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Transcriptome dynamics of hippocampal neurogenesis in macaques across the lifespan and aged humans

Abstract

Whether adult hippocampal neurogenesis (AHN) persists in adult and aged humans continues to be extensively debated. A major question is whether the markers identified in rodents are reliable enough to reveal new neurons and the neurogenic trajectory in primates. Here, to provide a better understanding of AHN in primates and to reveal more novel markers for distinct cell types, droplet-based single-nucleus RNA sequencing (snRNA-seq) is used to investigate the cellular heterogeneity and molecular characteristics of the hippocampi in macaques across the lifespan and in aged humans. All of the major cell types in the hippocampus and their expression profiles were identified. The dynamics of the neurogenic lineage was revealed and the diversity of astrocytes and microglia was delineated. In the neurogenic lineage, the regulatory continuum from adult neural stem cells (NSCs) to immature and mature granule cells was investigated. A group of primate-specific markers were identified. We validated ETNPPL as a primate-specific NSC marker and verified STMN1 and STMN2 as immature neuron markers in primates. Furthermore, we illustrate a cluster of active astrocytes and microglia exhibiting proinflammatory responses in aged samples. The interaction analysis and the comparative investigation on published datasets and ours imply that astrocytes provide signals inducing the proliferation, quiescence and inflammation of adult NSCs at different stages and that the proinflammatory status of astrocytes probably contributes to the decrease and variability of AHN in adults and elderly individuals.

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Fig. 1: Transcriptional profiles of the macaque hippocampi at single-nucleus resolution.
Fig. 2: ETNPPL is identified as a primate-specific NSC marker.
Fig. 3: Hippocampal neurogenesis analysis across the lifespan of macaques.
Fig. 4: Transcriptional heterogeneity of cells derived from macaque astrocytes and microglia.
Fig. 5: Proliferating NSCs and immature GCs are readily detected in aged human hippocampi.
Fig. 6: Persistent adult hippocampal neurogenesis was identified in aged humans.

Data availability

The single-nucleus RNA-seq data used in this study has been deposited in the Gene Expression Omnibus (GEO) under the accession number GSE163737. The scATAC-seq data has been deposited in the Genome Sequence Archive (HRA002222).

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Acknowledgements

This work was supported by the National Key R&D Program of China (2020YFA0112200, 2019YFA0110100), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB32010100, XDA16020601), the National Natural Science Foundation of China (NSFC) (32122037, 32192411 and 81891001), CAS Project for Young Scientists in Basic Research (YSBR-013), the China Brain Project (2021ZD0200102), BUAA-CCMU Big Data and Precision Medicine Advanced Innovation Center Project (BHME-2019001), Collaborative Research Fund of Chinese Institute for Brain Research, Beijing (2020-NKX-PT-02 and 2020-NKX-PT-03). Human tissues were provided by the National Human Brain Bank for Development and Function, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. This study was supported by the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Neuroscience Center, and the China Human Brain Banking Consortium.

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W.W., X.W., Q.W., and W.J. conceived the project. W.W., and X.W., designed the experiments. M. Y. and W.W. performed immunostaining and imaging. M.W., B.Z., X.J., and J.Z. analyzed the snRNA-seq data and scATAC-seq data. W.W., C.Y., and B. W. prepared the macaque samples. Q.M., Y.G., Y.L., and Q.Z. performed snRNA-seq and scATAC-seq experiments. W.Q., and C.M. prepared and provided the human samples. W.W, M.W., Q.W. and X.W. wrote the manuscript. All authors edited and proofread the manuscript.

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Correspondence to Qian Wu, Chao Ma or Xiaoqun Wang.

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Wang, W., Wang, M., Yang, M. et al. Transcriptome dynamics of hippocampal neurogenesis in macaques across the lifespan and aged humans. Cell Res 32, 729–743 (2022). https://doi.org/10.1038/s41422-022-00678-y

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