Abstract
In sub-mammalian vertebrates like fishes, amphibians, and reptiles, new neurons are produced during the entire lifespan. This capacity diminishes considerably in birds and even more in mammals where it persists only in the olfactory system and hippocampal dentate gyrus. Adult neurogenesis declines even more drastically in nonhuman primates and recent evidence shows that this is basically extinct in humans. Why should such seemingly useful capacity diminish during primate evolution? It has been proposed that this occurs because of the need to retain acquired complex knowledge in stable populations of neurons and their synaptic connections during many decades of human life. In this review, we will assess critically the claim of significant adult neurogenesis in humans and show how current evidence strongly indicates that humans lack this trait. In addition, we will discuss the allegation of many rodent studies that adult neurogenesis is involved in psychiatric diseases and that it is a potential mechanism for human neuron replacement and regeneration. We argue that these reports, which usually neglect significant structural and functional species-specific differences, mislead the general population into believing that there might be a cure for a variety of neuropsychiatric diseases as well as stroke and brain trauma by genesis of new neurons and their incorporation into existing synaptic circuitry.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Lois C, Alvarez-Buylla A. Long-distance neuronal migration in the adult mammalian brain. Science. 1994;264:1145–8.
Cameron HA, Woolley CS, McEwen BS, Gould E. Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience. 1993;56:337–44.
Gould E, Tanapat P, McEwen BS, Flugge G, Fuchs E. Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc Natl Acad Sci USA. 1998;95:3168–71.
Kornack DR, Rakic P. Continuation of neurogenesis in the hippocampus of the adult macaque monkey. Proc Natl Acad Sci USA. 1999;96:5768–73.
Nowakowski RS, Rakic P. The site of origin and route and rate of migration of neurons to the hippocampal region of the rhesus monkey. J Comp Neurol. 1981;196:129–54.
Rakic P, Nowakowski RS. The time of origin of neurons in the hippocampal region of the rhesus monkey. J Comp Neurol. 1981;196:99–128.
Gould E, Reeves AJ, Graziano MS, Gross CG. Neurogenesis in the neocortex of adult primates. Science. 1999;286:548–52.
Rakic P. Limits of neurogenesis in primates. Science. 1985;227:1054–6.
Kornack DR, Rakic P. The generation, migration, and differentiation of olfactory neurons in the adult primate brain. Proc Natl Acad Sci USA. 2001;98:4752–7.
Eckenhoff MF, Rakic P. Nature and fate of proliferative cells in the hippocampal dentate gyrus during the life span of the rhesus monkey. J Neurosci. 1988;8:2729–47.
Kornack DR, Rakic P. Cell proliferation without neurogenesis in adult primate neocortex. Science. 2001;294:2127–30.
Koketsu D, Mikami A, Miyamoto Y, Hisatsune T. Nonrenewal of neurons in the cerebral neocortex of adult macaque monkeys. J Neurosci. 2003;23:937–42.
Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, et al. Neurogenesis in the adult human hippocampus. Nat Med. 1998;4:1313–7.
Arellano JI, Harding B, Thomas JL. Adult human hippocampus: no new neurons in sight. Cereb Cortex. 2018;28:2479–81.
Knoth R, Singec I, Ditter M, Pantazis G, Capetian P, Meyer RP, et al. Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years. PLoS ONE. 2010;5:e8809.
Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, et al. Dynamics of hippocampal neurogenesis in adult humans. Cell. 2013;153:1219–27.
Boldrini M, Fulmore CA, Tartt AN, Simeon LR, Pavlova I, Poposka V, et al. Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell. 2018;22:589.e5–99.e5.
Moreno-Jimenez EP, Flor-Garcia M, Terreros-Roncal J, Rabano A, Cafini F, Pallas-Bazarra N, et al. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat Med. 2019;25:554–60.
Tobin MK, Musaraca K, Disouky A, Shetti A, Bheri A, Honer WG, et al. Human hippocampal neurogenesis persists in aged adults and Alzheimer’s disease patients. Cell Stem Cell. 2019;24:974.e3–82.e3.
Flor-Garcia M, Terreros-Roncal J, Moreno-Jimenez EP, Avila J, Rabano A, Llorens-Martin M. Unraveling human adult hippocampal neurogenesis. Nat Protoc. 2020;15:668–93.
