Effects of Microglia on Hippocampal Neurogenesis

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]。虽然关于神经源性生态位的要素和介导NSCs的产生、分化、存活和引导的因素已经获得了大量的信息，但仍有许多未解之谜。具体来说，研究表明小胶质细胞对成人神经发生有重要影响[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。本应用程序的目的是确定小胶质细胞是否在成人海马神经发生中发挥关键作用，并检查小胶质细胞对海马神经发生生态位的影响机制。为此，我们将利用一种转基因小鼠模型，允许一种新的和高度选择性的方法来解决研究问题，cd11b -单纯疱疹病毒胸苷激酶（CD11b-HSVTK (TK)）小鼠，由本应用程序bb0的高级研究员创建。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，通过直接输注药物更昔洛韦（GCV）[15]，可以完全从大脑中清除小胶质细胞。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，期望我们能更好地了解控制成人神经发生的因素，并获得关于小胶质细胞在中枢神经系统（CNS）中日益多样化的作用的知识。

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).