Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Formation and integration of new neurons in the adult hippocampus

Abstract

Neural stem cells (NSCs) generate new neurons throughout life in the mammalian brain. Adult-born neurons shape brain function, and endogenous NSCs could potentially be harnessed for brain repair. In this Review, focused on hippocampal neurogenesis in rodents, we highlight recent advances in the field based on novel technologies (including single-cell RNA sequencing, intravital imaging and functional observation of newborn cells in behaving mice) and characterize the distinct developmental steps from stem cell activation to the integration of newborn neurons into pre-existing circuits. Further, we review current knowledge of how levels of neurogenesis are regulated, discuss findings regarding survival and maturation of adult-born cells and describe how newborn neurons affect brain function. The evidence arguing for (and against) lifelong neurogenesis in the human hippocampus is briefly summarized. Finally, we provide an outlook of what is needed to improve our understanding of the mechanisms and functional consequences of adult neurogenesis and how the field may move towards more translational relevance in the context of acute and chronic neural injury and stem cell-based brain repair.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Neurogenesis in the adult hippocampus.
Fig. 2: Systemic regulators of adult hippocampal neurogenesis.
Fig. 3: Maturation of adult-born neurons in the hippocampus.
Fig. 4: Circuit function of newborn granule cells in the adult hippocampus.

References

  1. 1.

    Altman, J. & Das, G. D. Post-natal origin of microneurons in the rat brain. Nature 207, 953–956 (1965). Seminal study suggesting the postnatal birth of neurons in the mammalian brain.

    CAS  PubMed  Google Scholar 

  2. 2.

    Kuhn, H. G., Toda, T. & Gage, F. H. Adult hippocampal neurogenesis: a coming-of-age story. J. Neurosci. 38, 10401–10410 (2018).

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Goncalves, J. T., Schafer, S. T. & Gage, F. H. Adult neurogenesis in the hippocampus: from stem cells to behavior. Cell 167, 897–914 (2016).

    CAS  PubMed  Google Scholar 

  4. 4.

    Obernier, K. & Alvarez-Buylla, A. Neural stem cells: origin, heterogeneity and regulation in the adult mammalian brain. Development 146, dev.156059 (2019).

    Google Scholar 

  5. 5.

    Spalding, K. L. et al. Dynamics of hippocampal neurogenesis in adult humans. Cell 153, 1219–1227 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Eriksson, P. S. et al. Neurogenesis in the adult human hippocampus. Nat. Med. 4, 1313–1317 (1998). The first study suggesting the birth of neurons in the human adult hippocampus.

    CAS  PubMed  Google Scholar 

  7. 7.

    Knoth, R. et al. Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years. PLoS ONE 5, e8809 (2010).

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Moreno-Jimenez, E. P. et al. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat. Med. 25, 554–560 (2019).

    CAS  PubMed  Google Scholar 

  9. 9.

    Charvet, C. J. & Finlay, B. L. Comparing adult hippocampal neurogenesis across species: translating time to predict the tempo in humans. Front. Neurosci. 12, 706 (2018).

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Amrein, I. Adult hippocampal neurogenesis in natural populations of mammals. Cold Spring Harbor Perspect. Biol. 7, a021295 (2015).

    Google Scholar 

  11. 11.

    Kempermann, G. New neurons for ‘survival of the fittest’. Nat. Rev. Neurosci. 13, 727–736 (2012).

    CAS  PubMed  Google Scholar 

  12. 12.

    Doetsch, F., Caille, I., Lim, D. A., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97, 703–716 (1999).

    CAS  PubMed  Google Scholar 

  13. 13.

    Gould, E. How widespread is adult neurogenesis in mammals? Nat. Rev. Neurosci. 8, 481–488 (2007).

    CAS  PubMed  Google Scholar 

  14. 14.

    Ernst, A. et al. Neurogenesis in the striatum of the adult human brain. Cell 156, 1072–1083 (2014).

    CAS  PubMed  Google Scholar 

  15. 15.

    Bergmann, O. et al. The age of olfactory bulb neurons in humans. Neuron 74, 634–639 (2012).

    CAS  PubMed  Google Scholar 

  16. 16.

    Zhao, C., Teng, E. M., Summers, R. G. Jr., Ming, G. L. & Gage, F. H. Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J. Neurosci. 26, 3–11 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Toni, N. et al. Synapse formation on neurons born in the adult hippocampus. Nat. Neurosci. 10, 727–734 (2007).

    CAS  PubMed  Google Scholar 

  18. 18.

    van Praag, H. et al. Functional neurogenesis in the adult hippocampus. Nature 415, 1030–1034 (2002).

    PubMed  Google Scholar 

  19. 19.

    Encinas, J. M. et al. Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell 8, 566–579 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Urban, N. et al. Return to quiescence of mouse neural stem cells by degradation of a proactivation protein. Science 353, 292–295 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Bonaguidi, M. A. et al. In vivo clonal analysis reveals self-renewing and multipotent adult neural stem cell characteristics. Cell 145, 1142–1155 (2011). Seminal study that analyses the fate and potency of adult hippocampal NSCs on a clonal level.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Reynolds, B. A. & Weiss, S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255, 1707–1710 (1992).

    CAS  PubMed  Google Scholar 

  23. 23.