Moreno-Jimenez EP, Terreros-Roncal J, Flor-Garcia M, Rabano A, Llorens-Martin M. Evidences for adult hippocampal neurogenesis in humans. J Neurosci. 2021;41:2541–53.
Morrison JI, Loof S, He P, Simon A. Salamander limb regeneration involves the activation of a multipotent skeletal muscle satellite cell population. J Cell Biol. 2006;172:433–40.
Stangl D, Thuret S. Impact of diet on adult hippocampal neurogenesis. Genes Nutr. 2009;4:271–82.
Lindqvist A, Mohapel P, Bouter B, Frielingsdorf H, Pizzo D, Brundin P, et al. High-fat diet impairs hippocampal neurogenesis in male rats. Eur J Neurol. 2006;13:1385–8.
Aoki H, Kimoto K, Hori N, Toyoda M. Cell proliferation in the dentate gyrus of rat hippocampus is inhibited by soft diet feeding. Gerontology. 2005;51:369–74.
Wentz CT, Magavi SS. Caffeine alters proliferation of neuronal precursors in the adult hippocampus. Neuropharmacology. 2009;56:994–1000.
Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell. 2008;132:645–60.
Poulose SM, Miller MG, Scott T, Shukitt-Hale B. Nutritional factors affecting adult neurogenesis and cognitive function. Adv Nutr. 2017;8:804–11.
Clark PJ, Brzezinska WJ, Thomas MW, Ryzhenko NA, Toshkov SA, Rhodes JS. Intact neurogenesis is required for benefits of exercise on spatial memory but not motor performance or contextual fear conditioning in C57BL/6J mice. Neuroscience. 2008;155:1048–58.
Klaus F, Amrein I. Running in laboratory and wild rodents: differences in context sensitivity and plasticity of hippocampal neurogenesis. Behav Brain Res. 2012;227:363–70.
Schaefers AT. Rearing conditions and domestication background determine regulation of hippocampal cell proliferation and survival in adulthood-laboratory CD1 and C57Bl/6 mice versus wild house mice. Neuroscience. 2013;228:120–7.
Hauser T, Klaus F, Lipp HP, Amrein I. No effect of running and laboratory housing on adult hippocampal neurogenesis in wild caught long-tailed wood mouse. BMC Neurosci. 2009;10:43.
Duque A, Spector R. A balanced evaluation of the evidence for adult neurogenesis in humans: implication for neuropsychiatric disorders. Brain Struct Funct. 2019;224:2281–95.
Henn FA, Vollmayr B. Neurogenesis and depression: etiology or epiphenomenon? Biol Psychiatry. 2004;56:146–50.
Filipkowski RK, Kaczmarek L. Severely impaired adult brain neurogenesis in cyclin D2 knock-out mice produces very limited phenotypic changes. Prog Neuropsychopharmacol Biol Psychiatry. 2018;80:63–7.
Abdallah CG, Sanacora G, Duman RS, Krystal JH. Ketamine and rapid-acting antidepressants: a window into a new neurobiology for mood disorder therapeutics. Annu Rev Med. 2015;66:509–23.
Akers KG, Martinez-Canabal A, Restivo L, Yiu AP, De Cristofaro A, Hsiang HL, et al. Hippocampal neurogenesis regulates forgetting during adulthood and infancy. Science. 2014;344:598–602.
La Rosa C, Parolisi R, Bonfanti L. Brain structural plasticity: from adult neurogenesis to immature neurons. Front Neurosci. 2020;14:75.
Rakic P. Neurogenesis in adult primate neocortex: an evaluation of the evidence. Nat Rev Neurosci. 2002;3:65–71.
Taupin P. BrdU immunohistochemistry for studying adult neurogenesis: paradigms, pitfalls, limitations, and validation. Brain Res Rev. 2007;53:198–214.
Breunig JJ, Arellano JI, Macklis JD, Rakic P. Everything that glitters isn’t gold: a critical review of postnatal neural precursor analyses. Cell Stem Cell. 2007;1:612–27.
