Continuous neurogenesis in the mammalian hippocampus

作为我们目前R35资金的行政补充，我们建议延长我们的

As an Administrative Supplement to our current R35 funding, we are proposing to extend our rigorous and multifaceted analyses of hippocampal neurogenesis in mice and human induced pluripotent stem cell models to a focused study of human adult neurogenesis in postmortem hippocampal tissue obtained from age-matched neurotypical donors and Alzheimer’s Disease (AD) patients. In rodent models of AD, adult hippocampal neurogenesis is reduced, whereas enhancing adult hippocampal neurogenesis is sufficient to rescue the cognitive deficits. Little is known about the molecular characteristics of adult hippocampal neurogenesis in humans and in AD. We have recently completed a study using single-nucleus RNA-seq (snRNA-seq) to generate a transcriptional signature of human immature neurons in the hippocampus across the lifespan. Using this signature to profile neurogenesis in hippocampal tissue of the aging brain, in a pilot study we observed potential differences in both the number and transcriptional profile of immature neurons in samples from AD patients compared to matched controls. In this proposed study, we will expand our cohort size to rigorously test our hypotheses of both quantitative and qualitative changes in adult human hippocampal neurogenesis in the context of AD. Technically, we will build on our strengths using single-cell approaches to profile both the transcriptome and chromatin accessibility within the same cell. This combination of snRNA-seq and snATAC-seq will enhance our ability to identify additional cell types within the neurogenic trajectory and provide additional information on the epigenetic signatures of AD that may impact neurogenesis. We will also build on the strength of our machine learning-based analytical approach. Finally, we will take an integrated bioinformatic approach to combine single-cell profiling, pseudotime analyses to identify dynamic state transitions, and cellular interactions based on ligand-receptor expression levels. Together, our study will generate validated single-cell datasets from male and female AD patients and age-matched controls that will be a valuable resource for the AD research community and will generate mechanistic hypothesis about AD pathophysiology and potential therapeutic targets.