Effects of Microglia on Hippocampal Neurogenesis

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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).