Duque A, Rakic P. Identification of proliferating and migrating cells by BrdU and other thymidine analogues. Benefits and limitations. In: Merighi A, Lossi L, editors. Immunocytochemistry and related techniques. Totowa, NJ: Springer; 2015, p. 123–9.
Busser J, Geldmacher DS, Herrup K. Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer’s disease brain. J Neurosci. 1998;18:2801–7.
Hoozemans JJ, Veerhuis R, Rozemuller AJ, Eikelenboom P. The pathological cascade of Alzheimer’s disease: the role of inflammation and its therapeutic implications. Drugs Today. 2002;38:429–43.
Yang Y, Mufson EJ, Herrup K. Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer’s disease. J Neurosci. 2003;23:2557–63.
Kuan CY, Schloemer AJ, Lu A, Burns KA, Weng WL, Williams MT, et al. Hypoxia-ischemia induces DNA synthesis without cell proliferation in dying neurons in adult rodent brain. J Neurosci. 2004;24:10763–72.
Munzel M, Globisch D, Bruckl T, Wagner M, Welzmiller V, Michalakis S, et al. Quantification of the sixth DNA base hydroxymethylcytosine in the brain. Angew Chem Int Ed Engl. 2010;49:5375–7.
Guo JU, Su Y, Zhong C, Ming GL, Song H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell. 2011;145:423–34.
Arendt T, Holzer M, Gartner U, Bruckner MK. Aberrancies in signal transduction and cell cycle related events in Alzheimer’s disease. J Neural Transm Suppl. 1998;54:147–58.
Mattiesen WR, Tauber SC, Gerber J, Bunkowski S, Bruck W, Nau R. Increased neurogenesis after hypoxic-ischemic encephalopathy in humans is age related. Acta Neuropathol. 2009;117:525–34.
Sorrells SF, Paredes MF, Zhang Z, Kang G, Pastor-Alonso O, Biagiotti S, et al. Positive controls in adults and children support that very few, if any, new neurons are born in the adult human hippocampus. J Neurosci. 2021;41:2554–65.
Dennis CV, Suh LS, Rodriguez ML, Kril JJ, Sutherland GT. Human adult neurogenesis across the ages: an immunohistochemical study. Neuropathol Appl Neurobiol. 2016;42:621–38.
Sorrells SF, Paredes MF, Cebrian-Silla A, Sandoval K, Qi D, Kelley KW, et al. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature. 2018;555:377–81.
Parakalan R, Jiang B, Nimmi B, Janani M, Jayapal M, Lu J, et al. Transcriptome analysis of amoeboid and ramified microglia isolated from the corpus callosum of rat brain. BMC Neurosci. 2012;13:64.
Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S, et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014;34:11929–47.
Ernst A, Alkass K, Bernard S, Salehpour M, Perl S, Tisdale J, et al. Neurogenesis in the striatum of the adult human brain. Cell. 2014;156:1072–83.
Wang C, You Y, Qi D, Zhou X, Wang L, Wei S, et al. Human and monkey striatal interneurons are derived from the medial ganglionic eminence but not from the adult subventricular zone. J Neurosci. 2014;34:10906–23.
Doorn KJ, Drukarch B, van Dam AM, Lucassen PJ. Hippocampal proliferation is increased in presymptomatic Parkinson’s disease and due to microglia. Neural Plast. 2014;2014:959154.
Mathews KJ, Allen KM, Boerrigter D, Ball H, Shannon Weickert C, Double KL. Evidence for reduced neurogenesis in the aging human hippocampus despite stable stem cell markers. Aging Cell. 2017;16:1195–9.
Cipriani S, Ferrer I, Aronica E, Kovacs GG, Verney C, Nardelli J, et al. Hippocampal radial glial subtypes and their neurogenic potential in human fetuses and healthy and Alzheimer’s disease adults. Cereb Cortex. 2018;28:2458–78.
Seki T, Hori T, Miyata H, Maehara M, Namba T. Analysis of proliferating neuronal progenitors and immature neurons in the human hippocampus surgically removed from control and epileptic patients. Sci Rep. 2019;9:18194.
Sloviter RS, Sollas AL, Barbaro NM, Laxer KD. Calcium-binding protein (calbindin-D28K) and parvalbumin immunocytochemistry in the normal and epileptic human hippocampus. J Comp Neurol. 1991;308:381–96.
