Hippocampal Radial Glial Subtypes and Their Neurogenic Potential in Human Fetuses and Healthy and Alzheimer’s Disease Adults
Open accessAbstract
Neuropathological conditions might affect adult granulogenesis in the adult human dentate gyrus. However, radial glial cells (RGCs) have not been well characterized during human development and aging. We have previously described progenitor and neuronal layer establishment in the hippocampal pyramidal layer and dentate gyrus from embryonic life until mid-gestation. Here, we describe RGC subtypes in the hippocampus from 13 gestational weeks (GW) to mid-gestation and characterize their evolution and the dynamics of neurogenesis from mid-gestation to adulthood in normal and Alzheimer's disease (AD) subjects. In the pyramidal ventricular zone (VZ), RGC density declined with neurogenesis from mid-gestation until the perinatal period. In the dentate area, morphologic and antigenic differences among RGCs were observed from early ages of development to adulthood. Density and proliferative capacity of dentate RGCs as well as neurogenesis were strongly reduced during childhood until 5 years, few DCX+ cells are seen in adults. The dentate gyrus of both control and AD individuals showed Nestin+ and/or GFAPδ+ cells displaying different morphologies. In conclusion, pools of morphologically, antigenically, and topographically diverse neural progenitor cells are present in the human hippocampus from early developmental stages until adulthood, including in AD patients, while their neurogenic potential seems negligible in the adult.
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The brain has limited regenerative capacity compared to tissues such as skeletal muscle and skin, which rely on stem cells to repair damage.
“This is due to the brain’s limited regenerative capacity compared to tissues, such as skeletal muscle and skin, which rely on stem cells to repair damage [57,58].”
From The Impact of Neurotoxin Proteins Trafficked by Primary Cilia and Extracellular Vesicles in Neurodegenerative Diseases (2025) · cites this paper as [57]
The section “Neurogenic potential in the dentate gyrus during normal adulthood” (page not supplied) describes very few proliferating cells in the adult human hippocampus, supporting a narrower point about limited neurogenesis. It does not compare the brain’s repair capacity with skeletal muscle or skin, or discuss those tissues’ stem-cell-based repair. (LLM, conf=0.80)
Experimental — accuracy not yet measuredSome groups report absent or minimal hippocampal neurogenesis in the mature brain using double immunofluorescence and single nucleus transcriptomics.
“Some groups have reported absent or minimal hippocampal neurogenesis in the mature brain using double immunofluorescence targeting markers expressed by neuronal cells at different maturational stages95, 96 and single nucleus transcriptomics97.”
From Dysregulation of adult hippocampal neuroplasticity in major depression: Pathogenesis and therapeutic implications (2022) · cites this paper as [96]
Ageing significantly reduces adult hippocampal neurogenesis.
“Ageing has been shown to significantly reduce adult hippocampal neurogenesis [109].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [109]
The majority of reports provide positive evidence for adult neurogenesis in the human hippocampus, suggesting that studying this process in rodents is likely relevant to understanding human brain plasticity.
“A few studies contradict these findings (Cipriani et al., 2018; Sorrells et al., 2018), but the majority of reports provide positive evidence for adult neurogenesis in the hippocampus of humans, suggesting that studying this process in rodents is likely relevant to understanding human brain plasticity.”
From Adult neurogenesis, glia, and the extracellular matrix (2019) · cites this paper as Cipriani et al., 2018
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Functional dentate gyrus neurogenesis in a rapid kindling seizure model
Smith, P. D., McLean, K. J., Murphy, M. A., Turnley, A. M., & Cook, M. J. (2006) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2006.05205.x · Cited by 25 · see citing works
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Self-citationBroca's region revisited: Cytoarchitecture and intersubject variability
Amunts, K., Schleicher, A., B�rgel, U., Mohlberg, H., Uylings, H. B. M., & Zilles, K. (1999) · The Journal of Comparative Neurology · doi:10.1002/(sici)1096-9861(19990920)412:2
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Moreno-Jiménez, E. P., Flor-García, M., Terreros-Roncal, J., Rábano, A., Cafini, F., Pallas-Bazarra, N., Ávila, J., & Llorens-Martín, M. (2019) · Nature Medicine · doi:10.1038/s41591-019-0375-9 · Cited by 1,577 · see citing works
Neural stem cells: origin, heterogeneity and regulation in the adult mammalian brain
Obernier, K., & Alvarez-Buylla, A. (2019) · Development · doi:10.1242/dev.156059 · Cited by 578 · see citing works
“Surprisingly, in the same adult human brains in which young neurons are present in the walls of the ventricles, cells with clear marker expression and morphology of young neurons are not present in the DG or are extremely rare (Sorrells et al., 2018; Cipriani et al., 2018; Knoth et al., 2010; Dennis et al., 2016), whi…”
BackgroundAgeing, Cellular Senescence and Neurodegenerative Disease
Kritsilis, M., V. Rizou, S., Koutsoudaki, P. N., Evangelou, K., Gorgoulis, V. G., & Papadopoulos, D. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19102937 · Cited by 448 · see citing works
“Ageing has been shown to significantly reduce adult hippocampal neurogenesis [109].”
