Cross-species evaluation of immature neurons within the hippocampus. Leveraging machine-learning-augmented scRNA-seq evaluation, the crew recognized imGCs with transcriptome-wide immature neuronal traits in several mammals. They then carried out cross-species comparisons of imGCs and mature granule cells (mGCs) from people, monkeys, pigs and mice. Credit: Yi Zhou, Guo-li Ming, and Hongjun Tune.
Whereas the method by way of which various kinds of neurons are produced, also called neurogenesis, has been the main focus of quite a few neuroscience research, its genetic and organic underpinnings in people haven’t but been absolutely elucidated. That is additionally true for immature neurons arising from grownup hippocampal neurogenesis, often called immature dentate granule cells (imGCs), which help the mind’s adaptation in response to experiences all through maturity.
Researchers on the College of Pennsylvania, the Chinese language Academy of Sciences and different institutes lately carried out a research aimed toward higher understanding how imGCs evolve and figuring out whether or not the processes prompting their genesis in people may differ from these noticed in different species. Their findings, printed in Nature Neuroscience, counsel that whereas comparable organic processes affect these cells within the brains of mice, pigs, monkeys and people, the expression of genes in human imGCs differs significantly.
“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 creator of the paper, informed 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 goal of the latest research by Zhou and his colleagues was to attempt to establish molecular options and gene expression patterns that may very well be distinctive to human imGCs. To do that, they carried out a research specializing in 4 mammalian species, specifically mice, pigs, monkeys and people.
“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,” stated 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 a part of their earlier work, Zhou and his colleagues developed a machine learning-augmented method to establish human imGCs, which was discovered to attain exceptional outcomes. Characterizing imGCs within the brains of macaques, however, beforehand proved to be difficult, with earlier efforts reaching inconsistent outcomes.
Of their new research, the researchers developed a machine learning-powered method to characterize these hippocampal cells that relied on a classifier (i.e., an algorithm to categorise particular information). To coach the algorithm, they used excessive confidence imGCs (i.e., granule cells expressing classical imGC markers, similar to DCX and PROX1, however not mature counterparts, similar to CALB1 ). Knowledge for these cells was collected from younger macaques, during which there are many imGCs current.
Shared molecular signatures of immature neurons within the hippocampus of various species. Credit score: Nature Neuroscience (2025). DOI: 10.1038/s41593-025-02027-9
“The new classifier enabled us to identify transcriptome-wide immature neuronal characteristics of macaque imGCs using consistent criteria across datasets,” defined 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 evaluation carried out by the researchers confirmed that the richness of gene expression in imGCs differs vastly throughout species, strikingly greater than the gene expression in mature granule cells. Nonetheless, the organic processes governing the event of the cells seemed to be the identical for all of 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,” stated 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.”
Total, the findings gathered by this crew of researchers counsel that the organic processes driving the event of imGCs are the identical throughout species, but the regulation of genes driving these processes varies considerably. These variations in gene expression might play a key position within the adaptation of the cells and their contribution to numerous mind capabilities.
“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,” stated Zhou.
This latest research might quickly encourage additional cross-species analyses specializing in the processes driving neurogenesis and significantly the event of imGCs. Finally, it might additionally inform the event of therapeutic interventions aimed toward modulating the genesis of particular neurons within 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,” stated 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.”
Thus far, the crew’s analyses have targeted on imGCs, which aren’t but absolutely developed. As a part of their future research, Zhou and his colleagues hope to make use of comparable approaches to analyze different cell sorts within the mind of grownup mammals, similar to quiescent and energetic grownup neural stem cells.
Written for you by our creator Ingrid Fadelli, edited by Gaby Clark, and fact-checked and reviewed by Robert Egan—this text is the results of cautious human work. We depend on readers such as you to maintain impartial science journalism alive.
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Extra info:
Yi Zhou et al, Cross-species evaluation of grownup hippocampal neurogenesis reveals human-specific gene expression however convergent organic processes, Nature Neuroscience (2025). DOI: 10.1038/s41593-025-02027-9.
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