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

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.

Automated summary

This study investigates the cellular heterogeneity and molecular characteristics of the hippocampi in macaques and aged humans using droplet-based single-nucleus RNA sequencing (snRNA-seq). The findings reveal the dynamics of the neurogenic lineage and the diversity of astrocytes and microglia in the hippocampus. Primate-specific markers are identified and their functions are validated. Additionally, active astrocytes and microglia with proinflammatory responses are observed in aged samples, suggesting their contribution to the decrease and variability of adult hippocampal neurogenesis.