BackgroundTartt, A. N., Mariani, M. B., Hen, R., Mann, J. J., & Boldrini, M. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01520-y · Cited by 408 · see citing works
“Some groups have reported absent or minimal hippocampal neurogenesis in the mature brain using double immunofluorescence targeting markers expressed by neuronal cells at different maturational stages [95, 96] and single nucleus transcriptomics [97].”
BackgroundAdult Hippocampal Neurogenesis in Aging and Alzheimer's Disease
Babcock, K. R., Page, J. S., Fallon, J. R., & Webb, A. E. (2021) · Stem Cell Reports · doi:10.1016/j.stemcr.2021.01.019 · Cited by 312 · see citing works
“However, it should be noted that some studies have failed to detect significant generation of new neurons post-developmentally in humans (Cipriani et al., 2018; Sanai et al., 2011; Sorrells et al., 2018).”
BackgroundFranjic, D., Skarica, M., Ma, S., Arellano, J. I., Tebbenkamp, A. T. N., Choi, J., Xu, C., Li, Q., Morozov, Y. M., Andrijevic, D., et al. (2022) · Neuron · doi:10.1016/j.neuron.2021.10.036 · Cited by 308 · see citing works
“Conversely, other studies have failed to identify neural progenitors or DCX-expressing neuroblasts after childhood in human DG samples (Dennis et al., 2016; Cipriani et al., 2018; Sorrells et al., 2018; Seki et al., 2019).”
Molecular landscapes of human hippocampal immature neurons across lifespan
Zhou, Y. F., Su, Y., Li, S., Kennedy, B. C., Zhang, D. Y., Bond, A. M., Sun, Y. Y., Jacob, F., Lu, L., Hu, P., et al. (2022) · Nature · doi:10.1038/s41586-022-04912-w · Cited by 309 · see citing works
Cellular Senescence in Neurodegenerative Diseases
Martínez‐Cué, C., & Rueda, N. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00016 · Cited by 285 · see citing works
Formation and integration of new neurons in the adult hippocampus
Denoth‐Lippuner, A., & Jessberger, S. (2021) · Nature reviews. Neuroscience · doi:10.1038/s41583-021-00433-z · Cited by 274 · see citing works
Evidences for Adult Hippocampal Neurogenesis in Humans
Moreno-Jiménez, E. P., Terreros-Roncal, J., Flor-García, M., Rábano, A., & Llorens-Martín, M. (2021) · The Journal of Neuroscience · doi:10.1523/jneurosci.0675-20.2020 · Cited by 272 · see citing works
Aging and Rejuvenation of Neural Stem Cells and Their Niches
Navarro Negredo, P., Yeo, R. W., & Brunet, A. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2020.07.002 · Cited by 246 · see citing works
Adult neurogenesis, glia, and the extracellular matrix
Cope, E. C., & Gould, E. (2019) · Cell Stem Cell · doi:10.1016/j.stem.2019.03.023 · Cited by 236 · see citing works
“…in adult neurogenesis and those findings for the most part establish causality with regard to cognitive function with more unsupportive results in studies attempting to causally link new neurons with anxiety reduction (Bruel-Jungerman et al., 2005; Clark et al., 2008; Schoenfeld et al., 2016).”
Adult Hippocampal Neurogenesis in Major Depressive Disorder and Alzheimer’s Disease
Berger, T., Lee, H. A., Young, A. H., Aarsland, D., & Thuret, S. (2020) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2020.03.010 · Cited by 203 · see citing works
Walgrave, H., Balusu, S., Snoeck, S., Eynden, E. V., Craessaerts, K., Thrupp, N., Wolfs, L., Horré, K., Fourne, Y., Ronisz, A., et al. (2021) · Cell stem cell · doi:10.1016/j.stem.2021.05.001 · Cited by 193 · see citing works
“Substantial evidencehasdemonstrated that neurogenesis occurs in adult human brain, is impaired in Alzheimer’s disease (AD) patients, and could contribute to the memory decline observed in AD pathology (Boldrini et al., 2018; Cipriani et al., 2018; Gatt et al., 2019; Kempermann et al., 2018; Lucassen et al., 2020a, 202…”
BackgroundRecalibrating the Relevance of Adult Neurogenesis
Snyder, J. S. (2019) · Trends in Neurosciences · doi:10.1016/j.tins.2018.12.001 · Cited by 183 · see citing works
Adult neurogenesis in the mammalian dentate gyrus
Abbott, L. C., & Nigussie, F. (2019) · Anatomia Histologia Embryologia · doi:10.1111/ahe.12496 · Cited by 171 · see citing works
Adult hippocampal neurogenesis in Alzheimer’s disease: A roadmap to clinical relevance
Salta, E., Lazarov, O., Fitzsimons, C. P., Tanzi, R. E., Lucassen, P. J., & Choi, S. H. (2023) · Cell stem cell · doi:10.1016/j.stem.2023.01.002 · Cited by 165 · see citing works
Sorrells, S. F., Paredes, M. F., Zhang, Z., Kang, G., Pastor-Alonso, O., Biagiotti, S. W., Page, C. E., Sandoval, K., Knox, A., Connolly, A. J., et al. (2021) · Journal of Neuroscience · doi:10.1523/jneurosci.0676-20.2020 · Cited by 130 · see citing works
“1) (Dennis et al., 2016; Cipriani et al., 2018; Sorrells et al., 2018) and subventricular zone (SVZ) (Sanai et al.”
