状回是一个涉及学习和记忆的区域，成年后海马齿状回的神经发生随着年龄的增长而减少。这种减少是否反映了神经前体/干细胞内在属性的变化和/或衰老过程中局部环境的变化尚不清楚。虽然幼年成年啮齿动物的神经干细胞在培养和体内都能产生具有成熟中枢神经系统神经元基本特性的功能神经元，但衰老的神经干细胞是否能产生功能神经元，以及衰老的大脑是否能支持功能神经发生，目前尚不清楚。衰老与脑部炎症和氧化增加有关。最近研究表明，中枢神经系统炎症对成人神经发生有负性调节作用。我们之前已经证明，炎症改变了神经细胞的鞘脂和甾醇含量，扰乱了脂筏的结构和功能，进而通过细胞信号的扰动来改变神经细胞的功能。我们从幼年和老年大鼠的海马区分离了神经前体细胞，并建立了方法来研究它们在培养和体内的增殖、命运决定、功能和电生理特性。在这个项目中，我们建议在一个啮齿动物的衰老模型中，确定内在机制和外在机制在调节功能性成体神经发生的顺序步骤中的作用。特别是，我们将使用药理和饮食操作来改变氧化还原平衡、鞘脂和甾醇代谢，并在体外和体内定量比较青年和老年海马神经前体/干细胞的特性。

DESCRIPTION (provided by applicant): 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.