Regulation of adult neurogenesis during aging

描述（由申请人提供）：在包括人类在内的所有哺乳动物的成体中枢神经系统（CNS）中存在神经祖细胞/干细胞，这增加了通过激活内源性神经祖细胞/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神经元的可能性。由于大多数退行性神经系统疾病和损伤发生在老年人中，因此更好地了解神经干细胞如何与老年人大脑中的局部环境相互作用，对于开发基于干细胞的治疗策略至关重要。海马齿状回是一个涉及学习和记忆的区域，其成人神经发生已被证明随着年龄的增长而减少。这种减少是否反映了神经祖细胞/干细胞固有特性的变化和/或衰老过程中局部环境的变化尚不清楚。虽然幼龄成年啮齿动物的神经干细胞在培养和体内均能产生具有成熟中枢神经系统神经元基本特性的功能性神经元，但老年神经干细胞是否能产生功能性神经元以及老年大脑是否能支持功能性神经发生尚不清楚。衰老与大脑炎症和氧化的增加有关。中枢神经系统炎症最近被证明对成人神经发生有负性调节。我们之前已经表明，炎症改变神经细胞的鞘脂和固醇含量，破坏脂筏的结构和功能，这反过来又可以通过扰乱细胞信号传导来改变神经细胞的功能。我们从年轻成年大鼠和老年大鼠的海马体中分离出神经祖细胞，并开发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，我们建议在啮齿动物衰老模型中确定内在和外在机制在调节成年功能性神经发生顺序步骤中的作用。特别是，我们将使用药物和饮食操作来改变氧化还原平衡，鞘脂和固醇代谢，并定量比较体外和体内年轻成人和老年海马神经祖细胞/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.