BackgroundResultSurget, A., & Belzung, C. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01136-8 · Cited by 122 · see citing works
“occurrence has been disputed by some conflicting results [13, 14], possibly caused by differences in postmortem”
ResultBhattarai, P., Coşacak, M. İ., Mashkaryan, V., Demir, S., Popova, S. D., Govindarajan, N., Brandt, K., Zhang, Y., Chang, W., Ampatzis, K., et al. (2020) · PLoS Biology · doi:10.1371/journal.pbio.3000585 · Cited by 119 · see citing works
Transcriptome dynamics of hippocampal neurogenesis in macaques across the lifespan and aged humans
Wang, W., Wang, M., Yang, M., Zeng, B., Qiu, W., Ma, Q., Jing, X., Zhang, Q., Wang, B., Yin, C., et al. (2022) · Cell Research · doi:10.1038/s41422-022-00678-y · Cited by 121 · see citing works
“DISCUSSION Whether adult hippocampal neurogenesis exists and whether the proliferation of adult neural stem cells continues in adult humans have been controversial recently.(3,4,6,7,9,10,13,34,60) In the adult or elderly stages, newborn neurons are scarce and not evenly distributed in the hippocampal formation.”
BackgroundDoes Adult Neurogenesis Persist in the Human Hippocampus?
Paredes, M. F., Sorrells, S. F., Cebrián‐Silla, A., Sandoval, K., Qi, D., Kelley, K. W., James, D., Mayer, S., Chang, J. W., Auguste, K. I., et al. (2018) · Cell stem cell · doi:10.1016/j.stem.2018.11.006 · Cited by 115 · see citing works
“Consistently, other studies show young neurons with a typical elongated morphology before the age of 5 years (Cipriani et al., 2018; Knoth et al., 2010; Dennis et al., 2016).”
Unraveling human adult hippocampal neurogenesis
Flor-García, M., Terreros-Roncal, J., Moreno-Jiménez, E. P., Ávila, J., Rábano, A., & Llorens-Martín, M. (2020) · Nature Protocols · doi:10.1038/s41596-019-0267-y · Cited by 113 · see citing works
Altered adult neurogenesis and gliogenesis in patients with mesial temporal lobe epilepsy
Ammothumkandy, A., Rāviņa, K., Wolseley, V., Tartt, A. N., Yu, P.-N., Corona, L., Zhang, N., Nune, G. C., Kalayjian, L. A., Mann, J. J., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01044-2 · Cited by 95 · see citing works
Adult neurogenesis, human after all (again): Classic, optimized, and future approaches
Lucassen, P. J., Fitzsimons, C. P., Salta, E., & Maletić‐Savatić, M. (2019) · Behavioural Brain Research · doi:10.1016/j.bbr.2019.112458 · Cited by 93 · see citing works
“rogenic markers with increasing age [5,28,29,31,53,57].”
InfluentialBrain Structural Plasticity: From Adult Neurogenesis to Immature Neurons
Rosa, C. L., Parolisi, R., & Bonfanti, L. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00075 · Cited by 94 · see citing works
“, 2011) and in the hippocampal SGZ between age 5 and 13 years (Cipriani et al., 2018; Sorrells et al., 2018), other studies reported that neurogenesis was maintained in the human hippocampus (Boldrini et al.”
BackgroundIdentification of proliferating neural progenitors in the adult human hippocampus
Dumitru, I., Paterlini, M., Zamboni, M., Ziegenhain, C., Giatrellis, S., Saghaleyni, R., Björklund, Å. K., Alkass, K., Tata, M., Druid, H., et al. (2025) · Science · doi:10.1126/science.adu9575 · Cited by 92 · see citing works
Steps towards standardized quantification of adult neurogenesis
Zhao, X., & van Praag, H. (2020) · Nature Communications · doi:10.1038/s41467-020-18046-y · Cited by 89 · see citing works
Sex Differences in Maturation and Attrition of Adult Neurogenesis in the Hippocampus
Yagi, S., Splinter, J. E. J., Tai, D., Wong, S. J., Wen, Y., & Galea, L. A. M. (2020) · eNeuro · doi:10.1523/eneuro.0468-19.2020 · Cited by 80 · see citing works
Aging, Cellular Senescence, and Progressive Multiple Sclerosis
Papadopoulos, D., Magliozzi, R., Mitsikostas, D. D., Gorgoulis, V. G., & Nicholas, R. S. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00178 · Cited by 83 · see citing works
“Aging is associated with progressive reduction in adult neurogenesis (Lugert et al., 2010; Cipriani et al., 2018), which is ascribed to a diminution of the pool of stem cells capable of activation and division (Lugert et al.”