    Ray, J., Raymon, H. K. & Gage, F. H. Generation and culturing of precursor cells and neuroblasts from embryonic and adult central nervous system. Methods Enzymol. 254, 20–37 (1995).

    CAS  PubMed  Google Scholar 

  24. 24.

    Hsieh, J. et al. IGF-I instructs multipotent adult neural progenitor cells to become oligodendrocytes. J. Cell Biol. 164, 111–122 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Seri, B., Garcia-Verdugo, J. M., McEwen, B. S. & Alvarez-Buylla, A. Astrocytes give rise to new neurons in the adult mammalian hippocampus. J. Neurosci. 21, 7153–7160 (2001). Key study indicating the identity of adult NSCs and showing that cells with astroglial properties give rise to new neurons in the adult rodent hippocampus.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Filippov, V. et al. Subpopulation of nestin-expressing progenitor cells in the adult murine hippocampus shows electrophysiological and morphological characteristics of astrocytes. Mol. Cell. Neurosci. 23, 373–382 (2003).

    CAS  PubMed  Google Scholar 

  27. 27.

    Malatesta, P. et al. Neuronal or glial progeny: regional differences in radial glia fate. Neuron 37, 751–764 (2003).

    CAS  PubMed  Google Scholar 

  28. 28.

    Moss, J. et al. Fine processes of nestin-GFP-positive radial glia-like stem cells in the adult dentate gyrus ensheathe local synapses and vasculature. Proc. Natl Acad. Sci. USA 113, E2536–E2545 (2016).

    CAS  PubMed  Google Scholar 

  29. 29.

    DeCarolis, N. A. et al. In vivo contribution of nestin- and GLAST-lineage cells to adult hippocampal neurogenesis. Hippocampus 23, 708–719 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Lugert, S. et al. Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging. Cell Stem Cell 6, 445–456 (2010).

    CAS  PubMed  Google Scholar 

  31. 31.

    Pilz, G. A. et al. Live imaging of neurogenesis in the adult mouse hippocampus. Science 359, 658–662 (2018). First study to use in vivo imaging to follow single NSCs and their daughter cells over months.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Urban, N., Blomfield, I. M. & Guillemot, F. Quiescence of adult mammalian neural stem cells: a highly regulated rest. Neuron 104, 834–848 (2019).

    CAS  PubMed  Google Scholar 

  33. 33.

    Kempermann, G., Jessberger, S., Steiner, B. & Kronenberg, G. Milestones of neuronal development in the adult hippocampus. Trends Neurosci. 27, 447–452 (2004).

    CAS  PubMed  Google Scholar 

  34. 34.

    Imayoshi, I., Ohtsuka, T., Metzger, D., Chambon, P. & Kageyama, R. Temporal regulation of Cre recombinase activity in neural stem cells. Genesis 44, 233–238 (2006).

    CAS  PubMed  Google Scholar 

  35. 35.

    Berg, D. A. et al. A common embryonic origin of stem cells drives developmental and adult neurogenesis. Cell 177, 654–668 e615 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Lagace, D. C. et al. Dynamic contribution of nestin-expressing stem cells to adult neurogenesis. J. Neurosci. 27, 12623–12629 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Ninkovic, J., Mori, T. & Gotz, M. Distinct modes of neuron addition in adult mouse neurogenesis. J. Neurosci. 27, 10906–10911 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Bottes, S. et al. Long-term self-renewing stem cells in the adult mouse hippocampus identified by intravital imaging. Nat. Neurosci. 24, 225–233 (2020).

    PubMed  Google Scholar 

  39. 39.

    Rolando, C. et al. Multipotency of adult hippocampal NSCs in vivo is restricted by Drosha/NFIB. Cell Stem Cell 19, 653–662 (2016).

    CAS  PubMed  Google Scholar 

  40. 40.

    Sun, G. J. et al. Latent tri-lineage potential of adult hippocampal neural stem cells revealed by Nf1 inactivation. Nat. Neurosci. 18, 1722–1724 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Jessberger, S., Toni, N., Clemenson, G. D. Jr., Ray, J. & Gage, F. H. Directed differentiation of hippocampal stem/progenitor cells in the adult brain. Nat. Neurosci. 11, 888–893 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Shin, J. et al. Single-cell RNA-seq with waterfall reveals molecular cascades underlying adult neurogenesis. Cell Stem Cell 17, 360–372 (2015).

    CAS  PubMed  Google Scholar 

  43. 43.

    Artegiani, B. et al. A single-cell RNA sequencing study reveals cellular and molecular dynamics of the hippocampal neurogenic niche. Cell Rep. 21, 3271–3284 (2017).

    CAS  PubMed  Google Scholar 

  44. 44.

    Bowers, M. et al. FASN-dependent lipid metabolism links neurogenic stem/progenitor cell activity to learning and memory deficits. Cell Stem Cell 27, 98–109 e111 (2020).

    CAS  PubMed  Google Scholar 

  45. 45.

    Llorens-Bobadilla, E. et al. Single-cell transcriptomics reveals a population of dormant neural stem cells that become activated upon brain injury. Cell Stem Cell 17, 329–340 (2015).

    CAS  Google Scholar 

  46. 46.

    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. 21, 290–299 (2018).

    CAS  PubMed  Google Scholar 

  47. 47.