Nitsch R, Ohm TG. Calretinin immunoreactive structures in the human hippocampal formation. J Comp Neurol. 1995;360:475–87.
Lawrence YA, Kemper TL, Bauman ML, Blatt GJ. Parvalbumin-, calbindin-, and calretinin-immunoreactive hippocampal interneuron density in autism. Acta Neurol Scand. 2010;121:99–108.
Cannon JR, Greenamyre JT. NeuN is not a reliable marker of dopamine neurons in rat substantia nigra. Neurosci Lett. 2009;464:14–17.
Ohira K, Hagihara H, Miwa M, Nakamura K, Miyakawa T. Fluoxetine-induced dematuration of hippocampal neurons and adult cortical neurogenesis in the common marmoset. Mol Brain. 2019;12:69.
Lazic SE. Relating hippocampal neurogenesis to behavior: the dangers of ignoring confounding variables. Neurobiol Aging. 2010;31:2169–71. discussion 2172-2165
Lazic SE. Modeling hippocampal neurogenesis across the lifespan in seven species. Neurobiol Aging. 2012;33:1664–71.
Varea E, Castillo-Gomez E, Gomez-Climent MA, Blasco-Ibanez JM, Crespo C, Martinez-Guijarro FJ, et al. PSA-NCAM expression in the human prefrontal cortex. J Chem Neuroanat. 2007;33:202–9.
Bologna-Molina R, Mosqueda-Taylor A, Molina-Frechero N, Mori-Estevez AD, Sanchez-Acuna G. Comparison of the value of PCNA and Ki-67 as markers of cell proliferation in ameloblastic tumors. Med Oral Patol Oral Cir Bucal. 2013;18:e174–9.
Sanai N, Berger MS, Garcia-Verdugo JM, Alvarez-Buylla A. Comment on “Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension”. Science. 2007;318:393.
Blumcke I, Schewe JC, Normann S, Brustle O, Schramm J, Elger CE, et al. Increase of nestin-immunoreactive neural precursor cells in the dentate gyrus of pediatric patients with early-onset temporal lobe epilepsy. Hippocampus. 2001;11:311–21.
Geha S, Pallud J, Junier MP, Devaux B, Leonard N, Chassoux F, et al. NG2+/Olig2+ cells are the major cycle-related cell population of the adult human normal brain. Brain Pathol. 2010;20:399–411.
Liu YW, Curtis MA, Gibbons HM, Mee EW, Bergin PS, Teoh HH, et al. Doublecortin expression in the normal and epileptic adult human brain. Eur J Neurosci. 2008;28:2254–65.
Liu JYW, Matarin M, Reeves C, McEvoy AW, Miserocchi A, Thompson P, et al. Doublecortin-expressing cell types in temporal lobe epilepsy. Acta Neuropathol Commun. 2018;6:60.
D’Alessio L, Konopka H, Escobar E, Acuna A, Oddo S, Solis P, et al. Dentate gyrus expression of nestin-immunoreactivity in patients with drug-resistant temporal lobe epilepsy and hippocampal sclerosis. Seizure. 2015;27:75–79.
D’Alessio L, Konopka H, Lopez EM, Seoane E, Consalvo D, Oddo S, et al. Doublecortin (DCX) immunoreactivity in hippocampus of chronic refractory temporal lobe epilepsy patients with hippocampal sclerosis. Seizure. 2010;19:567–72.
Lucassen PJ, Stumpel MW, Wang Q, Aronica E. Decreased numbers of progenitor cells but no response to antidepressant drugs in the hippocampus of elderly depressed patients. Neuropharmacology. 2010;58:940–9.
Epp JR, Beasley CL, Galea LA. Increased hippocampal neurogenesis and p21 expression in depression: dependent on antidepressants, sex, age, and antipsychotic exposure. Neuropsychopharmacology. 2013;38:2297–306.
Boldrini M, Underwood MD, Hen R, Rosoklija GB, Dwork AJ, John Mann J, et al. Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology. 2009;34:2376–89.