BackgroundTosoni, G., Ayyildiz, D., Bryois, J., Macnair, W., Fitzsimons, C. P., Lucassen, P. J., & Salta, E. (2023) · Neuron · doi:10.1016/j.neuron.2023.03.010 · Cited by 74 · see citing works
“Of mice and humans: Same same but different Neurogenic cell types in the human brain have been so far largely defined on the basis of expression of (a few) rodent-inferred markers.(4,11,12,14,24) In the absence of more unbiased, genome-wide approaches to molecularly characterize these cells in humans, the use of (a li…”
BackgroundLeschik, J., Lutz, B., & Gentile, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147339 · Cited by 70 · see citing works
Charvet, C. J., & Finlay, B. L. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00706 · Cited by 69 · see citing works
“We selected SOX2, DCX, and DPYSL3 (aka TUC-4) because they are markers of immature neurons (Ngwenya et al., 2006; Cipriani et al., 2018).”
MethodDuque, A., Arellano, J. I., & Rakic, P. (2022) · Molecular Psychiatry · doi:10.1038/s41380-021-01314-8 · Cited by 63 · see citing works
Lino de Oliveira, C., Bolzan, J. A., Surget, A., & Belzung, C. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107515 · Cited by 61 · see citing works
Nestin Regulates Neurogenesis in Mice Through Notch Signaling From Astrocytes to Neural Stem Cells
Wilhelmsson, U., Lebkuechner, I., Leke, R., Marášek, P., Yang, X., Antfolk, D., Chen, M., Mohseni, P., Lasič, E., Bobnar, S. T., et al. (2018) · Cerebral Cortex · doi:10.1093/cercor/bhy284 · Cited by 62 · see citing works
Phenotypical and functional heterogeneity of neural stem cells in the aged hippocampus
Martín‐Suárez, S., Valero, J., Muro‐García, T., & Encinas, J. M. (2019) · Aging Cell · doi:10.1111/acel.12958 · Cited by 58 · see citing works
Adult Neural Stem Cells: Born to Last
Morales, A. V., & Mira, H. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00096 · Cited by 59 · see citing works
Domínguez-Rivas, E., Ávila-Muñoz, E., Schwarzacher, S. W., & Zepeda, A. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.06.014 · Cited by 57 · see citing works
Kerloch, T., Clavreul, S., Goron, A., Abrous, D. N., & Pacary, E. (2018) · Cerebral Cortex · doi:10.1093/cercor/bhy224 · Cited by 54 · see citing works
Zimmermann, T., Maroso, M., Beer, A., Baddenhausen, S., Ludewig, S., Fan, W., Vennin, C., Loch, S., Berninger, B., Hofmann, C., et al. (2018) · Cerebral Cortex · doi:10.1093/cercor/bhy258 · Cited by 52 · see citing works
“Additionally, three very recent publications were unable to demonstrate robust generation of newborn neurons in the adult human brain (Dennis et al. 2016; Cipriani et al. 2018; Sorrells et al. 2018), though another publication in 2018 came to the opposite conclusion and reported lifelong neurogenesis in humans (Boldri…”
BackgroundMethods to study adult hippocampal neurogenesis in humans and across the phylogeny
Terreros‐Roncal, J., Flor‐García, M., Moreno‐Jiménez, E. P., Rodríguez-Moreno, C. B., Márquez‐Valadez, B., Gallardo‐Caballero, M., Rábano, A., & Llorens-Martı́n, M. (2022) · Hippocampus · doi:10.1002/hipo.23474 · Cited by 51 · see citing works
Functional neurogenesis over the years
Snyder, J. S., & Drew, M. R. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.112470 · Cited by 51 · see citing works
Humans and Dolphins: Decline and Fall of Adult Neurogenesis
Parolisi, R., Cozzi, B., & Bonfanti, L. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00497 · Cited by 48 · see citing works
Rosa, C. L., Ghibaudi, M., & Bonfanti, L. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8050685 · Cited by 43 · see citing works
“Detailed studies carried out on postmortem and intraoperative samples of the human hippocampus from early gestation/postnatal stages to aging adults showed that proliferating progenitors and young neurons in the dentate gyrus sharply decline in early stages of life and only a few isolated young neurons were detected b…”
BackgroundDuque, A., & Spector, R. (2019) · Brain Structure and Function · doi:10.1007/s00429-019-01917-6 · Cited by 45 · see citing works
Adult neurogenesis and “immature” neurons in mammals: an evolutionary trade-off in plasticity?
Bonfanti, L., Rosa, C. L., Ghibaudi, M., & Sherwood, C. C. (2023) · Brain Structure and Function · doi:10.1007/s00429-023-02717-9 · Cited by 46 · see citing works
“…in the absence of a mor-phologically-recognizable stem cell niche (Sorrells et al. 2018) and with very low levels of cell division (reported by most studies, though with different methods; see for example Sorrells et al. 2018; Cipriani et al. 2018; Moreno-Jimenez et al., 2019; Seki et al. 2019).”
BackgroundMethodBrain Plasticity in Humans and Model Systems: Advances, Challenges, and Future Directions
Bonfanti, L., & Charvet, C. J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179358 · Cited by 42 · see citing works
Adult neurogenesis: a real hope or a delusion?