    Habib, N. et al. Div-Seq: single-nucleus RNA-Seq reveals dynamics of rare adult newborn neurons. Science 353, 925–928 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Zhong, S. et al. Decoding the development of the human hippocampus. Nature 577, 531–536 (2020).

    CAS  PubMed  Google Scholar 

  49. 49.

    Swaminathan, J. et al. Highly parallel single-molecule identification of proteins in zeptomole-scale mixtures. Nature Biotechnol. 36, 1076–1082 (2018).

    CAS  Google Scholar 

  50. 50.

    Clark, S. J., Lee, H. J., Smallwood, S. A., Kelsey, G. & Reik, W. Single-cell epigenomics: powerful new methods for understanding gene regulation and cell identity. Genome Biol. 17, 72 (2016).

    PubMed  PubMed Central  Google Scholar 

  51. 51.

    Morris, S. A., Eaves, D. W., Smith, A. R. & Nixon, K. Alcohol inhibition of neurogenesis: a mechanism of hippocampal neurodegeneration in an adolescent alcohol abuse model. Hippocampus 20, 596–607 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Snyder, J. S., Soumier, A., Brewer, M., Pickel, J. & Cameron, H. A. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature 476, 458–461 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Tobin, M. K. et al. Human hippocampal neurogenesis persists in aged adults and Alzheimer’s disease patients. Cell Stem Cell 24, 974–982 e973 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Boldrini, M. et al. Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell 22, 589–599 e585 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Parent, J. M. et al. Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J. Neurosci. 17, 3727–3738 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Toda, T., Parylak, S. L., Linker, S. B. & Gage, F. H. The role of adult hippocampal neurogenesis in brain health and disease. Mol. Psychiatry 24, 67–87 (2019).

    CAS  PubMed  Google Scholar 

  57. 57.

    Li, Y. et al. MDM2 inhibition rescues neurogenic and cognitive deficits in a mouse model of fragile X syndrome. Sci. Transl Med. 8, 336ra361 (2016).

    Google Scholar 

  58. 58.

    Cho, K. O. et al. Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. Nat. Commun. 6, 6606 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809 (2003). Seminal study that functionally links adult hippocampal neurogenesis to the efficacy of certain antidepressants in rodents.

    CAS  PubMed  Google Scholar 

  60. 60.

    Kuhn, H. G., Dickinson-Anson, H. & Gage, F. H. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J. Neurosci. 16, 2027–2033 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Ben Abdallah, N. M., Slomianka, L., Vyssotski, A. L. & Lipp, H. P. Early age-related changes in adult hippocampal neurogenesis in C57 mice. Neurobiol. Aging 31, 151–161 (2010).

    PubMed  Google Scholar 

  62. 62.

    Kempermann, G., Kuhn, H. G. & Gage, F. H. More hippocampal neurons in adult mice living in an enriched environment. Nature 386, 493–495 (1997). Pioneering study that shows dynamic regulation of hippocampal neurogenesis with environmental enrichment in rodents.

    CAS  PubMed  Google Scholar 

  63. 63.

    Van Praag, H., Kempermann, G. & Gage, F. H. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat. Neurosci. 2, 266–270 (1999).

    PubMed  Google Scholar 

  64. 64.

    Olson, A. K., Eadie, B. D., Ernst, C. & Christie, B. R. Environmental enrichment and voluntary exercise massively increase neurogenesis in the adult hippocampus via dissociable pathways. Hippocampus 16, 250–260 (2006).

    CAS  PubMed  Google Scholar 

  65. 65.

    Song, J. et al. Parvalbumin interneurons mediate neuronal circuitry-neurogenesis coupling in the adult hippocampus. Nat. Neurosci. 16, 1728–1730 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Song, J. et al. Neuronal circuitry mechanism regulating adult quiescent neural stem-cell fate decision. Nature 489, 150–154 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Mira, H. et al. Signaling through BMPR-IA regulates quiescence and long-term activity of neural stem cells in the adult hippocampus. Cell Stem Cell 7, 78–89 (2010).

    CAS  PubMed  Google Scholar 

  68. 68.

    Ables, J. L., Breunig, J. J., Eisch, A. J. & Rakic, P. Not(ch) just development: Notch signalling in the adult brain. Nat. Rev. Neurosci. 12, 269–283 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Kannangara, T. S. & Lagace, D. C. The multi-pronged regulation of adult neurogenesis by Forkhead Box O family members. Neuron 99, 1099–1101 (2018).

    CAS  PubMed  Google Scholar 

  70. 70.

    Schaffner, I. et al. FoxO function is essential for maintenance of autophagic flux and neuronal morphogenesis in adult neurogenesis. Neuron 99, 1188–1203 e1186 (2018).

    PubMed  PubMed Central  Google Scholar 

  71. 71.

    Cameron, H. A. & Gould, E. Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus. Neuroscience 61, 203–209 (1994).

    CAS  PubMed  Google Scholar 

  72. 72.

    Brezun, J. M. & Daszuta, A. Depletion in serotonin decreases neurogenesis in the dentate gyrus and the subventricular zone of adult rats. Neuroscience 89, 999–1002 (1999).

    CAS  PubMed  Google Scholar 

  73. 73.

    Aimone, J. B. et al. Regulation and function of adult neurogenesis: from genes to cognition. Physiol. Rev. 94, 991–1026 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Hsieh, J. & Zhao, X. Genetics and epigenetics in adult neurogenesis. Cold Spring Harbor Perspect. Biol. 8, a018911 (2016).

