Effects of Microglia on Hippocampal Neurogenesis

小胶质细胞对海马神经发生的影响

• 批准号: 243590644
• 负责人: Professor Dr. Frank Heppner
• 金额: --
• 依托单位: Institut für Neuropathologie (CCM)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/243590644?language=en
• 关键词: Effects; Microglia; Hippocampal; Neurogenesis

Adult neurogenesis plays a critical role in the overall health of, and repair processes occurring within the nervous system [1-4]. While a great deal of information has been gained about the elements of the neurogenic niche and factors that mediate the production, differentiation, survival and guidance of NSCs, many unanswered questions remain. Specifically, studies suggest that microglia have a significant impact on adult neurogenesis [5-13], but no unifying theory exists to explain their exact role in this process. The objective of this application is to determine if microglia play a pivotal role in adult hippocampal neurogenesis and to examine the mechanisms through which microglia exert their effects on the hippocampal neurogenic niche. To this end, we will utilize a transgenic mouse model that allows for a novel and highly selective approach to the research question, the CD11b-herpes simplex virus thymidine kinase (CD11b-HSVTK (TK)) mouse, created by the senior investigator of this application [14]. The CD11b-HSVTK mouse expresses a suicide gene under the control of a microglia/macrophage-specific promoter, CD11b. In this mouse, microglial cells can be depleted exclusively from the brain via direct infusion of a drug, ganciclovir (GCV) [15]. Therefore, we plan to study hippocampal neurogenesis in the presence or absence of microglial cells with the expectation that we will gain a better understanding of the factors governing adult neurogenesis and acquire knowledge about the increasingly diverse role of microglia in the central nervous system (CNS).

成人神经发生在神经系统的整体健康和修复过程中起着关键作用[1-4]。虽然已经获得了大量关于神经源性生态位的要素以及调节神经干细胞的产生、分化、存活和指导的因素的信息，但仍有许多问题没有得到解答。具体地说，研究表明，小胶质细胞对成人神经发生有重大影响[5-13]，但没有统一的理论来解释它们在这一过程中的确切作用。该应用的目的是确定小胶质细胞是否在成年海马神经发生中起关键作用，并研究小胶质细胞对海马神经源性生态位发挥作用的机制。为此，我们将利用转基因小鼠模型，允许采用一种新的和高度选择性的方法来解决这一研究问题，CD11b-单纯疱疹病毒胸苷激酶(CD11b-HSVtk(TK))小鼠，由这一应用的高级研究员创建[14]。CD11b-HSVtk小鼠在小胶质细胞/巨噬细胞特异性启动子CD11b的控制下表达自杀基因。在这只小鼠中，通过直接注射药物更昔洛韦(GCV)，小胶质细胞可以完全从大脑中耗尽[15]。因此，我们计划在小胶质细胞存在或不存在的情况下研究海马神经发生，以期更好地了解支配成人神经发生的因素，并了解小胶质细胞在中枢神经系统(CNS)中日益多样化的作用。