Human hippocampal neurogenesis shows unique gene expression patterns compared to other mammals

While the process via which different types of neurons are produced, also known as neurogenesis, has been the focus of numerous neuroscience studies, its genetic and biological underpinnings in humans have not yet been fully elucidated. This is also true for immature neurons arising from adult hippocampal neurogenesis, known as immature dentate granule cells (imGCs), which support the brain’s adaptation in response to experiences throughout adulthood.

Researchers at the University of Pennsylvania, the Chinese Academy of Sciences and other institutes recently carried out a study aimed at better understanding how imGCs evolve and determining whether the processes prompting their genesis in humans might differ from those observed in other species. Their findings, published in Nature Neuroscience, suggest that while similar biological processes influence these cells in the brains of mice, pigs, monkeys and humans, the expression of genes in human imGCs differs considerably.

“ImGCs arising from adult hippocampal neurogenesis in mammals play critical roles in brain plasticity, learning and memory, and hold great potential for regenerative medicine,” Yi Zhou, first author of the paper, told Medical Xpress.

“However, little is known about the molecular traits of imGCs in humans and macaques, as most research has relied on knowledge and molecular signatures of imGCs in mice, which has resulted in inconsistencies in identifying and characterizing imGCs in primates.”

A key objective of the recent study by Zhou and his colleagues was to try to identify molecular features and gene expression patterns that could be unique to human imGCs. To do this, they carried out a study focusing on four mammalian species, namely mice, pigs, monkeys and humans.

“We aimed to accurately identify imGCs in published single-cell RNA-sequencing (scRNA-seq) data and then perform a systematic comparison of the molecular landscapes of imGCs in the hippocampus across mammalian species to reveal their evolutionary changes and human-specialized features,” said Zhou. “Given potential interspecies variation , we refrained from using mouse-derived molecular markers to accurately annotate imGCs in the published human and macaque scRNA-seq datasets we examined.”

As part of their previous work, Zhou and his colleagues developed a machine learning-augmented approach to identify human imGCs, which was found to achieve remarkable results. Characterizing imGCs in the brains of macaques, on the other hand, previously proved to be challenging, with earlier efforts achieving inconsistent results.

In their new study, the researchers developed a machine learning-powered approach to characterize these hippocampal cells that relied on a classifier (i.e., an algorithm to classify specific data). To train the algorithm, they used high confidence imGCs (i.e., granule cells expressing classical imGC markers, such as DCX and PROX1, but not mature counterparts, such as CALB1 ). Data for these cells was collected from young macaques, in which there are plenty of imGCs present.

“The new classifier enabled us to identify transcriptome-wide immature neuronal characteristics of macaque imGCs using consistent criteria across datasets,” explained Zhou. “To systematically compare the conserved and divergent molecular features of imGCs across species, we then conducted a cross-species analysis of imGCs versus their mature counterparts from humans, macaques, pigs and mice using all published scRNA-seq datasets at the time of our research.”

The analysis carried out by the researchers showed that the richness of gene expression in imGCs differs greatly across species, strikingly more than the gene expression in mature granule cells. Nonetheless, the biological processes governing the development of the cells appeared to be the same for all the species they studied.

“We also identified enrichment of several gene families in human imGCs versus mature granule cells, with no such enrichment in macaques, pigs or mice,” said Zhou.

“In particular, we identified the enriched expression of an ATP6 gene family that encodes proton-transporting vacuolar-type ATPase subtypes. We further developed a human pluripotent stem cell-based model of imGCs and demonstrated in vitro that vacuolar-type ATPase has a critical role in regulating imGC neurite outgrowth and neuronal network activity.”

Overall, the findings gathered by this team of researchers suggest that the biological processes driving the development of imGCs are the same across species, yet the regulation of genes driving these processes varies significantly. These differences in gene expression could play a key role in the adaptation of the cells and their contribution to various brain functions.

“Moreover, our work highlights the need for independent molecular and functional analyses of adult neurogenesis across species and the value of human cell-based models (human stem cell-derived cultures and surgical samples) in elucidating molecular, functional and regulatory traits of human imGCs,” said Zhou.

This recent study could soon inspire further cross-species analyses focusing on the processes driving neurogenesis and particularly the development of imGCs. Ultimately, it could also inform the development of therapeutic interventions aimed at modulating the genesis of specific neurons in the hippocampus.

“Owing to sequencing depth limitations in scRNA-seq, our analysis focused on highly expressed genes, leaving unexplored whether genes with lower expression that are enriched in imGCs exhibit cross-species similarities or differences,” said Zhou.

“In addition, we did not account for species-specific genomic features or isoform usage. Future research, with larger sample sizes, deeper sequencing and multi-omics integration, could reduce sampling variability and enable further investigation in different data modalities of imGCs across sexes, developmental stages and disease states.”

So far, the team’s analyses have focused on imGCs, which are not yet fully developed. As part of their future studies, Zhou and his colleagues hope to use similar approaches to investigate other cell types in the brain of adult mammals, such as quiescent and active adult neural stem cells.