Boldrini M, Hen R, Underwood MD, Rosoklija GB, Dwork AJ, Mann JJ, et al. Hippocampal angiogenesis and progenitor cell proliferation are increased with antidepressant use in major depression. Biol Psychiatry. 2012;72:562–71.
Campbell S, Marriott M, Nahmias C, MacQueen GM. Lower hippocampal volume in patients suffering from depression: a meta-analysis. Am J Psychiatry. 2004;161:598–607.
MacQueen G, Frodl T. The hippocampus in major depression: evidence for the convergence of the bench and bedside in psychiatric research? Mol Psychiatry. 2011;16:252–64.
Schmaal L, Hibar DP, Samann PG, Hall GB, Baune BT, Jahanshad N, et al. Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group. Mol Psychiatry. 2017;22:900–9.
Nogovitsyn N, Muller M, Souza R, Hassel S, Arnott SR, Davis AD, et al. Hippocampal tail volume as a predictive biomarker of antidepressant treatment outcomes in patients with major depressive disorder: a CAN-BIND report. Neuropsychopharmacology. 2020;45:283–91.
Klosovskii B. Fundamental priciples of the development, structure and function of the vaso-capillary network of the brain In: Haigh B, editor. The development of the brain and its disturbance by harmful factors. Oxford: Pergamon Press; 1963, p. 44–54.
Pereira AC, Huddleston DE, Brickman AM, Sosunov AA, Hen R, McKhann GM, et al. An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci USA. 2007;104:5638–43.
Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. J Comp Neurol. 2000;425:479–94.
Hochgerner H, Zeisel A, Lonnerberg P, Linnarsson S. Conserved properties of dentate gyrus neurogenesis across postnatal development revealed by single-cell RNA sequencing. Nat Neurosci. 2018;21:290–9.
Kempermann G, Gage FH, Aigner L, Song H, Curtis MA, Thuret S, et al. Human adult neurogenesis: evidence and remaining questions. Cell Stem Cell. 2018;23:25–30.
Kuhn HG, Toda T, Gage FH. Adult hippocampal neurogenesis: a coming-of-age story. J Neurosci. 2018;38:10401–10.
Lee H, Thuret S. Adult human hippocampal neurogenesis: controversy and evidence. Trends Mol Med. 2018;24:521–2.
Paredes MF, Sorrells SF, Cebrian-Silla A, Sandoval K, Qi D, Kelley KW, et al. Does adult neurogenesis persist in the human hippocampus? Cell Stem Cell. 2018;23:780–1.
Habib N, Avraham-Davidi I, Basu A, Burks T, Shekhar K, Hofree M, et al. Massively parallel single-nucleus RNA-seq with DroNc-seq. Nat Methods. 2017;14:955–8.
Franjic D, Choi J, Skarica M, Xu C, Li Q, Ma S, et al. Molecular diversity among adult human hippocampal and entorhinal cells. bioRxiv [Preprint] 2020 [cited 2020 Jan 2]: [75 p.]. Available from: https://doi.org/10.1101/2019.12.31.889139.
Funding
This study was partly supported by the NIH grant DA023999 to PR and MacBrainResource (supported by MH113257 to AD).
Author information
Authors and Affiliations
Contributions
PR was invited to write this Expert Review and conceived the scope of the paper. AD, JIA, and PR examined the literature on this large subject and wrote the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Duque, A., Arellano, J.I. & Rakic, P. An assessment of the existence of adult neurogenesis in humans and value of its rodent models for neuropsychiatric diseases. Mol Psychiatry 27, 377–382 (2022). https://doi.org/10.1038/s41380-021-01314-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41380-021-01314-8
This article is cited by
-
The impact of adult neurogenesis on affective functions: of mice and men
Molecular Psychiatry (2024)
-
Clinical relevance of animal models in aging-related dementia research
Nature Aging (2023)
-
Adult neurogenesis and “immature” neurons in mammals: an evolutionary trade-off in plasticity?
Brain Structure and Function (2023)
-
Ablated Sonic Hedgehog Signaling in the Dentate Gyrus of the Dorsal and Ventral Hippocampus Impairs Hippocampal-Dependent Memory Tasks and Emotion in a Rat Model of Depression
Molecular Neurobiology (2023)
-
Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications
Molecular Psychiatry (2022)