    Google Scholar 

  75. 75.

    Knobloch, M. et al. Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis. Nature 493, 226–230 (2013).

    CAS  PubMed  Google Scholar 

  76. 76.

    Knobloch, M. et al. A fatty acid oxidation-dependent metabolic shift regulates adult neural stem cell activity. Cell Rep. 20, 2144–2155 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Stoll, E. A. et al. Neural stem cells in the adult subventricular zone oxidize fatty acids to produce energy and support neurogenic activity. Stem Cell 33, 2306–2319 (2015).

    CAS  Google Scholar 

  78. 78.

    Beckervordersandforth, R. et al. Role of mitochondrial metabolism in the control of early lineage progression and aging phenotypes in adult hippocampal neurogenesis. Neuron 93, 560–573.e6 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Otsuki, L. & Brand, A. H. Cell cycle heterogeneity directs the timing of neural stem cell activation from quiescence. Science 360, 99–102 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Harris, L. et al. Progressive changes in hippocampal stem cell properties ensure lifelong neurogenesis. bioRxiv https://doi.org/10.1101/2020.03.12.987107 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Denoth-Lippuner, A. et al. Visualization of individual cell division history in complex tissues. bioRxiv https://doi.org/10.1101/2020.08.26.266171 (2020).

    Article  Google Scholar 

  82. 82.

    Kempermann, G., Gast, D., Kronenberg, G., Yamaguchi, M. & Gage, F. H. Early determination and long-term persistence of adult-generated new neurons in the hippocampus of mice. Development 130, 391–399 (2003).

    CAS  PubMed  Google Scholar 

  83. 83.

    Sierra, A. et al. Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7, 483–495 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Snyder, J. S. et al. Adult-born hippocampal neurons are more numerous, faster maturing, and more involved in behavior in rats than in mice. J. Neurosci. 29, 14484–14495 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Lu, Z. et al. Phagocytic activity of neuronal progenitors regulates adult neurogenesis. Nat. Cell Biol. 13, 1076–1083 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Sahay, A. et al. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 472, 466–470 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Dupret, D. et al. Spatial learning depends on both the addition and removal of new hippocampal neurons. PLoS Biol. 5, e214 (2007).

    PubMed  PubMed Central  Google Scholar 

  88. 88.

    Lodato, M. A. et al. Aging and neurodegeneration are associated with increased mutations in single human neurons. Science 359, 555–559 (2018).

    CAS  PubMed  Google Scholar 

  89. 89.

    McConnell, M. J. et al. Mosaic copy number variation in human neurons. Science 342, 632–637 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Tashiro, A., Sandler, V. M., Toni, N., Zhao, C. & Gage, F. H. NMDA-receptor-mediated, cell-specific integration of new neurons in adult dentate gyrus. Nature 442, 929–933 (2006).

    CAS  PubMed  Google Scholar 

  91. 91.

    Bayer, S. A., Yackel, J. W. & Puri, P. S. Neurons in the rat dentate gyrus granular layer substantially increase during juvenile and adult life. Science 216, 890–892 (1982).

    CAS  PubMed  Google Scholar 

  92. 92.

    Ngwenya, L. B., Heyworth, N. C., Shwe, Y., Moore, T. L. & Rosene, D. L. Age-related changes in dentate gyrus cell numbers, neurogenesis, and associations with cognitive impairments in the rhesus monkey. Front. Syst. Neurosci. 9, 102 (2015).

    PubMed  PubMed Central  Google Scholar 

  93. 93.

    Cahill, S. P., Yu, R. Q., Green, D., Todorova, E. V. & Snyder, J. S. Early survival and delayed death of developmentally-born dentate gyrus neurons. Hippocampus 27, 1155–1167 (2017).

    CAS  PubMed  Google Scholar 

  94. 94.

    Imayoshi, I. et al. Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. Nat. Neurosci. 11, 1153–1161 (2008).

    CAS  PubMed  Google Scholar 

  95. 95.

    Saxe, M. D. et al. Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc. Natl Acad. Sci. USA 103, 17501–17506 (2006).

    CAS  PubMed  Google Scholar 

  96. 96.

    Sun, G. J. et al. Tangential migration of neuronal precursors of glutamatergic neurons in the adult mammalian brain. Proc. Natl Acad. Sci. USA 112, 9484–9489 (2015).

    CAS  PubMed  Google Scholar 

  97. 97.

    Wang, J. et al. Lateral dispersion is required for circuit integration of newly generated dentate granule cells. Nat. Commun. 10, 3324 (2019).

    PubMed  PubMed Central  Google Scholar 

  98. 98.

    Goncalves, J. T. et al. In vivo imaging of dendritic pruning in dentate granule cells. Nat. Neurosci. 19, 788–791 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Faulkner, R. L. et al. Development of hippocampal mossy fiber synaptic outputs by new neurons in the adult brain. Proc. Natl Acad. Sci. USA 105, 14157–14162 (2008).

    CAS  PubMed  Google Scholar 

  100. 100.

    Sun, G. J. et al. Seamless reconstruction of intact adult-born neurons by serial end-block imaging reveals complex axonal guidance and development in the adult hippocampus. J. Neurosci. 33, 11400–11411 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Markakis, E. A. & Gage, F. H. Adult-generated neurons in the dentate gyrus send axonal projections to field CA3 and are surrounded by synaptic vesicles. J. Comp. Neurol. 406, 449–460 (1999).

