PROJECT SUMMARY Dynamic changes in the spatiotemporal patterning of transcription factor binding on cis-regulatory DNA elements drives the developmental transition of cell lineages during neurogenesis. In the human brain, neurons are generated from early embryonic development until early postnatal stages. The main neurogenic region in the adult brain is the dentate gyrus in the hippocampus. While adult hippocampal neurogenesis has been confirmed in the majority of mammals, it is unclear if this phenomenon exists in the human brain. Multiple neuropsychiatric conditions, including depression, schizophrenia and Alzheimer's disease are rooted in hippocampal defects. Despite role Therefore, the obvious importance of on and its in neurogenesis, our understanding of the cell diversity and tissue organization is highly incomplete. a dentate gyrus neuropsychiatric conditions, more complete cell census of the dentate gyrus across lifetime will increase our understanding of the mechanisms underlying fetal, early postnatal and adult neurogenesis, which could have a key role in the etiology of disease in humans. tools chromatin gyrus world computational resources The overarching goal of our proposal is to optimize and accelerate the use of scalable technologies and to perform unbiased, multimodal single-nucleus omics-based assessment of gene expression and accessibility combined with spatial transcriptomics profiling on tissue sections of human across stages. In this study, we bring together an interdisciplinary team of experts anatomy, spatial transcriptomics, neurodevelopment and biology to create a cell census of the dentate gyrus that will be integrated with existing from the BRAIN Initiative Cell Census Network and will be made freely available to the scientific dentate fetal, early postnatal and adult in single cell omics, human community. analyses early embryonic hippocampal and This Utilizing this large resource of omics data from the human dentate gyrus, we will perform the following three that aim to: (1) identify the cell diversity and tissue organization of human dentate gyrus across fetal, postnatal and adult stages; (2) uncover shared and distinct gene regulatory networks associated with and adult human hippocampal neurogenesis; and (3) study the evolution conservation of neurogenesis by performing comparative analysis with mouse and non-human primate single-cell spatial transcriptomic data that are readily accessible through the BRAIN Initiative Cell Census Network. innovative research program will, if successful,provide scalable technologies for multimodal and spatial omics profiling and a developmental and adult cell atlas of cell type diversity in the dentate gyrus , which will serve as a blueprint for studies of human hippocampal neurogenesis, selective vulnerability of cell types in disease, and the features of brain evolution that differentiates humans from other species.

PROJECT SUMMARY The overarching goal of our proposal is to accelerate the use of scalable technologies and tools to perform unbiased, multimodal single-nucleus omics-based assessment combined with spatial transcriptomics profiling on tissue sections of the developing dentate gyrus in the human hippocampus. The resulting high-resolution map will identify the cell diversity and tissue organization of the developing human dentate gyrus and uncover shared and distinct gene regulatory networks associated with hippocampal neurogenesis. Novel therapeutics for brain disorders rooted in hippocampal defects, such as depression, schizophrenia and Alzheimer's disease will require an understanding of the human-specific features of hippocampal neurogenesis.