Hussain, G., Akram, R., Anwar, H., Sajid, F., Iman, T., Han, H., Raza, C., & de Aguilar, J. D. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.375317 · Cited by 38 · see citing works
“However, although neurogenesis is thought to occur only during development, recent advances in neuroscience are challenging this old view (Dennis et al., 2016; Cipriani et al., 2018; Moreno-Jiménez et al., 2019; Terstege et al., 2022).”
BackgroundNeurogenesis in primates versus rodents and the value of non-human primate models
Zhang, R., Quan, H., Wang, Y., & Luo, F. (2023) · National Science Review · doi:10.1093/nsr/nwad248 · Cited by 42 · see citing works
“Some research laboratories have reported that hippocampal neurogenesis terminates in humans after chi ld hood [ 10 , 14 , 190 ], while others have observed its persistence into old age and even its detection in indiv iduals w ith neurological disorders [ 9 , 13 , 15 , 16 ].”
BackgroundOppenheim, R. W. (2019) · Developmental Neurobiology · doi:10.1002/dneu.22674 · Cited by 38 · see citing works
“Later, however, two studies failed to observe AHN in humans after age three to five (Dennis et al., 2016; Capriani et al., 2018; also see Seress et al., 2001).”
BackgroundZhang, R., Cai, Y., Xiao, R., Zhong, H., Li, X., Guo, L., Xu, H., & Fan, X. (2019) · Stem Cell Research & Therapy · doi:10.1186/s13287-019-1267-0 · Cited by 36 · see citing works
The dentate gyrus in depression
Umschweif, G., Greengard, P., & Sagi, Y. (2019) · European Journal of Neuroscience · doi:10.1111/ejn.14640 · Cited by 38 · see citing works
“Nonetheless, the magnitude of neurogenesis in humans is at a center of an ongoing debate (Cipriani et al., 2018; Sorrells et al., 2018; Moreno-Jimenez et al., 2019).”
BackgroundProtracted neuronal recruitment in the temporal lobes of young children
Nascimento, M. A., Biagiotti, S. W., Herranz‐Pérez, V., Santiago, S., Bueno, R., Ye, C., Abel, T. J., Zhang, Z., Rubio-Moll, J. S., Kriegstein, A. R., et al. (2023) · Nature · doi:10.1038/s41586-023-06981-x · Cited by 38 · see citing works
“Our data 10 , and those of others 3,36 , indicate that dentate neurogenesis rapidly decreases postnatally, as is the case for the EC, with few—if any—new neurons added in adults.”
Novel Approaches Used to Examine and Control Neurogenesis in Parkinson′s Disease
Salmina, A. B., Рафаилевна, К. М., Vetchinova, A. S., & Illarioshkin, S. N. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179608 · Cited by 38 · see citing works
“Indeed, in human SVZ, the density of RGCs reduces from mid-gestation until the perinatal period, and in the human SGZ, the decline of RGCs number is observed from early ages of development until 5 years old and then in adulthood [12].”
BackgroundGarcía‐Cabrerizo, R., Ledesma‐Corvi, S., Bis‐Humbert, C., & García-Fuster, M. J. (2020) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2020.10.008 · Cited by 31 · see citing works
Astrogenesis in the murine dentate gyrus is a life‐long and dynamic process
Schneider, J., Weigel, J., Wittmann, M., Švehla, P., Ehrt, S., Zheng, F., Elmzzahi, T., Karpf, J., Paniagua‐Herranz, L., Başak, O., et al. (2022) · The EMBO Journal · doi:10.15252/embj.2021110409 · Cited by 32 · see citing works
“…, 2015), but its existence in the human brain is a currently highly debated topic with conflicting results (Spalding et al , 2013; Boldrini et al , 2018; Cipriani et al , 2018; Sorrells et al , 2018; Moreno-Jim (cid:1) enez et al , 2019; Seki et al , 2019; Tobin et al , 2019; Franjic et al , 2022).”
Wakhloo, D., Mahajani, S. U., Oberhauser, J., & Madira, A. E. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.336138 · Cited by 37 · see citing works
“However, contradictory reports highlight a reduced number of neurogenesis markers, questioning the existence of adult neurogenesis in humans (Cipriani et al., 2018; Sorrells et al., 2018).”
Perspective: Of Mice and Men – How Widespread Is Adult Neurogenesis?
Petřík, D., & Encinas, J. M. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00923 · Cited by 32 · see citing works
“While it is not the first time that the existence of adult neurogenesis has been discredited (Rakic, 1985), the findings that adult neurogenesis may not exist in adult human hippocampus (Cipriani et al., 2018; Sorrells et al., 2018) come at a time when research on adult neurogenesis constitutes a major field in neuros…”
BackgroundInfluentialTissue Engineering and Biomaterial Strategies to Elicit Endogenous Neuronal Replacement in the Brain
Purvis, E. M., O’Donnell, J. C., Chen, H.-C. I., & Cullen, D. K. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.00344 · Cited by 31 · see citing works
“While some studies suggest that hippocampal neurogenesis continues throughout human life (68–70), competing evidence argues that hippocampal neurogenesis ceases during childhood (71, 72).”