© 2025 Science X Network

While the process via which different types of neurons are produced, also known as neurogenesis, has been the focus of numerous neuroscience studies, its genetic and biological underpinnings in humans have not yet been fully elucidated. This is also true for immature neurons arising from adult hippocampal neurogenesis, known as immature dentate granule cells (imGCs), which support the brain’s adaptation in response to experiences throughout adulthood.

Researchers at the University of Pennsylvania, the Chinese Academy of Sciences and other institutes recently carried out a study aimed at better understanding how imGCs evolve and determining whether the processes prompting their genesis in humans might differ from those observed in other species. Their findings, published in Nature Neuroscience, suggest that while similar biological processes influence these cells in the brains of mice, pigs, monkeys and humans, the expression of genes in human imGCs differs considerably.

“ImGCs arising from adult hippocampal neurogenesis in mammals play critical roles in brain plasticity, learning and memory, and hold great potential for regenerative medicine,” Yi Zhou, first author of the paper, told Medical Xpress.

“However, little is known about the molecular traits of imGCs in humans and macaques, as most research has relied on knowledge and molecular signatures of imGCs in mice, which has resulted in inconsistencies in identifying and characterizing imGCs in primates.”

A key objective of the recent study by Zhou and his colleagues was to try to identify molecular features and gene expression patterns that could be unique to human imGCs. To do this, they carried out a study focusing on four mammalian species, namely mice, pigs, monkeys and humans.

“We aimed to accurately identify imGCs in published single-cell RNA-sequencing (scRNA-seq) data and then perform a systematic comparison of the molecular landscapes of imGCs in the hippocampus across mammalian species to reveal their evolutionary changes and human-specialized features,” said Zhou. “Given potential interspecies variation , we refrained from using mouse-derived molecular markers to accurately annotate imGCs in the published human and macaque scRNA-seq datasets we examined.”

As part of their previous work, Zhou and his colleagues developed a machine learning-augmented approach to identify human imGCs, which was found to achieve remarkable results. Characterizing imGCs in the brains of macaques, on the other hand, previously proved to be challenging, with earlier efforts achieving inconsistent results.

In their new study, the researchers developed a machine learning-powered approach to characterize these hippocampal cells that relied on a classifier (i.e., an algorithm to classify specific data). To train the algorithm, they used high confidence imGCs (i.e., granule cells expressing classical imGC markers, such as DCX and PROX1, but not mature counterparts, such as CALB1 ). Data for these cells was collected from young macaques, in which there are plenty of imGCs present.

“The new classifier enabled us to identify transcriptome-wide immature neuronal characteristics of macaque imGCs using consistent criteria across datasets,” explained Zhou. “To systematically compare the conserved and divergent molecular features of imGCs across species, we then conducted a cross-species analysis of imGCs versus their mature counterparts from humans, macaques, pigs and mice using all published scRNA-seq datasets at the time of our research.”

The analysis carried out by the researchers showed that the richness of gene expression in imGCs differs greatly across species, strikingly more than the gene expression in mature granule cells. Nonetheless, the biological processes governing the development of the cells appeared to be the same for all the species they studied.

“We also identified enrichment of several gene families in human imGCs versus mature granule cells, with no such enrichment in macaques, pigs or mice,” said Zhou.

“In particular, we identified the enriched expression of an ATP6 gene family that encodes proton-transporting vacuolar-type ATPase subtypes. We further developed a human pluripotent stem cell-based model of imGCs and demonstrated in vitro that vacuolar-type ATPase has a critical role in regulating imGC neurite outgrowth and neuronal network activity.”

Overall, the findings gathered by this team of researchers suggest that the biological processes driving the development of imGCs are the same across species, yet the regulation of genes driving these processes varies significantly. These differences in gene expression could play a key role in the adaptation of the cells and their contribution to various brain functions.

“Moreover, our work highlights the need for independent molecular and functional analyses of adult neurogenesis across species and the value of human cell-based models (human stem cell-derived cultures and surgical samples) in elucidating molecular, functional and regulatory traits of human imGCs,” said Zhou.

This recent study could soon inspire further cross-species analyses focusing on the processes driving neurogenesis and particularly the development of imGCs. Ultimately, it could also inform the development of therapeutic interventions aimed at modulating the genesis of specific neurons in the hippocampus.

“Owing to sequencing depth limitations in scRNA-seq, our analysis focused on highly expressed genes, leaving unexplored whether genes with lower expression that are enriched in imGCs exhibit cross-species similarities or differences,” said Zhou.

“In addition, we did not account for species-specific genomic features or isoform usage. Future research, with larger sample sizes, deeper sequencing and multi-omics integration, could reduce sampling variability and enable further investigation in different data modalities of imGCs across sexes, developmental stages and disease states.”

So far, the team’s analyses have focused on imGCs, which are not yet fully developed. As part of their future studies, Zhou and his colleagues hope to use similar approaches to investigate other cell types in the brain of adult mammals, such as quiescent and active adult neural stem cells.

© 2025 Science X Network