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

Wei Wang1,2,5,† , Mengdi Wang2,3,4,5,† , Meng Yang2,4,5,† , Bo Zeng3,† , Wenying Qiu2,5,† , Qiang Ma2,4,5 , Xiaoxi Jing1 , Qianqian Zhang2,4,5 , Bosong Wang1 , Chonghai Yin3 , Jiyao Zhang1 , Yuxin Ge1 , Yufeng Lu2,5 , Weizhi Ji6 , Qian Wu1,3,* , Chao Ma2,5,* , Xiaoqun Wang1,2,3,5,6,7,*

1State Key Laboratory of Cognitive Neuroscience and Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China
2State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology (Shanghai), Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
3Changping Laboratory, Beijing, China
4University of Chinese Academy of Sciences, Beijing, China
5State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology (Shanghai), Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
6Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunan, China
7Advanced Innovation Center for Human Brain Protection, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China
These authors contributed equally: Wei Wang, Mengdi Wang, Meng Yang, Bo Zeng, Wenying Qiu
* Correspondence: Qian Wu(qianwu@bnu.edu.cn)Chao Ma(machao@ibms.cams.cn)Xiaoqun Wang(xiaoqunwang@bnu.edu.cn)

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.

https://doi.org/10.1038/s41422-022-00678-y

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