BackgroundDietary Flavonoids and Adult Neurogenesis: Potential Implications for Brain Aging
Davinelli, S., Medoro, A., Alì, S., Passarella, D., Intrieri, M., & Scapagnini, G. (2022) · Current Neuropharmacology · doi:10.2174/1570159x21666221031103909 · Cited by 30 · see citing works
Memory circuits in dementia: The engram, hippocampal neurogenesis and Alzheimer’s disease
Lazarov, O., Gupta, M., Kumar, P., Morrissey, Z. D., & Phan, T. (2024) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2024.102601 · Cited by 29 · see citing works
“Some studies failed to detect new neurons in the adult hippocampus (Cipriani et al., 2018; Franjic et al., 2022; Sorrells et al., 2018, 2021), while others have described the presence of hippocampal neurogenesis even in elderly primates and humans (Bol-drini et al., 2018; Eriksson et al., 1998; Li…”
BackgroundZhao, J., Taylor, C. J., Newcombe, E. A., Spanevello, M., O’Keeffe, I., Cooper, L. T., Jhaveri, D. J., Boyd, A., & Bartlett, P. F. (2018) · Cerebral Cortex · doi:10.1093/cercor/bhy319 · Cited by 29 · see citing works
García‐González, D., Dumitru, I., Zuccotti, A., Yen, T.-Y., Herranz‐Pérez, V., Tan, L. L., Neitz, A., García‐Verdugo, J. M., Kuner, R., Alfonso, J., et al. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0823-4 · Cited by 28 · see citing works
Is Adult Hippocampal Neurogenesis Really Relevant for the Treatment of Psychiatric Disorders?
Carli, M., Aringhieri, S., Kolachalam, S., Longoni, B., Grenno, G., Rossi, M., Gemignani, A., Fornai, F., Maggio, R., & Scarselli, M. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200818194948 · Cited by 28 · see citing works
Predicting progression to Alzheimer’s disease with human hippocampal progenitors exposed to serum
Maruszak, A., Silajdžić, E., Lee, H.-A., Murphy, T., Liu, B., Shi, L., de Lucia, C., Douiri, A., Salta, E., Nevado‐Holgado, A. J., et al. (2022) · Brain · doi:10.1093/brain/awac472 · Cited by 27 · see citing works
Switching From Fear to No Fear by Different Neural Ensembles in Mouse Retrosplenial Cortex
Wang, G., Xie, H. B., Wang, L., Luo, W., Wang, Y., Jiang, J., Xiao, C. L., Feng, X., & Guan, J. (2019) · Cerebral Cortex · doi:10.1093/cercor/bhz050 · Cited by 28 · see citing works
Hippocampal neurogenesis and pro‐neurogenic therapies for Alzheimer's disease
Zheng, J. (2022) · Animal Models and Experimental Medicine · doi:10.1002/ame2.12212 · Cited by 25 · see citing works
Muro‐García, T., Martín‐Suárez, S., Espinosa, N., Valcárcel‐Martín, R., Marinas, A., Zaldumbide, L., Galbarriatu, L., Sierra, A., Fuentealba, P., & Encinas, J. M. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00158 · Cited by 25 · see citing works
To Become or Not to Become Tumorigenic: Subventricular Zone Versus Hippocampal Neural Stem Cells
Fontán‐Lozano, Á., Morcuende, S., de Carrizosa, M. A. D., Benítez‐Temiño, B., Mejı́as, R., & Matarredona, E. R. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.602217 · Cited by 26 · see citing works
“The absence of NSCs in the adult human hippocampus reported by some authors (47, 48) may account for the lack of hippocampal involvement in glioma formation or invasion.”
BackgroundResultBorroto‐Escuela, D. O., Fores‐Pons, R., Pita, M., Barbancho, M. Á., Zamorano-González, P., Casares, N. G., Fuxé, K., & Narváez, M. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.820210 · Cited by 25 · see citing works
Adult neurogenesis in the primate hippocampus
Li, Y., 中山大学中山眼科中心, 广. 广. 5., Xu, N., Hao, Z.-Z., Liu, S., & 广东省脑功能与疾病重点实验室, 广. 广. 5. (2023) · 动物学研究 · doi:10.24272/j.issn.2095-8137.2022.399 · Cited by 24 · see citing works
Brain Plasticity in Mammals: An Example for the Role of Comparative Medicine in the Neurosciences
Rosa, C. L., & Bonfanti, L. (2018) · Frontiers in Veterinary Science · doi:10.3389/fvets.2018.00274 · Cited by 24 · see citing works
Mitochondrial and Autophagic Regulation of Adult Neurogenesis in the Healthy and Diseased Brain
Büeler, H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073342 · Cited by 24 · see citing works
The molecular basis of depression: implications of sex-related differences in epigenetic regulation
Kawatake-Kuno, A., Murai, T., & Uchida, S. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.708004 · Cited by 23 · see citing works
Adult Human Hippocampus: No New Neurons in Sight
Arellano, J. I., Harding, B. N., & Thomas, J. (2018) · Cerebral Cortex · doi:10.1093/cercor/bhy106 · Cited by 23 · see citing works
Ramnauth, A. D., Tippani, M., Divecha, H. R., Papariello, A. R., Miller, R. A., Nelson, E. D., Thompson, J. R., Pattie, E. A., Kleinman, J. E., Maynard, K. R., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115300 · Cited by 22 · see citing works
Genetic Constructs for the Control of Astrocytes’ Activity
Borodinova, A. A., Balaban, P. M., Борисович, Б. И., Salmina, A. B., & Власова, О. Л. (2021) · Cells · doi:10.3390/cells10071600 · Cited by 22 · see citing works
New neurons in old brains: implications of age in the analysis of neurogenesis in post-mortem tissue
Terstege, D. J., Addo-Osafo, K., Teskey, G. C., & Epp, J. R. (2022) · Molecular Brain · doi:10.1186/s13041-022-00926-7 · Cited by 21 · see citing works
Adult Hippocampal Neurogenesis in the Human Brain: Updates, Challenges, and Perspectives
Simard, S., Matosin, N., & Mechawar, N. (2024) · The Neuroscientist · doi:10.1177/10738584241252581 · Cited by 21 · see citing works
“In addition, some studies reported a reduction of proliferative progenitor cells in adults (Cipriani and others 2018; Seki and others 2019) with a sharp decline during the first year of life (Sorrells and others 2018), suggesting a limited reserve of multipotent neural stem cells during physiologic…”
InfluentialTau Pathology and Adult Hippocampal Neurogenesis: What Tau Mouse Models Tell us?
