Multimodal transcriptomics reveal neurogenic aging trajectories and age-related regional inflammation in the dentate gyrus

Abstract The mammalian dentate gyrus (DG) is involved in certain forms of learning and memory, and DG dysfunction has been implicated in age-related diseases. Although neurogenic potential is maintained throughout life in the DG as neural stem cells (NSCs) continue to generate new neurons, neurogenesis decreases with advancing age, with implications for age-related cognitive decline and disease. In this study, we used single-cell RNA sequencing to characterize transcriptomic signatures of neurogenic cells and their surrounding DG niche, identifying molecular changes associated with neurogenic aging from the activation of quiescent NSCs to the maturation of fate-committed progeny. By integrating spatial transcriptomics data, we identified the regional invasion of inflammatory cells into the hippocampus with age and show here that early-onset neuroinflammation decreases neurogenic activity. Our data reveal the lifelong molecular dynamics of NSCs and their surrounding neurogenic DG niche with age and provide a powerful resource to understand age-related molecular alterations in the aging hippocampus.