    CAS  PubMed  Google Scholar 

  102. 102.

    Laplagne, D. A. et al. Functional convergence of neurons generated in the developing and adult hippocampus. PLoS Biol. 4, e409 (2006).

    PubMed  PubMed Central  Google Scholar 

  103. 103.

    Ge, S. et al. GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 439, 589–593 (2006). Seminal study that shows how the cellular environment affects neurogenesis in the adult rodent hippocampus.

    CAS  PubMed  Google Scholar 

  104. 104.

    Markwardt, S. J., Wadiche, J. I. & Overstreet-Wadiche, L. S. Input-specific GABAergic signaling to newborn neurons in adult dentate gyrus. J. Neurosci. 29, 15063–15072 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Bergami, M. et al. A critical period for experience-dependent remodeling of adult-born neuron connectivity. Neuron 85, 710–717 (2015).

    CAS  PubMed  Google Scholar 

  106. 106.

    Deshpande, A. et al. Retrograde monosynaptic tracing reveals the temporal evolution of inputs onto new neurons in the adult dentate gyrus and olfactory bulb. Proc. Natl Acad. Sci. USA 110, E1152–E1161 (2013).

    CAS  PubMed  Google Scholar 

  107. 107.

    Vivar, C. et al. Monosynaptic inputs to new neurons in the dentate gyrus. Nat. Commun. 3, 1107 (2012).

    PubMed  PubMed Central  Google Scholar 

  108. 108.

    Toni, N. et al. Neurons born in the adult dentate gyrus form functional synapses with target cells. Nat. Neurosci. 11, 901–907 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Luna, V. M. et al. Adult-born hippocampal neurons bidirectionally modulate entorhinal inputs into the dentate gyrus. Science 364, 578–583 (2019). Pioneering study that shows how adult-born hippocampal granule cells can shape the behaviour and activity of the rodent DG circuit in vivo.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Steib, K., Schaffner, I., Jagasia, R., Ebert, B. & Lie, D. C. Mitochondria modify exercise-induced development of stem cell-derived neurons in the adult brain. J. Neurosci. 34, 6624–6633 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Duan, X. et al. Disrupted-in-schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell 130, 1146–1158 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Vadodaria, K. C., Brakebusch, C., Suter, U. & Jessberger, S. Stage-specific functions of the small Rho GTPases Cdc42 and Rac1 for adult hippocampal neurogenesis. J. Neurosci. 33, 1179–1189 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Karalay, O. et al. Prospero-related homeobox 1 gene (Prox1) is regulated by canonical Wnt signaling and has a stage-specific role in adult hippocampal neurogenesis. Proc. Natl Acad. Sci. USA 108, 5807–5812 (2011).

    CAS  PubMed  Google Scholar 

  114. 114.

    Sultan, S. et al. Synaptic integration of adult-born hippocampal neurons is locally controlled by astrocytes. Neuron 88, 957–972 (2015).

    CAS  PubMed  Google Scholar 

  115. 115.

    Wang, S., Scott, B. W. & Wojtowicz, J. M. Heterogenous properties of dentate granule neurons in the adult rat. J. Neurobiol. 42, 248–257 (2000).

    CAS  PubMed  Google Scholar 

  116. 116.

    Ge, S., Yang, C. H., Hsu, K. S., Ming, G. L. & Song, H. A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain. Neuron 54, 559–566 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Schmidt-Hieber, C., Jonas, P. & Bischofberger, J. Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature 429, 184–187 (2004).

    CAS  PubMed  Google Scholar 

  118. 118.

    Brunner, J. et al. Adult-born granule cells mature through two functionally distinct states. eLife 3, e03104 (2014).

    PubMed  PubMed Central  Google Scholar 

  119. 119.

    Beining, M. et al. Adult-born dentate granule cells show a critical period of dendritic reorganization and are distinct from developmentally born cells. Brain Struct. Funct. 222, 1427–1446 (2017).

    PubMed  Google Scholar 

  120. 120.

    Cole, J. D. et al. Adult-born hippocampal neurons undergo extended development and are morphologically distinct from neonatally-born neurons. J. Neurosci. 40, 5740–5756 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Toni, N. & Schinder, A. F. Maturation and functional integration of new granule cells into the adult hippocampus. Cold Spring Harb. Perspect. Biol. 8, a018903 (2015).

    PubMed  Google Scholar 

  122. 122.

    Drapeau, E. et al. Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis. Proc. Natl Acad. Sci. USA 100, 14385–14390 (2003).

    CAS  PubMed  Google Scholar 

  123. 123.

    Gu, Y. et al. Optical controlling reveals time-dependent roles for adult-born dentate granule cells. Nat. Neurosci. 15, 1700–1706 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Shors, T. J. et al. Neurogenesis in the adult is involved in the formation of trace memories. Nature 410, 372–376 (2001).

    CAS  PubMed  Google Scholar 

  125. 125.

    Dupret, D. et al. Spatial relational memory requires hippocampal adult neurogenesis. PLoS ONE 3, e1959 (2008).

    PubMed  PubMed Central  Google Scholar 

  126. 126.

    Jessberger, S. et al. Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats. Learn. Mem. 16, 147–154 (2009).