Houben, S., Homa, M., Yilmaz, Z., Leroy, K., Brion, J., & Ando, K. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.610330 · Cited by 21 · see citing works
“There are some contradictory findings pointing to hardly detectable levels of AHN in human brains due to a sharp decrease in childhood (33, 34).”
BackgroundAdult hippocampal neurogenesis: New avenues for treatment of brain disorders
Chen, L., Li, Z., Wang, W., Zhou, Y., Li, W., & Wang, Y. (2025) · Stem Cell Reports · doi:10.1016/j.stemcr.2025.102600 · Cited by 22 · see citing works
Borroto‐Escuela, D. O., Pita-Rodríguez, M., Fores‐Pons, R., Barbancho, M. Á., Fuxé, K., & Narváez, M. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.30092 · Cited by 20 · see citing works
“, 2013) but also questioned (Cipriani et al., 2018; Sorrells et al., 2018) by other studies.”
ResultImmunohistochemical evidence for adult human neurogenesis in health and disease
Gault, N., & Szele, F. G. (2021) · WIREs Mechanisms of Disease · doi:10.1002/wsbm.1526 · Cited by 21 · see citing works
Androgens and Adult Neurogenesis in the Hippocampus
Blankers, S. A., & Galea, L. A. M. (2021) · Androgens Clinical Research and Therapeutics · doi:10.1089/andro.2021.0016 · Cited by 19 · see citing works
“esis in the human hippocampus is evident throughout adult life, although this claim is not entirely undisputed.(71,72) This review will focus on the influence of androgens in hippocampal neurogenesis, and the reader is directed to other reviews on hormones and the SVZ.”
BackgroundAlvarez‐Contino, J. E., Díaz‐Sánchez, E., Mirchandani‐Duque, M., Sánchez‐Pérez, J. A., Barbancho, M. Á., López‐Salas, A., García‐Casares, N., Fuxé, K., Borroto‐Escuela, D. O., & Narváez, M. (2023) · Journal of Cellular Physiology · doi:10.1002/jcp.30944 · Cited by 20 · see citing works
Yeh, C., Wu, K., Huang, G., & Verkhratsky, A. (2023) · Acta Physiologica · doi:10.1111/apha.13967 · Cited by 20 · see citing works
Delayed maturation and migration of excitatory neurons in the juvenile mouse paralaminar amygdala
Alderman, P. J., Saxon, D. S., Torrijos‐Saiz, L. I., Sharief, M., Page, C. E., Baroudi, J. K., Biagiotti, S. W., Butyrkin, V. A., Melamed, A., Kuo, C. T., et al. (2023) · Neuron · doi:10.1016/j.neuron.2023.11.010 · Cited by 23 · see citing works
Kumar, A., Pareek, V., Faiq, M. A., Kumar, P., Kumari, C., Singh, H. N., & Ghosh, S. K. (2020) · IBRO Reports · doi:10.1016/j.ibror.2020.08.003 · Cited by 18 · see citing works
Zhao, R. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00428-7 · Cited by 17 · see citing works
“However, there are still discrepancies in the findings related to this phenomenon [12–14 , 76– 78].”
BackgroundMolecular Diversity Among Adult Human Hippocampal and Entorhinal CellsPreprint
Franjic, D., Choi, J., Škarica, M., Xu, C., Li, Q., Ma, S., Tebbenkamp, A. T. N., Santpere, G., Arellano, J. I., Gudelj, I., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2019.12.31.889139 · Cited by 16 · see citing works
Ghibaudi, M., Amenta, A., Agosti, M., Riva, M., Graïc, J., Bifari, F., & Bonfanti, L. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032514 · Cited by 16 · see citing works
Hippocampal neurogenesis in adult primates: a systematic review
Elliott, T., Liu, K. Y., Hazan, J., Wilson, J., Vallipuram, H., Jones, K. M., Mahmood, J., Gitlin-Leigh, G., & Howard, R. J. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02815-y · Cited by 16 · see citing works
“Outcomes from individual studies are presented in Supplementary Table 1.”
