Abstract
Neural stem cells (NSCs) in the hippocampal dentate gyrus (DG) generate new neurons throughout life that are relevant to the functions of learning and emotional response. The ability of NSCs to proliferate and to give rise to new neurons strongly decreases with advancing age, contributing to the susceptibility of cognitive impairments in the aged brain. In the thesis, I first used in vivo two-photon (2P) laser scanning microscopy and showed that impaired neurogenesis in the aged brain is caused by the combinatorial effects of increased quiescence of NSCs, elongated cell cycle dynamics of progenitor cells, and increased early cell death of neuronal progeny (Project 1). Then, I combined single cell RNA-sequencing (scRNA-seq) and spatial transcriptomics (ST) to characterize the cellular diversity and spatial organization of the adult hippocampal neurogenic niche, with the aim to decode the spatiotemporal gene expression dynamics during aging (Project 2). Using scRNA-seq, I first identified molecular changes associated with neurogenic aging from the activation of quiescent NSCs to the maturation of fate-committed progeny that starts at middle-age and lasts to more advanced ages. By combining scRNA-seq with ST, I further identified the regional emergence of inflammatory cell invasion, especially T cells, into the hippocampus with advancing age and showed that early-onset neuroinflammation decreases neurogenic activity using a transgenic mouse model that develops leakiness of blood-brain barrier and induce immune cell infiltration. Thus, my work was able to identify the consequences of advancing age on NSCs and their progeny using chronic intravital imaging. Further, I identified novel molecular mechanisms using scRNA-seq and ST that underlie the neurogenic aging process in the mammalian hippocampus.
Wu, Yicheng