    PubMed  PubMed Central  Google Scholar 

  127. 127.

    Zhang, C. L., Zou, Y., He, W., Gage, F. H. & Evans, R. M. A role for adult TLX-positive neural stem cells in learning and behaviour. Nature 451, 1004–1007 (2008).

    CAS  PubMed  Google Scholar 

  128. 128.

    Cameron, H. A. & Glover, L. R. Adult neurogenesis: beyond learning and memory. Annu. Rev. Psychol. 66, 53–81 (2015).

    PubMed  Google Scholar 

  129. 129.

    Deng, W., Aimone, J. B. & Gage, F. H. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat. Rev. Neurosci. 11, 339–350 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Leutgeb, J. K., Leutgeb, S., Moser, M. B. & Moser, E. I. Pattern separation in the dentate gyrus and CA3 of the hippocampus. Science 315, 961–966 (2007).

    CAS  Google Scholar 

  131. 131.

    Bakker, A., Kirwan, C. B., Miller, M. & Stark, C. E. Pattern separation in the human hippocampal CA3 and dentate gyrus. Science 319, 1640–1642 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Clelland, C. D. et al. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 325, 210–213 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Nakashiba, T. et al. Young dentate granule cells mediate pattern separation, whereas old granule cells facilitate pattern completion. Cell 149,188–201 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Swan, A. A. et al. Characterization of the role of adult neurogenesis in touch-screen discrimination learning. Hippocampus 24, 1581–1591 (2014).

    PubMed  PubMed Central  Google Scholar 

  135. 135.

    Whoolery, C. W. et al. Multi-domain cognitive assessment of male mice shows space radiation is not harmful to high-level cognition and actually improves pattern separation. Sci. Rep. 10, 2737 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Garthe, A., Behr, J. & Kempermann, G. Adult-generated hippocampal neurons allow the flexible use of spatially precise learning strategies. PLoS ONE 4, e5464 (2009).

    PubMed  PubMed Central  Google Scholar 

  137. 137.

    Akers, K. G. et al. Hippocampal neurogenesis regulates forgetting during adulthood and infancy. Science 344, 598–602 (2014). First study that links forgetting to hippocampal neurogenesis.

    CAS  PubMed  Google Scholar 

  138. 138.

    Gao, A. et al. Elevation of hippocampal neurogenesis induces a temporally graded pattern of forgetting of contextual fear memories. J. Neurosci. 38, 3190–3198 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Noonan, M. A., Bulin, S. E., Fuller, D. C. & Eisch, A. J. Reduction of adult hippocampal neurogenesis confers vulnerability in an animal model of cocaine addiction. J. Neurosci. 30, 304–315 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Seib, D. R., Espinueva, D. F., Floresco, S. B. & Snyder, J. S. A role for neurogenesis in probabilistic reward learning. Behav. Neurosci. 134, 283–295 (2020).

    CAS  PubMed  Google Scholar 

  141. 141.

    Malberg, J. E., Eisch, A. J., Nestler, E. J. & Duman, R. S. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J. Neurosci. 20, 9104–9110 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Anacker, C. & Hen, R. Adult hippocampal neurogenesis and cognitive flexibility - linking memory and mood. Nat. Rev. Neurosci. 18, 335–346 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    David, D. J. et al. Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron 62, 479–493 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Hill, A. S., Sahay, A. & Hen, R. Increasing adult hippocampal neurogenesis is sufficient to reduce anxiety and depression-like behaviors. Neuropsychopharmacology 40, 2368–2378 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Yun, S. et al. Stimulation of entorhinal cortex-dentate gyrus circuitry is antidepressive. Nat. Med. 24, 658–666 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Jungenitz, T. et al. Structural homo- and heterosynaptic plasticity in mature and adult newborn rat hippocampal granule cells. Proc. Natl Acad. Sci. USA 115, E4670–E4679 (2018).

    CAS  PubMed  Google Scholar 

  147. 147.

    Kee, N., Teixeira, C. M., Wang, A. H. & Frankland, P. W. Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat. Neurosci. 10, 355–362 (2007).

    CAS  PubMed  Google Scholar 

  148. 148.

    Jessberger, S. & Kempermann, G. Adult-born hippocampal neurons mature into activity-dependent responsiveness. Eur. J. Neurosci. 18, 2707–2712 (2003).

    PubMed  Google Scholar 

  149. 149.

    Jungenitz, T., Radic, T., Jedlicka, P. & Schwarzacher, S. W. High-frequency stimulation induces gradual immediate early gene expression in maturing adult-generated hippocampal granule cells. Cereb. Cortex 24, 1845–1857 (2014).

    PubMed  Google Scholar 

  150. 150.

    Marin-Burgin, A., Mongiat, L. A., Pardi, M. B. & Schinder, A. F. Unique processing during a period of high excitation/inhibition balance in adult-born neurons. Science 335, 1238–1242 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Dieni, C. V., Nietz, A. K., Panichi, R., Wadiche, J. I. & Overstreet-Wadiche, L. Distinct determinants of sparse activation during granule cell maturation. J. Neurosci. 33, 19131–19142 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152.

    Drew, L. J. et al. Activation of local inhibitory circuits in the dentate gyrus by adult-born neurons. Hippocampus 26, 763–778 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153.

    Adlaf, E. W. et al. Adult-born neurons modify excitatory synaptic transmission to existing neurons. eLife 6, e19886 (2017).