Microglial Caspase-3 is essential for modulating hippocampal neurogenesis
Alonso-Bellido, I. M., Posada-Pérez, M., Hernández-Rasco, F., Vázquez‐Reyes, S., Cabanillas, M., Herrera, A. J., Bachiller, S., Soldán-Hidalgo, J., Espinosa‐Oliva, A. M., Joseph, B., et al. (2023) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2023.06.013 · Cited by 15 · see citing works
van Dijk, M. T., Talati, A., Kashyap, P., Desai, K. A., Kelsall, N. C., Gameroff, M. J., Aw, N., Abraham, E., Cullen, B., Cha, J., et al. (2023) · Biological Psychiatry · doi:10.1016/j.biopsych.2023.06.026 · Cited by 15 · see citing works
Walking and Hippocampal Formation Volume Changes: A Systematic Review
Khalil, M. H. (2025) · Brain Sciences · doi:10.3390/brainsci15010052 · Cited by 15 · see citing works
“Cipriani et al. [15] found that neurogenesis declines sharply after childhood, with few DCX+ cells in adults, concluding that it is negligible in adulthood.”
Comment on “Impact of neurodegenerative diseases on human adult hippocampal neurogenesis”
Álvarez-Buylla, A., Cebrián‐Silla, A., Sorrells, S. F., Nascimento, M. A., Paredes, M. F., García‐Verdugo, J. M., Yang, Z., & Huang, E. J. (2022) · Science · doi:10.1126/science.abn8861 · Cited by 15 · see citing works
Terreros‐Roncal, J., Moreno‐Jiménez, E. P., Flor‐García, M., Rodríguez-Moreno, C. B., Trinchero, M. F., Márquez‐Valadez, B., Cafini, F., Rábano, A., & Llorens-Martı́n, M. (2022) · Science · doi:10.1126/science.abn7270 · Cited by 15 · see citing works
Yao, J., Dai, S., Zhu, R., Tan, J., Zhao, Q., Yin, Y., Sun, J., Du, X., Ge, L., Xu, J., et al. (2023) · eLife · doi:10.7554/elife.89507 · Cited by 17 · see citing works
“Since hippocampal neurogenesis is controversial in the adult human brain ( Zhong et al., 2020 ; Cipriani et al., 2018 ; Sorrells et al., 2018 ; Franjic et al., 2022 ; Boldrini et al., 2018 ; Moreno-Jiménez et al., 2019 ; Tobin et al., 2019 ; Terreros-Roncal et al., 2021 ) and the dramatic…”
BackgroundUntangling human neurogenesis to understand and counteract brain disorders
Beckervordersandforth, R., & Rolando, C. (2019) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2019.12.002 · Cited by 14 · see citing works
- Authors
- Cipriani, S., Ferrer, I., Aronica, E., Kovacs, G. G., Verney, C., Nardelli, J., Khung, S., Delezoide, A.-L., Milenkovic, I., Rasika, S., Manivet, P., Benifla, J.-L., Deriot, N., Gressens, P., & Adle-Biassette, H.
- Affiliations
- Inserm (FR)
- Department of Pathology and Experimental Therapeutics, University of Barcelona, Bellvitge Campus, L’Hospitalet de Llobregat, Spain; Centre for Networked Biomedical Research in Neurodegenerative Diseases (CIBERNED), Institute Carlos III, Madrid, Spain
- Amsterdam UMC Location University of Amsterdam (NL)
- Institute of Neurology, Medical University of Vienna, Vienna, Austria
- APHP, Service de Biologie du Développement, Hôpital Robert-Debré, APHP, Paris, France
- Assistance Publique – Hôpitaux de Paris (FR)
- PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France
- APHP, Service de Gynécologie-Obstétrique, Hôpital Lariboisère, Paris, France
- Venue
- Cerebral Cortex
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-05-02
- Volume
- 28
- Issue
- 7
- Pages
- 2458-2478
- ISSN
- 1047-3211 (ISSN-L)
- 1460-2199
- OpenAlex
- W2802269477
- Cited by
- 169
- References
- 96
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 18 · 2023: 25 · 2022: 21 · 2021: 23 · 2020: 28 · 2019: 19 · 2018: 15
- FWCI
- 7.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cerebral Cortex (publishedVersion)
- PubMed (publishedVersion)
- RECERCAT (Consorci de Serveis Universitaris de Catalunya) (acceptedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, public-domain)
- Funders
- European Commission (HEALTH-2011-2.2.2-2)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- radial glia, hippocampus, dentate gyrus, adult neurogenesis, Alzheimer's disease, neural progenitor cells, human fetal development, ventricular zone, doublecortin, nestin, aging
- MeSH terms
- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Alzheimer Disease, Child, Child, Preschool, Female, Fetus, Gestational Age, Hippocampus, Humans, Infant, Infant, Newborn, Male, Middle Aged, Nerve Tissue Proteins, Neurons, Ki-67 Antigen, Neurogenesis, Young Adult, Neural Stem Cells
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