    PubMed  PubMed Central  Google Scholar 

  154. 154.

    Danielson, N. B. et al. Distinct contribution of adult-born hippocampal granule cells to context encoding. Neuron 90, 101–12 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155.

    Anacker, C. et al. Hippocampal neurogenesis confers stress resilience by inhibiting the ventral dentate gyrus. Nature 559, 98–102 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Hainmueller, T. & Bartos, M. Parallel emergence of stable and dynamic memory engrams in the hippocampus. Nature 558, 292–296 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157.

    Stahl, P. L. et al. Visualization and analysis of gene expression in tissue sections by spatial transcriptomics. Science 353, 78–82 (2016).

    CAS  PubMed  Google Scholar 

  158. 158.

    Budnik, B., Levy, E., Harmange, G. & Slavov, N. SCoPE-MS: mass spectrometry of single mammalian cells quantifies proteome heterogeneity during cell differentiation. Genome Biol. 19, 161 (2018).

    PubMed  PubMed Central  Google Scholar 

  159. 159.

    Cusanovich, D. A. et al. Multiplex single cell profiling of chromatin accessibility by combinatorial cellular indexing. Science 348, 910–914 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160.

    Jackson, H. W. et al. The single-cell pathology landscape of breast cancer. Nature 578, 615–620 (2020).

    CAS  PubMed  Google Scholar 

  161. 161.

    Sawamoto, K. et al. Direct isolation of committed neuronal progenitor cells from transgenic mice coexpressing spectrally distinct fluorescent proteins regulated by stage-specific neural promoters. J. Neurosci. Res. 65, 220–227 (2001).

    CAS  PubMed  Google Scholar 

  162. 162.

    Pereira, A. C. et al. An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc. Natl Acad. Sci. USA 104, 5638–5643 (2007).

    CAS  PubMed  Google Scholar 

  163. 163.

    Manganas, L. N. et al. Magnetic resonance spectroscopy identifies neural progenitor cells in the live human brain. Science 318, 980–985 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164.

    Duque, A. & Spector, R. A balanced evaluation of the evidence for adult neurogenesis in humans: implication for neuropsychiatric disorders. Brain Struct. Funct. 224, 2281–2295 (2019).

    PubMed  PubMed Central  Google Scholar 

  165. 165.

    Kempermann, G. et al. Human adult neurogenesis: evidence and remaining questions. Cell Stem Cell 23, 25–30 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166.

    Knobloch, M. & Jessberger, S. Metabolism and neurogenesis. Curr. Opin. Neurobiol. 42, 45–52 (2017).

    CAS  PubMed  Google Scholar 

  167. 167.

    Miller, S. M. & Sahay, A. Functions of adult-born neurons in hippocampal memory interference and indexing. Nat. Neurosci. 22, 1565–1575 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168.

    Sorrells, S. F. et al. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature 555, 377–381 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169.

    Cipriani, S. et al. Hippocampal radial glial subtypes and their neurogenic potential in human fetuses and healthy and Alzheimer’s disease adults. Cereb. Cortex 28, 2458–2478 (2018).

    PubMed  Google Scholar 

  170. 170.

    Nacher, J., Crespo, C. & McEwen, B. S. Doublecortin expression in the adult rat telencephalon. Eur. J. Neurosci. 14, 629–644 (2001).

    CAS  PubMed  Google Scholar 

  171. 171.

    La Rosa, C. et al. Phylogenetic variation in cortical layer II immature neuron reservoir of mammals. eLife 9, e55456 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172.

    Paredes, M. F. et al. Does adult neurogenesis persist in the human hippocampus? Cell Stem Cell 23, 780–781 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173.

    Dennis, C. V., Suh, L. S., Rodriguez, M. L., Kril, J. J. & Sutherland, G. T. Human adult neurogenesis across the ages: an immunohistochemical study. Neuropathol. Appl. Neurobiol. 42, 621–638 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174.

    Bauer, S. & Patterson, P. H. The cell cycle–apoptosis connection revisited in the adult brain. J. Cell Biol. 171, 641–650 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175.

    Martin-Suarez, S., Valero, J., Muro-Garcia, T. & Encinas, J. M. Phenotypical and functional heterogeneity of neural stem cells in the aged hippocampus. Aging Cell 18, e12958 (2019).

    PubMed  PubMed Central  Google Scholar 

  176. 176.

    Hafezi-Moghadam, A., Thomas, K. L. & Wagner, D. D. ApoE deficiency leads to a progressive age-dependent blood-brain barrier leakage. Am. J. Physiol. Cell Physiol. 292, C1256–C1262 (2007).

    CAS  PubMed  Google Scholar 

  177. 177.

    Verbitsky, M. et al. Altered hippocampal transcript profile accompanies an age-related spatial memory deficit in mice. Learn. Mem. 11, 253–260 (2004).

    PubMed  PubMed Central  Google Scholar 

  178. 178.

    Dulken, B. W. et al. Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature 571, 205–210 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. 179.

    Navarro Negredo, P., Yeo, R. W. & Brunet, A. Aging and rejuvenation of neural stem cells and their niches. Cell Stem Cell 27, 202–223 (2020).

    CAS  PubMed  Google Scholar 

  180. 180.

    Fan, X., Wheatley, E. G. & Villeda, S. A. Mechanisms of hippocampal aging and the potential for rejuvenation. Annu. Rev. Neurosci. 40, 251–272 (2017).

    CAS  PubMed  Google Scholar 

  181. 181.

    Horowitz, A. M. et al. Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain. Science 369, 167–173 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182.

    Villeda, S. A. et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90–94 (2011). Pioneering study that links humoral factors to reduced neurogenesis in the aged brain.

    CAS  PubMed  PubMed Central  Google Scholar 

  183. 183.

    Katsimpardi, L. et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344, 630–634 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184.

    Ozek, C., Krolewski, R. C., Buchanan, S. M. & Rubin, L. L. Growth differentiation factor 11 treatment leads to neuronal and vascular improvements in the hippocampus of aged mice. Sci. Rep. 8, 17293 (2018).

    PubMed  PubMed Central  Google Scholar 

  185. 185.

    McAvoy, K. M. et al. Modulating neuronal competition dynamics in the dentate gyrus to rejuvenate aging memory circuits. Neuron 91, 1356–1373 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. 186.

    Berdugo-Vega, G. et al. Increasing neurogenesis refines hippocampal activity rejuvenating navigational learning strategies and contextual memory throughout life. Nat. Commun. 11, 135 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187.

    Vonk, W. I. M. et al. Differentiation drives widespread rewiring of the neural stem cell chaperone network. Mol. Cell 78, 329–345 e329 (2020).

    CAS  PubMed  Google Scholar 

  188. 188.

    Leeman, D. S. et al. Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging. Science 359, 1277–1283 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 189.

    Morrow, C. S. et al. Vimentin coordinates protein turnover at the aggresome during neural stem cell quiescence exit. Cell Stem Cell 26, 558–568.e9 (2020).

    CAS  PubMed  Google Scholar 

  190. 190.

    Moore, D. L., Pilz, G. A., Arauzo-Bravo, M. J., Barral, Y. & Jessberger, S. A mechanism for the segregation of age in mammalian neural stem cells. Science 349, 1334–1338 (2015).

    CAS  Google Scholar 

Download references

Acknowledgements

The authors thank D. C. Lie for comments. The authors’ laboratory is supported by the European Research Council (STEMBAR to S.J.), the Swiss National Science Foundation (BSCGI0_157859 and 310030_196869 to S.J.), the Novartis Foundation (to A.D.-L. and S.J.), the Helmut Horten Foundation (to S.J.), the Betty & David Koetser Foundation (to S.J.), a Forschungskredit of the University of Zurich (to A.D.-L.) and the Zurich Neuroscience Center (to S.J.).

Author information

Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Sebastian Jessberger.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Neuroscience thanks L. Bonfanti, who co-reviewed with C. La Rosa; S. Schwarzacher; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Granule cell layer

The granule cell layer consists mainly of excitatory granule cells, the principal neurons of the dentate gyrus.

Thymidine analogues

Analogues of the DNA component thymidine that can be injected in animals and are integrated into replicating DNA strands and detected using antibodies.

Vascular end-feet

Terminals of astrocytic processes at the vascular surface that regulate vascular function.

Asymmetric divisions

Divisions generating daughter cells with different fates or properties.

Symmetric divisions

Divisions generating daughter cells with similar or identical fates or properties.

Heterochronic parabiosis

Cross-circulation of humoral factors via shared blood circulation, most commonly used by connecting the vasculature (and thus blood circulation) of young and aged mice.

Vimentin

A type III intermediate filament protein that is a cytoskeletal component in various cell types.

Intersectional genetics

Approaches that increase the accuracy of genetic access to cells by combining two or more regulatory elements for a single synthetic output.

Genetic mosaicism

The presence of different genotypes in individual cells arising from a single zygote within an individual.

Na+–K+–Cl transporter NKCC1

A co-transporter that regulates the transport of sodium, potassium and chloride through cellular membranes.

Multiple-synapse boutons

Synapses with two or more postsynaptic terminals on a single presynaptic terminal.

Morris water maze

A behavioural, spatial navigational task, mostly used in laboratory rodents, to study spatial learning and memory.

Behavioural flexibility

Adaptive changes in the behaviour of an animal in response to changes of the external or internal environment.

Memory traces

Units of cognitive information in the brain that may cause structural or biochemical alterations allowing the storage of memory.

Homosynaptic long-term potentiation

Changes in synaptic strength that are specific for postsynaptic targets that are specifically stimulated by presynaptic cells.

Heterosynaptic long-term depression

A reduction in synaptic strength at unactivated synaptic connections that are input nonspecific.

Gradient-index lens

A lens that makes use of a gradient of the refractive index of a material, allowing a lens with a flat surface or that does not have aberrations of traditional spherical lenses.

Lateral entorhinal cortex

Part of the medial temporal lobe; it projects via the lateral perforant path into the dentate gyrus.

Medial entorhinal cortex

Part of the medial temporal lobe; it projects via the medial perforant path into the dentate gyrus.

Spatial transcriptomics

The characterization of mRNA composition in individual cells while maintaining information regarding their spatial position within complex tissues.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Denoth-Lippuner, A., Jessberger, S. Formation and integration of new neurons in the adult hippocampus. Nat Rev Neurosci 22, 223–236 (2021). https://doi.org/10.1038/s41583-021-00433-z

Download citation

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing