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.

The role of adult hippocampal neurogenesis in brain health and disease

Abstract

Adult neurogenesis in the dentate gyrus of the hippocampus is highly regulated by a number of environmental and cell-intrinsic factors to adapt to environmental changes. Accumulating evidence suggests that adult-born neurons may play distinct physiological roles in hippocampus-dependent functions, such as memory encoding and mood regulation. In addition, several brain diseases, such as neurological diseases and mood disorders, have deleterious effects on adult hippocampal neurogenesis, and some symptoms of those diseases can be partially explained by the dysregulation of adult hippocampal neurogenesis. Here we review a possible link between the physiological functions of adult-born neurons and their roles in pathological conditions.

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
Fig. 2

References

  1. 1.

    Altman J. Autoradiographic investigation of cell proliferation in the brains of rats and cats. Anat Rec. 1963;145:573–91.

    CAS  PubMed  Google Scholar 

  2. 2.

    Altman J. Are new neurons formed in the brains of adult mammals? Science. 1962;135:1127–8.

    CAS  PubMed  Google Scholar 

  3. 3.

    Kempermann G, Kuhn HG, Gage FH. More hippocampal neurons in adult mice living in an enriched environment. Nature. 1997;386:493–5.

    CAS  PubMed  Google Scholar 

  4. 4.

    Kuhn HG, Dickinson-Anson H, Gage FH. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci. 1996;16:2027–33.

    CAS  Google Scholar 

  5. 5.

    Seki T, Arai Y. Temporal and spacial relationships between PSA-NCAM-expressing, newly generated granule cells, and radial glia-like cells in the adult dentate gyrus. J Comp Neurol. 1999;410:503–13.

    CAS  PubMed  Google Scholar 

  6. 6.

    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.

    CAS  PubMed  Google Scholar 

  7. 7.

    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.

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Roy NS, Wang S, Jiang L, Kang J, Benraiss A, Harrison-Restelli C, et al. In vitro neurogenesis by progenitor cells isolated from the adult human hippocampus. Nat Med. 2000;6:271–7.

    CAS  PubMed  Google Scholar 

  9. 9.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    van Praag H, Kempermann G, Gage FH. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci. 1999;2:266–70.

    PubMed  Google Scholar 

  12. 12.

    Ge S, Yang CH, Hsu KS, Ming GL, Song H. A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain. Neuron. 2007;54:559–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Bergami M, Masserdotti G, Temprana SG, Motori E, Eriksson TM, Gobel J, et al. A critical period for experience-dependent remodeling of adult-born neuron connectivity. Neuron. 2015;85:710–7.

    CAS  PubMed  Google Scholar 

  14. 14.

    Tashiro A, Sandler VM, Toni N, Zhao C, Gage FH. NMDA-receptor-mediated, cell-specific integration of new neurons in adult dentate gyrus. Nature. 2006;442:929–33.

    CAS  PubMed  Google Scholar 

  15. 15.

    Tashiro A, Makino H, Gage FH. Experience-specific functional modification of the dentate gyrus through adult neurogenesis: a critical period during an immature stage. J Neurosci. 2007;27:3252–9.

    CAS  PubMed  Google Scholar 

  16. 16.

    Alvarez DD, Giacomini D, Yang SM, Trinchero MF, Temprana SG, Buttner KA, et al. A disynaptic feedback network activated by experience promotes the integration of new granule cells. Science. 2016;354:459–65.

    CAS  PubMed  Google Scholar 

  17. 17.

    Jessberger S, Kempermann G. Adult-born hippocampal neurons mature into activity-dependent responsiveness. Eur J Neurosci. 2003;18:2707–12.

    PubMed  Google Scholar 

  18. 18.

    Chancey JH, Adlaf EW, Sapp MC, Pugh PC, Wadiche JI, Overstreet-Wadiche LS. GABA depolarization is required for experience-dependent synapse unsilencing in adult-born neurons. J Neurosci. 2013;33:6614–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Heigele S, Sultan S, Toni N, Bischofberger J. Bidirectional GABAergic control of action potential firing in newborn hippocampal granule cells. Nat Neurosci. 2016;19:263–70.

    CAS  PubMed  Google Scholar 

  20. 20.

    Piatti VC, Davies-Sala MG, Esposito MS, Mongiat LA, Trinchero MF, Schinder AF. The timing for neuronal maturation in the adult hippocampus is modulated by local network activity. J Neurosci. 2011;31:7715–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Goncalves JT, Bloyd CW, Shtrahman M, Johnston ST, Schafer ST, Parylak SL, et al. In vivo imaging of dendritic pruning in dentate granule cells. Nat Neurosci. 2016;19:788–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Kirschen GW, Shen J, Tian M, Schroeder B, Wang J, Man G, et al. Active dentate granule cells encode experience to promote the addition of adult-born hippocampal neurons. J Neurosci. 2017;37:4661–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Kee N, Teixeira CM, Wang AH, Frankland PW. Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat Neurosci. 2007;10:355–62.

    CAS  PubMed  Google Scholar 

  24. 24.

    Vivar C, Peterson BD, van Praag H. Running rewires the neuronal network of adult-born dentate granule cells. Neuroimage. 2016;131:29–41.

    PubMed  Google Scholar 

  25. 25.

    Cameron HA, McKay RD. Restoring production of hippocampal neurons in old age. Nat Neurosci. 1999;2:894–7.

    CAS  PubMed  Google Scholar 

  26. 26.

    Snyder JS, Soumier A, Brewer M, Pickel J, Cameron HA. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature. 2011;476:458–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Gould E, McEwen BS, Tanapat P, Galea LA, Fuchs E. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J Neurosci. 1997;17:2492–8.

    CAS  PubMed  Google Scholar 

  28. 28.

    Mirescu C, Peters JD, Gould E. Early life experience alters response of adult neurogenesis to stress. Nat Neurosci. 2004;7:841–6.

    CAS  PubMed  Google Scholar 

  29. 29.

    Tanapat P, Hastings NB, Reeves AJ, Gould E. Estrogen stimulates a transient increase in the number of new neurons in the dentate gyrus of the adult female rat. J Neurosci. 1999;19:5792–801.

    CAS  PubMed  Google Scholar 

  30. 30.

    Montero-Pedrazuela A, Venero C, Lavado-Autric R, Fernandez-Lamo I, Garcia-Verdugo JM, Bernal J, et al. Modulation of adult hippocampal neurogenesis by thyroid hormones: implications in depressive-like behavior. Mol Psychiatry. 2006;11:361–71.

    CAS  PubMed  Google Scholar 

  31. 31.

    Esposito MS, Piatti VC, Laplagne DA, Morgenstern NA, Ferrari CC, Pitossi FJ, et al. Neuronal differentiation in the adult hippocampus recapitulates embryonic development. J Neurosci. 2005;25:10074–86.

    CAS  PubMed  Google Scholar 

  32. 32.

    Ming GL, Song H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron. 2011;70:687–702.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Ge S, Goh EL, Sailor KA, Kitabatake Y, Ming GL, Song H. GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature. 2006;439:589–93.

    CAS  PubMed  Google Scholar 

  34. 34.

    Deshpande A, Bergami M, Ghanem A, Conzelmann KK, Lepier A, Gotz M, 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. 2013;110:E1152–61.

    CAS  PubMed  Google Scholar 

  35. 35.

    Faulkner RL, Jang MH, Liu XB, Duan X, Sailor KA, Kim JY, et al. Development of hippocampal mossy fiber synaptic outputs by new neurons in the adult brain. Proc Natl Acad Sci USA. 2008;105:14157–62.

    CAS  PubMed  Google Scholar 

  36. 36.

    Toni N, Laplagne DA, Zhao C, Lombardi G, Ribak CE, Gage FH, et al. Neurons born in the adult dentate gyrus form functional synapses with target cells. Nat Neurosci. 2008;11:901–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Restivo L, Niibori Y, Mercaldo V, Josselyn SA, Frankland PW. Development of adult-generated cell connectivity with excitatory and inhibitory cell populations in the hippocampus. J Neurosci. 2015;35:10600–12.

    CAS  PubMed  Google Scholar 

  38. 38.

    Parent JM, Yu TW, Leibowitz RT, Geschwind DH, Sloviter RS, Lowenstein DH. Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci. 1997;17:3727–38.

    CAS  PubMed  Google Scholar 

  39. 39.

    Li G, Bien-Ly N, Andrews-Zwilling Y, Xu Q, Bernardo A, Ring K, et al. GABAergic interneuron dysfunction impairs hippocampal neurogenesis in adult apolipoprotein E4 knockin mice. Cell Stem Cell. 2009;5:634–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Marin-Burgin A, Mongiat LA, Pardi MB, Schinder AF. Unique processing during a period of high excitation/inhibition balance in adult-born neurons. Science. 2012;335:1238–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Schmidt-Hieber C, Jonas P, Bischofberger J. Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature. 2004;429:184–7.

    CAS  PubMed  Google Scholar 

  42. 42.

    Mongiat LA, Esposito MS, Lombardi G, Schinder AF. Reliable activation of immature neurons in the adult hippocampus. PLoS One. 2009;4:e5320.

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Danielson NB, Kaifosh P, Zaremba JD, Lovett-Barron M, Tsai J, Denny CA, et al. Distinct contribution of adult-born hippocampal granule cells to context encoding. Neuron. 2016;90:101–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Stone SS, Teixeira CM, Zaslavsky K, Wheeler AL, Martinez-Canabal A, Wang AH, et al. Functional convergence of developmentally and adult-generated granule cells in dentate gyrus circuits supporting hippocampus-dependent memory. Hippocampus. 2011;21:1348–62.

    PubMed  Google Scholar 

  45. 45.

    Dieni CV, Nietz AK, Panichi R, Wadiche JI, Overstreet-Wadiche L. Distinct determinants of sparse activation during granule cell maturation. J Neurosci. 2013;33:19131–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Ikrar T, Guo N, He K, Besnard A, Levinson S, Hill A, et al. Adult neurogenesis modifies excitability of the dentate gyrus. Front Neural Circuits. 2013;7:204.

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Burghardt NS, Park EH, Hen R, Fenton AA. Adult-born hippocampal neurons promote cognitive flexibility in mice. Hippocampus. 2012;22:1795–808.

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    Drew LJ, Kheirbek MA, Luna VM, Denny CA, Cloidt MA, Wu MV, et al. Activation of local inhibitory circuits in the dentate gyrus by adult-born neurons. Hippocampus. 2016;26:763–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    McAvoy KM, Scobie KN, Berger S, Russo C, Guo N, Decharatanachart P, et al. Modulating neuronal competition dynamics in the dentate gyrus to rejuvenate aging memory circuits. Neuron. 2016;91:1356–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Niibori Y, Yu TS, Epp JR, Akers KG, Josselyn SA, Frankland PW. Suppression of adult neurogenesis impairs population coding of similar contexts in hippocampal CA3 region. Nat Commun. 2012;3:1253.

    PubMed  PubMed Central  Google Scholar 

  51. 51.

    Temprana SG, Mongiat LA, Yang SM, Trinchero MF, Alvarez DD, Kropff E, et al. Delayed coupling to feedback inhibition during a critical period for the integration of adult-born granule cells. Neuron. 2015;85:116–30.

    CAS  PubMed  Google Scholar 

  52. 52.

    Adlaf EW, Vaden RJ, Niver AJ, Manuel AF, Onyilo VC, Araujo MT et al. Adult-born neurons modify excitatory synaptic transmission to existing neurons. Elife. 2017;6:e19886.

  53. 53.

    Marr D. Simple memory: a theory for archicortex. Philos Trans R Soc Lond B Biol Sci. 1971;262:23–81.

    CAS  PubMed  Google Scholar 

  54. 54.

    Rolls ET, Kesner RP. A computational theory of hippocampal function, and empirical tests of the theory. Prog Neurobiol. 2006;79:1–48.

    CAS  PubMed  Google Scholar 

  55. 55.

    Jung HJ, Lee JM, Yang SH, Young SG, Fong LG. Nuclear lamins in the brain—new insights into function and regulation. Mol Neurobiol. 2013;47:290–301.

    CAS  PubMed  Google Scholar 

  56. 56.

    Jung MW, McNaughton BL. Spatial selectivity of unit activity in the hippocampal granular layer. Hippocampus. 1993;3:165–82.

    CAS  PubMed  Google Scholar 

  57. 57.

    Chawla MK, Guzowski JF, Ramirez-Amaya V, Lipa P, Hoffman KL, Marriott LK, et al. Sparse, environmentally selective expression of Arc RNA in the upper blade of the rodent fascia dentata by brief spatial experience. Hippocampus. 2005;15:579–86.

    CAS  PubMed  Google Scholar 

  58. 58.

    Leutgeb JK, Leutgeb S, Moser MB, Moser EI. Pattern separation in the dentate gyrus and CA3 of the hippocampus. Science. 2007;315:961–6.

    CAS  PubMed  Google Scholar 

  59. 59.

    Deng W, Mayford M, Gage FH. Selection of distinct populations of dentate granule cells in response to inputs as a mechanism for pattern separation in mice. Elife. 2013;2:e00312.

    PubMed  PubMed Central  Google Scholar 

  60. 60.

    McNaughton BL, Morris RG. Hippocampal synaptic enhancement and information storage within a distributed memory system. Trends Neurosci. 1987;10:408–15.

    Google Scholar 

  61. 61.

    Tronel S, Belnoue L, Grosjean N, Revest JM, Piazza PV, Koehl M, et al. Adult-born neurons are necessary for extended contextual discrimination. Hippocampus. 2012;22:292–8.

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    Nakashiba T, Cushman JD, Pelkey KA, Renaudineau S, Buhl DL, McHugh TJ, et al. Young dentate granule cells mediate pattern separation, whereas old granule cells facilitate pattern completion. Cell. 2012;149:188–201.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Clelland CD, Choi M, Romberg C, Clemenson GD Jr., Fragniere A, Tyers P, et al. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science. 2009;325:210–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Bekinschtein P, Kent BA, Oomen CA, Clemenson GD, Gage FH, Saksida LM, et al. Brain-derived neurotrophic factor interacts with adult-born immature cells in the dentate gyrus during consolidation of overlapping memories. Hippocampus. 2014;24:905–11.

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    Garthe A, Behr J, Kempermann G. Adult-generated hippocampal neurons allow the flexible use of spatially precise learning strategies. PLoS One. 2009;4:e5464.

    PubMed  PubMed Central  Google Scholar 

  66. 66.

    Park EH, Burghardt NS, Dvorak D, Hen R, Fenton AA. Experience-dependent regulation of dentate gyrus excitability by adult-born granule cells. J Neurosci. 2015;35:11656–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Swan AA, Clutton JE, Chary PK, Cook SG, Liu GG, Drew MR. Characterization of the role of adult neurogenesis in touch-screen discrimination learning. Hippocampus. 2014;24:1581–91.

    PubMed  PubMed Central  Google Scholar 

  68. 68.

    Creer DJ, Romberg C, Saksida LM, van Praag H, Bussey TJ. Running enhances spatial pattern separation in mice. Proc Natl Acad Sci USA. 2010;107:2367–72.

    CAS  PubMed  Google Scholar 

  69. 69.

    Sahay A, Scobie KN, Hill AS, O’Carroll CM, Kheirbek MA, Burghardt NS, et al. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature. 2011;472:466–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Franca TFA, Bitencourt AM, Maximilla NR, Barros DM, Monserrat JM. Hippocampal neurogenesis and pattern separation: a meta-analysis of behavioral data. Hippocampus. 2017;27:937–50.

    PubMed  Google Scholar 

  71. 71.

    Deng W, Saxe MD, Gallina IS, Gage FH. Adult-born hippocampal dentate granule cells undergoing maturation modulate learning and memory in the brain. J Neurosci. 2009;29:13532–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Jessberger S, Clark RE, Broadbent NJ, Clemenson GD Jr, Consiglio A, Lie DC, et al. Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats. Learn Mem. 2009;16:147–54.

    PubMed  PubMed Central  Google Scholar 

  73. 73.

    Dupret D, Revest JM, Koehl M, Ichas F, De Giorgi F, Costet P, et al. Spatial relational memory requires hippocampal adult neurogenesis. PLoS One. 2008;3:e1959.

    PubMed  PubMed Central  Google Scholar 

  74. 74.

    Wojtowicz JM, Askew ML, Winocur G. The effects of running and of inhibiting adult neurogenesis on learning and memory in rats. Eur J Neurosci. 2008;27:1494–502.

    PubMed  Google Scholar 

  75. 75.

    Denny CA, Burghardt NS, Schachter DM, Hen R, Drew MR. 4- to 6-week-old adult-born hippocampal neurons influence novelty-evoked exploration and contextual fear conditioning. Hippocampus. 2012;22:1188–201.

    PubMed  Google Scholar 

  76. 76.

    Clemenson GD, Lee SW, Deng W, Barrera VR, Iwamoto KS, Fanselow MS, et al. Enrichment rescues contextual discrimination deficit associated with immediate shock. Hippocampus. 2015;25:385–92.

    PubMed  Google Scholar 

  77. 77.

    Denny CA, Kheirbek MA, Alba EL, Tanaka KF, Brachman RA, Laughman KB, et al. Hippocampal memory traces are differentially modulated by experience, time, and adult neurogenesis. Neuron. 2014;83:189–201.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Aimone JB. Computational modeling of adult neurogenesis. Cold Spring Harb Perspect Biol. 2016;8:a018960.

    PubMed  PubMed Central  Google Scholar 

  79. 79.

    Besnard A, Sahay A. Adult hippocampal neurogenesis, fear generalization, and stress. Neuropsychopharmacology. 2016;41:24–44.

    Google Scholar 

  80. 80.

    Luu P, Sill OC, Gao L, Becker S, Wojtowicz JM, Smith DM. The role of adult hippocampal neurogenesis in reducing interference. Behav Neurosci. 2012;126:381–91.

    PubMed  PubMed Central  Google Scholar 

  81. 81.

    Becker S. Neurogenesis and pattern separation: time for a divorce. Wiley Interdiscip Rev Cogn Sci 2017;8:e1427.

    Google Scholar 

  82. 82.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Epp JR, Silva Mera R, Kohler S, Josselyn SA, Frankland PW. Neurogenesis-mediated forgetting minimizes proactive interference. Nat Commun. 2016;7:10838.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Encinas JM, Michurina TV, Peunova N, Park JH, Tordo J, Peterson DA, et al. Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell. 2011;8:566–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Aizawa K, Ageyama N, Yokoyama C, Hisatsune T. Age-dependent alteration in hippocampal neurogenesis correlates with learning performance of macaque monkeys. Exp Anim. 2009;58:403–7.

    CAS  PubMed  Google Scholar 

  86. 86.

    Amrein I, Isler K, Lipp HP. Comparing adult hippocampal neurogenesis in mammalian species and orders: influence of chronological age and life history stage. Eur J Neurosci. 2011;34:978–87.

    PubMed  Google Scholar 

  87. 87.

    Patzke N, Spocter MA, Karlsson KAE, Bertelsen MF, Haagensen M, Chawana R, et al. In contrast to many other mammals, cetaceans have relatively small hippocampi that appear to lack adult neurogenesis. Brain Struct Funct. 2015;220:361–83.

    PubMed  Google Scholar 

  88. 88.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Yassa MA, Mattfeld AT, Stark SM, Stark CE. Age-related memory deficits linked to circuit-specific disruptions in the hippocampus. Proc Natl Acad Sci USA. 2011;108:8873–8.

    CAS  PubMed  Google Scholar 

  90. 90.

    Yassa MA, Lacy JW, Stark SM, Albert MS, Gallagher M, Stark CE. Pattern separation deficits associated with increased hippocampal CA3 and dentate gyrus activity in nondemented older adults. Hippocampus. 2011;21:968–79.

    Google Scholar 

  91. 91.

    Manganas LN, Zhang X, Li Y, Hazel RD, Smith SD, Wagshul ME, et al. Magnetic resonance spectroscopy identifies neural progenitor cells in the live human brain. Science. 2007;318:980–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Tamura Y, Takahashi K, Takata K, Eguchi A, Yamato M, Kume S, et al. Noninvasive Evaluation of Cellular Proliferative Activity in Brain Neurogenic Regions in Rats under Depression and Treatment by Enhanced [18F]FLT-PET Imaging. J Neurosci. 2016;36:8123–31.

    CAS  PubMed  Google Scholar 

  93. 93.

    Kempermann G, Kuhn HG, Gage FH. Experience-induced neurogenesis in the senescent dentate gyrus. J Neurosci. 1998;18:3206–12.

    CAS  PubMed  Google Scholar 

  94. 94.

    Itou Y, Nochi R, Kuribayashi H, Saito Y, Hisatsune T. Cholinergic activation of hippocampal neural stem cells in aged dentate gyrus. Hippocampus. 2011;21:446–59.

    CAS  PubMed  Google Scholar 

  95. 95.

    Kempermann G, Gast D, Gage FH. Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment. Ann Neurol. 2002;52:135–43.

    PubMed  Google Scholar 

  96. 96.

    van Praag H, Shubert T, Zhao C, Gage FH. Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci. 2005;25:8680–5.

    PubMed  PubMed Central  Google Scholar 

  97. 97.

    Meyers EA, Gobeske KT, Bond AM, Jarrett JC, Peng CY, Kessler JA. Increased bone morphogenetic protein signaling contributes to age-related declines in neurogenesis and cognition. Neurobiol Aging. 2016;38:164–75.

    CAS  PubMed  Google Scholar 

  98. 98.

    Yousef H, Morgenthaler A, Schlesinger C, Bugaj L, Conboy IM, Schaffer DV. Age-Associated Increase in BMP Signaling Inhibits Hippocampal Neurogenesis. Stem Cells. 2015;33:1577–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011;477:90–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Huh GS, Boulanger LM, Du H, Riquelme PA, Brotz TM, Shatz CJ. Functional requirement for class I MHC in CNS development and plasticity. Science. 2000;290:2155–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Corriveau RA, Huh GS, Shatz CJ. Regulation of class I MHC gene expression in the developing and mature CNS by neural activity. Neuron. 1998;21:505–20.

    CAS  PubMed  Google Scholar 

  102. 102.

    Smith LK, He Y, Park JS, Bieri G, Snethlage CE, Lin K, et al. beta2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis. Nat Med. 2015;21:932–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med. 2014;20:659–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Castellano JM, Mosher KI, Abbey RJ, McBride AA, James ML, Berdnik D, et al. Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature. 2017;544:488–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Sasaguri H, Nilsson P, Hashimoto S, Nagata K, Saito T, De Strooper B, et al. APP mouse models for Alzheimer’s disease preclinical studies. EMBO J. 2017;36:2473–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Khan UA, Liu L, Provenzano FA, Berman DE, Profaci CP, Sloan R, et al. Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer’s disease. Nat Neurosci. 2014;17:304–11.

    CAS  PubMed  Google Scholar 

  107. 107.

    Boekhoorn K, Joels M, Lucassen PJ. Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus. Neurobiol Dis. 2006;24:1–14.

    CAS  PubMed  Google Scholar 

  108. 108.

    Crews L, Adame A, Patrick C, Delaney A, Pham E, Rockenstein E, et al. Increased BMP6 levels in the brains of Alzheimer’s disease patients and APP transgenic mice are accompanied by impaired neurogenesis. J Neurosci. 2010;30:12252–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Li B, Yamamori H, Tatebayashi Y, Shafit-Zagardo B, Tanimukai H, Chen S, et al. Failure of neuronal maturation in Alzheimer disease dentate gyrus. J Neuropathol Exp Neurol. 2008;67:78–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Jin K, Peel AL, Mao XO, Xie L, Cottrell BA, Henshall DC, et al. Increased hippocampal neurogenesis in Alzheimer’s disease. Proc Natl Acad Sci USA. 2004;101:343–7.

    CAS  PubMed  Google Scholar 

  111. 111.

    Feng R, Rampon C, Tang YP, Shrom D, Jin J, Kyin M, et al. Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces. Neuron. 2001;32:911–26.

    CAS  PubMed  Google Scholar 

  112. 112.

    Haughey NJ, Nath A, Chan SL, Borchard AC, Rao MS, Mattson MP. Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer’s disease. J Neurochem. 2002;83:1509–24.

    CAS  PubMed  Google Scholar 

  113. 113.

    Donovan MH, Yazdani U, Norris RD, Games D, German DC, Eisch AJ. Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer’s disease. J Comp Neurol. 2006;495:70–83.

    PubMed  Google Scholar 

  114. 114.

    Dong H, Goico B, Martin M, Csernansky CA, Bertchume A, Csernansky JG. Modulation of hippocampal cell proliferation, memory, and amyloid plaque deposition in APPsw (Tg2576) mutant mice by isolation stress. Neuroscience. 2004;127:601–9.

    CAS  PubMed  Google Scholar 

  115. 115.

    Wang R, Dineley KT, Sweatt JD, Zheng H. Presenilin 1 familial Alzheimer’s disease mutation leads to defective associative learning and impaired adult neurogenesis. Neuroscience. 2004;126:305–12.

    CAS  PubMed  Google Scholar 

  116. 116.

    Rodriguez JJ, Jones VC, Tabuchi M, Allan SM, Knight EM, LaFerla FM, et al. Impaired adult neurogenesis in the dentate gyrus of a triple transgenic mouse model of Alzheimer’s disease. PLoS One. 2008;3:e2935.

    PubMed  PubMed Central  Google Scholar 

  117. 117.

    Zhang C, McNeil E, Dressler L, Siman R. Long-lasting impairment in hippocampal neurogenesis associated with amyloid deposition in a knock-in mouse model of familial Alzheimer’s disease. Exp Neurol. 2007;204:77–87.

    CAS  PubMed  Google Scholar 

  118. 118.

    Mirochnic S, Wolf S, Staufenbiel M, Kempermann G. Age effects on the regulation of adult hippocampal neurogenesis by physical activity and environmental enrichment in the APP23 mouse model of Alzheimer disease. Hippocampus. 2009;19:1008–18.

    CAS  PubMed  Google Scholar 

  119. 119.

    Hoglinger GU, Rizk P, Muriel MP, Duyckaerts C, Oertel WH, Caille I, et al. Dopamine depletion impairs precursor cell proliferation in Parkinson disease. Nat Neurosci. 2004;7:726–35.

    PubMed  Google Scholar 

  120. 120.

    Winner B, Regensburger M, Schreglmann S, Boyer L, Prots I, Rockenstein E, et al. Role of alpha-synuclein in adult neurogenesis and neuronal maturation in the dentate gyrus. J Neurosci. 2012;32:16906–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Agnihotri SK, Shen R, Li J, Gao X, Bueler H. Loss of PINK1 leads to metabolic deficits in adult neural stem cells and impedes differentiation of newborn neurons in the mouse hippocampus. FASEB J. 2017;31:2839–53.

    CAS  PubMed  Google Scholar 

  122. 122.

    Winner B, Lie DC, Rockenstein E, Aigner R, Aigner L, Masliah E, et al. Human wild-type alpha-synuclein impairs neurogenesis. J Neuropathol Exp Neurol. 2004;63:1155–66.

    CAS  PubMed  Google Scholar 

  123. 123.

    Nuber S, Petrasch-Parwez E, Winner B, Winkler J, von Horsten S, Schmidt T, et al. Neurodegeneration and motor dysfunction in a conditional model of Parkinson’s disease. J Neurosci. 2008;28:2471–84.

    CAS  PubMed  Google Scholar 

  124. 124.

    Crews L, Mizuno H, Desplats P, Rockenstein E, Adame A, Patrick C, et al. Alpha-synuclein alters Notch-1 expression and neurogenesis in mouse embryonic stem cells and in the hippocampus of transgenic mice. J Neurosci. 2008;28:4250–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301:805–9.

    CAS  Google Scholar 

  126. 126.

    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.

    PubMed  Google Scholar 

  127. 127.

    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.

    CAS  PubMed  Google Scholar 

  128. 128.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Anacker C, Zunszain PA, Cattaneo A, Carvalho LA, Garabedian MJ, Thuret S, et al. Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor. Mol Psychiatry. 2011;16:738–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Perera TD, Coplan JD, Lisanby SH, Lipira CM, Arif M, Carpio C, et al. Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates. J Neurosci. 2007;27:4894–901.

    CAS  PubMed  Google Scholar 

  132. 132.

    Boldrini M, Santiago AN, Hen R, Dwork AJ, Rosoklija GB, Tamir H, et al. Hippocampal granule neuron number and dentate gyrus volume in antidepressant-treated and untreated major depression. Neuropsychopharmacology. 2013;38:1068–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    David DJ, Samuels BA, Rainer Q, Wang JW, Marsteller D, Mendez I, et al. Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron. 2009;62:479–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Surget A, Saxe M, Leman S, Ibarguen-Vargas Y, Chalon S, Griebel G, et al. Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal. Biol Psychiatry. 2008;64:293–301.

    CAS  PubMed  Google Scholar 

  135. 135.

    Huang GJ, Bannerman D, Flint J. Chronic fluoxetine treatment alters behavior, but not adult hippocampal neurogenesis, in BALB/cJ mice. Mol Psychiatry. 2008;13:119–21.

    CAS  PubMed  Google Scholar 

  136. 136.

    Holick KA, Lee DC, Hen R, Dulawa SC. Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor. Neuropsychopharmacology. 2008;33:406–17.

    CAS  PubMed  Google Scholar 

  137. 137.

    Lehmann ML, Brachman RA, Martinowich K, Schloesser RJ, Herkenham M. Glucocorticoids orchestrate divergent effects on mood through adult neurogenesis. J Neurosci. 2013;33:2961–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Coe CL, Kramer M, Czeh B, Gould E, Reeves AJ, Kirschbaum C, et al. Prenatal stress diminishes neurogenesis in the dentate gyrus of juvenile rhesus monkeys. Biol Psychiatry. 2003;54:1025–34.

    CAS  PubMed  Google Scholar 

  139. 139.

    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.

    CAS  PubMed  Google Scholar 

  140. 140.

    Tanti A, Rainer Q, Minier F, Surget A, Belzung C. Differential environmental regulation of neurogenesis along the septo-temporal axis of the hippocampus. Neuropharmacology. 2012;63:374–84.

    CAS  PubMed  Google Scholar 

  141. 141.

    Cameron HA, Gould E. Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus. Neuroscience. 1994;61:203–9.

    CAS  PubMed  Google Scholar 

  142. 142.

    Bessa JM, Ferreira D, Melo I, Marques F, Cerqueira JJ, Palha JA, et al. The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Mol Psychiatry. 2009;14:764–73. 739

    CAS  PubMed  Google Scholar 

  143. 143.

    Surget A, Tanti A, Leonardo ED, Laugeray A, Rainer Q, Touma C, et al. Antidepressants recruit new neurons to improve stress response regulation. Mol Psychiatry. 2011;16:1177–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Hill AS, Sahay A, Hen R. Increasing adult hippocampal neurogenesis is sufficient to reduce anxiety and depression-like behaviors. Neuropsychopharmacology. 2015;40:2368–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Revest JM, Dupret D, Koehl M, Funk-Reiter C, Grosjean N, Piazza PV, et al. Adult hippocampal neurogenesis is involved in anxiety-related behaviors. Mol Psychiatry. 2009;14:959–67.

    PubMed  PubMed Central  Google Scholar 

  146. 146.

    Tsai CY, Tsai CY, Arnold SJ, Huang GJ. Ablation of hippocampal neurogenesis in mice impairs the response to stress during the dark cycle. Nat Commun. 2015;6:8373.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Saxe MD, Battaglia F, Wang JW, Malleret G, David DJ, Monckton JE, et al. Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc Natl Acad Sci USA. 2006;103:17501–6.

    CAS  PubMed  Google Scholar 

  148. 148.

    Kitamura T, Saitoh Y, Takashima N, Murayama A, Niibori Y, Ageta H, et al. Adult neurogenesis modulates the hippocampus-dependent period of associative fear memory. Cell. 2009;139:814–27.

    CAS  PubMed  Google Scholar 

  149. 149.

    Deng W, Gage FH. The effect of immature adult-born dentate granule cells on hyponeophagial behavior is related to their roles in learning and memory. Front Syst Neurosci. 2015;9:34.

    PubMed  PubMed Central  Google Scholar 

  150. 150.

    Okuyama T, Kitamura T, Roy DS, Itohara S, Tonegawa S. Ventral CA1 neurons store social memory. Science. 2016;353:1536–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Kheirbek MA, Drew LJ, Burghardt NS, Costantini DO, Tannenholz L, Ahmari SE, et al. Differential control of learning and anxiety along the dorsoventral axis of the dentate gyrus. Neuron. 2013;77:955–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152.

    Ally BA, Hussey EP, Ko PC, Molitor RJ. Pattern separation and pattern completion in Alzheimer’s disease: evidence of rapid forgetting in amnestic mild cognitive impairment. Hippocampus. 2013;23:1246–58.

    PubMed  PubMed Central  Google Scholar 

  153. 153.

    Huffman DJ, Stark CE. Age-related impairment on a forced-choice version of the Mnemonic Similarity Task. Behav Neurosci. 2017;131:55–67.

    PubMed  Google Scholar 

  154. 154.

    Pereira Dias G, Hollywood R, Bevilaqua MC, da Luz AC, Hindges R, Nardi AE, et al. Consequences of cancer treatments on adult hippocampal neurogenesis: implications for cognitive function and depressive symptoms. Neuro Oncol. 2014;16:476–92.

    PubMed  PubMed Central  Google Scholar 

  155. 155.

    Parent JM, Elliott RC, Pleasure SJ, Barbaro NM, Lowenstein DH. Aberrant seizure-induced neurogenesis in experimental temporal lobe epilepsy. Ann Neurol. 2006;59:81–91.

    PubMed  Google Scholar 

  156. 156.

    Jessberger S, Romer B, Babu H, Kempermann G. Seizures induce proliferation and dispersion of doublecortin-positive hippocampal progenitor cells. Exp Neurol. 2005;196:342–51.

    CAS  PubMed  Google Scholar 

  157. 157.

    Bengzon J, Kokaia Z, Elmer E, Nanobashvili A, Kokaia M, Lindvall O. Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures. Proc Natl Acad Sci USA. 1997;94:10432–7.

    CAS  PubMed  Google Scholar 

  158. 158.

    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.

    CAS  PubMed  Google Scholar 

  159. 159.

    Huttmann K, Sadgrove M, Wallraff A, Hinterkeuser S, Kirchhoff F, Steinhauser C, et al. Seizures preferentially stimulate proliferation of radial glia-like astrocytes in the adult dentate gyrus: functional and immunocytochemical analysis. Eur J Neurosci. 2003;18:2769–78.

    PubMed  Google Scholar 

  160. 160.

    Sierra A, Martin-Suarez S, Valcarcel-Martin R, Pascual-Brazo J, Aelvoet SA, Abiega O, et al. Neuronal hyperactivity accelerates depletion of neural stem cells and impairs hippocampal neurogenesis. Cell Stem Cell. 2015;16:488–503.

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161.

    Hattiangady B, Rao MS, Shetty AK. Chronic temporal lobe epilepsy is associated with severely declined dentate neurogenesis in the adult hippocampus. Neurobiol Dis. 2004;17:473–90.

    CAS  PubMed  Google Scholar 

  162. 162.

    Ribak CE, Tran PH, Spigelman I, Okazaki MM, Nadler JV. Status epilepticus-induced hilar basal dendrites on rodent granule cells contribute to recurrent excitatory circuitry. J Comp Neurol. 2000;428:240–53.

    CAS  PubMed  Google Scholar 

  163. 163.

    Shapiro LA, Ribak CE. Newly born dentate granule neurons after pilocarpine-induced epilepsy have hilar basal dendrites with immature synapses. Epilepsy Res. 2006;69:53–66.

    PubMed  Google Scholar 

  164. 164.

    Scharfman HE, Goodman JH, Sollas AL. Granule-like neurons at the hilar/CA3 border after status epilepticus and their synchrony with area CA3 pyramidal cells: functional implications of seizure-induced neurogenesis. J Neurosci. 2000;20:6144–58.

    CAS  PubMed  Google Scholar 

  165. 165.

    Gong C, Wang TW, Huang HS, Parent JM. Reelin regulates neuronal progenitor migration in intact and epileptic hippocampus. J Neurosci. 2007;27:1803–11.

    CAS  PubMed  Google Scholar 

  166. 166.

    Overstreet-Wadiche LS, Bromberg DA, Bensen AL, Westbrook GL. Seizures accelerate functional integration of adult-generated granule cells. J Neurosci. 2006;26:4095–103.

    CAS  PubMed  Google Scholar 

  167. 167.

    Pun RY, Rolle IJ, Lasarge CL, Hosford BE, Rosen JM, Uhl JD, et al. Excessive activation of mTOR in postnatally generated granule cells is sufficient to cause epilepsy. Neuron. 2012;75:1022–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168.

    Kron MM, Zhang H, Parent JM. The developmental stage of dentate granule cells dictates their contribution to seizure-induced plasticity. J Neurosci. 2010;30:2051–9.

    CAS  PubMed  Google Scholar 

  169. 169.

    Jessberger S, Zhao C, Toni N, Clemenson GD,Jr., Li Y, Gage FH. Seizure-associated, aberrant neurogenesis in adult rats characterized with retrovirus-mediated cell labeling. J Neurosci. 2007;27:9400–7.

    CAS  PubMed  Google Scholar 

  170. 170.

    Cho KO, Lybrand ZR, Ito N, Brulet R, Tafacory F, Zhang L, et al. Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. Nat Commun. 2015;6:6606.

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171.

    Bredenoord AL, Clevers H, Knoblich JA. Human tissues in a dish: The research and ethical implications of organoid technology. Science. 2017;355,eaaf9414.

    PubMed  Google Scholar 

  172. 172.

    Sakaguchi H, Kadoshima T, Soen M, Narii N, Ishida Y, Ohgushi M, et al. Generation of functional hippocampal neurons from self-organizing human embryonic stem cell-derived dorsomedial telencephalic tissue. Nat Commun. 2015;6:8896.

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173.

    Muotri AR, Marchetto MC, Coufal NG, Oefner R, Yeo G, Nakashima K, et al. L1 retrotransposition in neurons is modulated by MeCP2. Nature. 2010;468:443–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174.

    Rehen SK, McConnell MJ, Kaushal D, Kingsbury MA, Yang AH, Chun J. Chromosomal variation in neurons of the developing and adult mammalian nervous system. Proc Natl Acad Sci USA. 2001;98:13361–6.

    CAS  PubMed  Google Scholar 

  175. 175.

    Westra JW, Peterson SE, Yung YC, Mutoh T, Barral S, Chun J. Aneuploid mosaicism in the developing and adult cerebellar cortex. J Comp Neurol. 2008;507:1944–51.

    PubMed  Google Scholar 

  176. 176.

    McConnell MJ, Moran JV, Abyzov A, Akbarian S, Bae T, Cortes-Ciriano I et al. Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network. Science. 2017;356,eaal1641.

    PubMed  PubMed Central  Google Scholar 

  177. 177.

    Lodato MA, Woodworth MB, Lee S, Evrony GD, Mehta BK, Karger A, et al. Somatic mutation in single human neurons tracks developmental and transcriptional history. Science. 2015;350:94–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178.

    Kaushal D, Contos JJ, Treuner K, Yang AH, Kingsbury MA, Rehen SK, et al. Alteration of gene expression by chromosome loss in the postnatal mouse brain. J Neurosci. 2003;23:5599–606.

    CAS  PubMed  Google Scholar 

  179. 179.

    Knouse KA, Wu J, Whittaker CA, Amon A. Single cell sequencing reveals low levels of aneuploidy across mammalian tissues. Proc Natl Acad Sci USA. 2014;111:13409–14.

    CAS  PubMed  Google Scholar 

  180. 180.

    van den Bos H, Spierings DC, Taudt AS, Bakker B, Porubsky D, Falconer E, et al. Single-cell whole genome sequencing reveals no evidence for common aneuploidy in normal and Alzheimer’s disease neurons. Genome Biol. 2016;17:116.

    PubMed  PubMed Central  Google Scholar 

  181. 181.

    Vitak SA, Torkenczy KA, Rosenkrantz JL, Fields AJ, Christiansen L, Wong MH, et al. Sequencing thousands of single-cell genomes with combinatorial indexing. Nat Methods. 2017;14:302–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182.

    McConnell MJ, Kaushal D, Yang AH, Kingsbury MA, Rehen SK, Treuner K, et al. Failed clearance of aneuploid embryonic neural progenitor cells leads to excess aneuploidy in the Atm-deficient but not the Trp53-deficient adult cerebral cortex. J Neurosci. 2004;24:8090–6.

    CAS  PubMed  Google Scholar 

  183. 183.

    Cai X, Evrony GD, Lehmann HS, Elhosary PC, Mehta BK, Poduri A, et al. Single-cell, genome-wide sequencing identifies clonal somatic copy-number variation in the human brain. Cell Rep. 2014;8:1280–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184.

    Knouse KA, Wu J, Amon A. Assessment of megabase-scale somatic copy number variation using single-cell sequencing. Genome Res. 2016;26:376–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  185. 185.

    Wei PC, Chang AN, Kao J, Du Z, Meyers RM, Alt FW, et al. Long neural genes harbor recurrent DNA Break clusters in neural stem/progenitor cells. Cell. 2016;164:644–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  186. 186.

    Schwer B, Wei PC, Chang AN, Kao J, Du Z, Meyers RM, et al. Transcription-associated processes cause DNA double-strand breaks and translocations in neural stem/progenitor cells. Proc Natl Acad Sci USA. 2016;113:2258–63.

    CAS  PubMed  Google Scholar 

  187. 187.

    Muotri AR, Chu VT, Marchetto MC, Deng W, Moran JV, Gage FH. Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition. Nature. 2005;435:903–10.

    CAS  PubMed  Google Scholar 

  188. 188.

    Bundo M, Toyoshima M, Okada Y, Akamatsu W, Ueda J, Nemoto-Miyauchi T, et al. Increased l1 retrotransposition in the neuronal genome in schizophrenia. Neuron. 2014;81:306–13.

    CAS  PubMed  Google Scholar 

  189. 189.

    Mira H, Andreu Z, Suh H, Lie DC, Jessberger S, Consiglio A, et al. Signaling through BMPR-IA regulates quiescence and long-term activity of neural stem cells in the adult hippocampus. Cell Stem Cell. 2010;7:78–89.

    CAS  PubMed  Google Scholar 

  190. 190.

    Bonaguidi MA, Peng CY, McGuire T, Falciglia G, Gobeske KT, Czeisler C, et al. Noggin expands neural stem cells in the adult hippocampus. J Neurosci. 2008;28:9194–204.

    CAS  PubMed  PubMed Central  Google Scholar 

  191. 191.

    Martynoga B, Mateo JL, Zhou B, Andersen J, Achimastou A, Urban N, et al. Epigenomic enhancer annotation reveals a key role for NFIX in neural stem cell quiescence. Genes Dev. 2013;27:1769–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 192.

    Brooker SM, Gobeske KT, Chen J, Peng CY, Kessler JA. Hippocampal bone morphogenetic protein signaling mediates behavioral effects of antidepressant treatment. Mol Psychiatry. 2017;22:910–9.

    CAS  PubMed  Google Scholar 

  193. 193.

    Kirby ED, Kuwahara AA, Messer RL, Wyss-Coray T. Adult hippocampal neural stem and progenitor cells regulate the neurogenic niche by secreting VEGF. Proc Natl Acad Sci USA. 2015;112:4128–33.

    CAS  PubMed  Google Scholar 

  194. 194.

    Ahn S, Joyner AL. In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog. Nature. 2005;437:894–7.

    CAS  PubMed  Google Scholar 

  195. 195.

    Breunig JJ, Sarkisian MR, Arellano JI, Morozov YM, Ayoub AE, Sojitra S, et al. Primary cilia regulate hippocampal neurogenesis by mediating sonic hedgehog signaling. Proc Natl Acad Sci USA. 2008;105:13127–32.

    CAS  PubMed  Google Scholar 

  196. 196.

    Han YG, Spassky N, Romaguera-Ros M, Garcia-Verdugo JM, Aguilar A, Schneider-Maunoury S, et al. Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nat Neurosci. 2008;11:277–84.

    CAS  PubMed  Google Scholar 

  197. 197.

    Li G, Fang L, Fernandez G, Pleasure SJ. The ventral hippocampus is the embryonic origin for adult neural stem cells in the dentate gyrus. Neuron. 2013;78:658–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  198. 198.

    Bracko O, Singer T, Aigner S, Knobloch M, Winner B, Ray J, et al. Gene expression profiling of neural stem cells and their neuronal progeny reveals IGF2 as a regulator of adult hippocampal neurogenesis. J Neurosci. 2012;32:3376–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  199. 199.

    Gage FH, Coates PW, Palmer TD, Kuhn HG, Fisher LJ, Suhonen JO, et al. Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc Natl Acad Sci USA. 1995;92:11879–83.

    CAS  PubMed  Google Scholar 

  200. 200.

    Kuhn HG, Winkler J, Kempermann G, Thal LJ, Gage FH. Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain. J Neurosci. 1997;17:5820–9.

    CAS  PubMed  Google Scholar 

  201. 201.

    Ray J, Gage FH. Differential properties of adult rat and mouse brain-derived neural stem/progenitor cells. Mol Cell Neurosci. 2006;31:560–73.

    CAS  PubMed  Google Scholar 

  202. 202.

    Pan YW, Zou J, Wang W, Sakagami H, Garelick MG, Abel G, et al. Inducible and conditional deletion of extracellular signal-regulated kinase 5 disrupts adult hippocampal neurogenesis. J Biol Chem. 2012;287:23306–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  203. 203.

    Lie DC, Colamarino SA, Song HJ, Desire L, Mira H, Consiglio A, et al. Wnt signalling regulates adult hippocampal neurogenesis. Nature. 2005;437:1370–5.

    CAS  PubMed  Google Scholar 

  204. 204.

    Kuwabara T, Hsieh J, Muotri A, Yeo G, Warashina M, Lie DC, et al. Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis. Nat Neurosci. 2009;12:1097–105.

    CAS  PubMed  PubMed Central  Google Scholar 

  205. 205.

    Karalay O, Doberauer K, Vadodaria KC, Knobloch M, Berti L, Miquelajauregui A, 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. 2011;108:5807–12.

    CAS  PubMed  Google Scholar 

  206. 206.

    Hsieh J, Aimone JB, Kaspar BK, Kuwabara T, Nakashima K, Gage FH. IGF-I instructs multipotent adult neural progenitor cells to become oligodendrocytes. J Cell Biol. 2004;164:111–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  207. 207.

    Aberg MA, Aberg ND, Hedbacker H, Oscarsson J, Eriksson PS. Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus. J Neurosci. 2000;20:2896–903.

    CAS  PubMed  Google Scholar 

  208. 208.

    Li Y, Luikart BW, Birnbaum S, Chen J, Kwon CH, Kernie SG, et al. TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment. Neuron. 2008;59:399–412.

    CAS  PubMed  PubMed Central  Google Scholar 

  209. 209.

    Bond AM, Peng CY, Meyers EA, McGuire T, Ewaleifoh O, Kessler JA. BMP signaling regulates the tempo of adult hippocampal progenitor maturation at multiple stages of the lineage. Stem Cells. 2014;32:2201–14.

    CAS  PubMed  Google Scholar 

  210. 210.

    Eisch AJ, Barrot M, Schad CA, Self DW, Nestler EJ. Opiates inhibit neurogenesis in the adult rat hippocampus. Proc Natl Acad Sci USA. 2000;97:7579–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  211. 211.

    Schafer ST, Han J, Pena M, von Bohlen Und Halbach O, Peters J, Gage FH. The Wnt adaptor protein ATP6AP2 regulates multiple stages of adult hippocampal neurogenesis. J Neurosci. 2015;35:4983–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  212. 212.

    Scharfman H, Goodman J, Macleod A, Phani S, Antonelli C, Croll S. Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Exp Neurol. 2005;192:348–56.

    CAS  PubMed  Google Scholar 

  213. 213.

    Rossi C, Angelucci A, Costantin L, Braschi C, Mazzantini M, Babbini F, et al. Brain-derived neurotrophic factor (BDNF) is required for the enhancement of hippocampal neurogenesis following environmental enrichment. Eur J Neurosci. 2006;24:1850–6.

    PubMed  Google Scholar 

  214. 214.

    Ehm O, Goritz C, Covic M, Schaffner I, Schwarz TJ, Karaca E, et al. RBPJkappa-dependent signaling is essential for long-term maintenance of neural stem cells in the adult hippocampus. J Neurosci. 2010;30:13794–807.

    CAS  PubMed  Google Scholar 

  215. 215.

    Ables JL, Decarolis NA, Johnson MA, Rivera PD, Gao Z, Cooper DC, et al. Notch1 is required for maintenance of the reservoir of adult hippocampal stem cells. J Neurosci. 2010;30:10484–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  216. 216.

    Lugert S, Basak O, Knuckles P, Haussler U, Fabel K, Gotz M, et al. Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging. Cell Stem Cell. 2010;6:445–56.

    CAS  PubMed  Google Scholar 

  217. 217.

    Porcheri C, Suter U, Jessberger S. Dissecting integrin-dependent regulation of neural stem cell proliferation in the adult brain. J Neurosci. 2014;34:5222–32.

    PubMed  Google Scholar 

  218. 218.

    Brooker SM, Bond AM, Peng CY, Kessler JA. beta1-integrin restricts astrocytic differentiation of adult hippocampal neural stem cells. Glia. 2016;64:1235–51.

    PubMed  Google Scholar 

  219. 219.

    Ashton RS, Conway A, Pangarkar C, Bergen J, Lim KI, Shah P, et al. Astrocytes regulate adult hippocampal neurogenesis through ephrin-B signaling. Nat Neurosci. 2012;15:1399–406.

    CAS  PubMed  PubMed Central  Google Scholar 

  220. 220.

    Duan Y, Wang SH, Song J, Mironova Y, Ming GL, Kolodkin AL et al. Semaphorin 5A inhibits synaptogenesis in early postnatal- and adult-born hippocampal dentate granule cells. Elife. 2014;3:e04390.

  221. 221.

    Ng T, Hor CH, Chew B, Zhao J, Zhong Z, Ryu JR, et al. Neuropilin 2 signaling is involved in cell positioning of adult-born neurons through glycogen synthase kinase-3beta (GSK3beta). J Biol Chem. 2016;291:25088–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  222. 222.

    Xu JC, Xiao MF, Jakovcevski I, Sivukhina E, Hargus G, Cui YF, et al. The extracellular matrix glycoprotein tenascin-R regulates neurogenesis during development and in the adult dentate gyrus of mice. J Cell Sci. 2014;127:641–52.

    CAS  PubMed  Google Scholar 

  223. 223.

    Mukherjee S, Brulet R, Zhang L, Hsieh J. REST regulation of gene networks in adult neural stem cells. Nat Commun. 2016;7:13360.

    CAS  PubMed  PubMed Central  Google Scholar 

  224. 224.

    Gao Z, Ure K, Ding P, Nashaat M, Yuan L, Ma J, et al. The master negative regulator REST/NRSF controls adult neurogenesis by restraining the neurogenic program in quiescent stem cells. J Neurosci. 2011;31:9772–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  225. 225.

    Favaro R, Valotta M, Ferri AL, Latorre E, Mariani J, Giachino C, et al. Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh. Nat Neurosci. 2009;12:1248–56.

    CAS  PubMed  Google Scholar 

  226. 226.

    Renault VM, Rafalski VA, Morgan AA, Salih DA, Brett JO, Webb AE, et al. FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell. 2009;5:527–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  227. 227.

    Rolando C, Erni A, Grison A, Beattie R, Engler A, Gokhale PJ, et al. Multipotency of adult hippocampal NSCs in vivo is restricted by drosha/NFIB. Cell Stem Cell. 2016;19:653–62.

    CAS  PubMed  Google Scholar 

  228. 228.

    Urban N, van den Berg DL, Forget A, Andersen J, Demmers JA, Hunt C, et al. Return to quiescence of mouse neural stem cells by degradation of a proactivation protein. Science. 2016;353:292–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  229. 229.

    Andersen J, Urban N, Achimastou A, Ito A, Simic M, Ullom K, et al. A transcriptional mechanism integrating inputs from extracellular signals to activate hippocampal stem cells. Neuron. 2014;83:1085–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  230. 230.

    Amador-Arjona A, Cimadamore F, Huang CT, Wright R, Lewis S, Gage FH, et al. SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis. Proc Natl Acad Sci USA. 2015;112:E1936–1945.

    CAS  PubMed  Google Scholar 

  231. 231.

    Shi Y, Chichung Lie D, Taupin P, Nakashima K, Ray J, Yu RT, et al. Expression and function of orphan nuclear receptor TLX in adult neural stem cells. Nature. 2004;427:78–83.

    CAS  PubMed  Google Scholar 

  232. 232.

    Zhang CL, Zou Y, He W, Gage FH, Evans RM. A role for adult TLX-positive neural stem cells in learning and behaviour. Nature. 2008;451:1004–7.

    CAS  PubMed  Google Scholar 

  233. 233.

    Shimozaki K, Zhang CL, Suh H, Denli AM, Evans RM, Gage FH. SRY-box-containing gene 2 regulation of nuclear receptor tailless (Tlx) transcription in adult neural stem cells. J Biol Chem. 2012;287:5969–78.

    CAS  PubMed  Google Scholar 

  234. 234.

    Kim HJ, Denli AM, Wright R, Baul TD, Clemenson GD, Morcos AS, et al. REST regulates non-cell-autonomous neuronal differentiation and maturation of neural progenitor cells via secretogranin II. J Neurosci. 2015;35:14872–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  235. 235.

    Jessberger S, Toni N, Clemenson GD Jr, Ray J, Gage FH. Directed differentiation of hippocampal stem/progenitor cells in the adult brain. Nat Neurosci. 2008;11:888–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  236. 236.

    Hodge RD, Nelson BR, Kahoud RJ, Yang R, Mussar KE, Reiner SL, et al. Tbr2 is essential for hippocampal lineage progression from neural stem cells to intermediate progenitors and neurons. J Neurosci. 2012;32:6275–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  237. 237.

    Ozen I, Galichet C, Watts C, Parras C, Guillemot F, Raineteau O. Proliferating neuronal progenitors in the postnatal hippocampus transiently express the proneural gene Ngn2. Eur J Neurosci. 2007;25:2591–603.

    PubMed  Google Scholar 

  238. 238.

    Galichet C, Guillemot F, Parras CM. Neurogenin 2 has an essential role in development of the dentate gyrus. Development. 2008;135:2031–41.

    CAS  PubMed  Google Scholar 

  239. 239.

    Iwano T, Masuda A, Kiyonari H, Enomoto H, Matsuzaki F. Prox1 postmitotically defines dentate gyrus cells by specifying granule cell identity over CA3 pyramidal cell fate in the hippocampus. Development. 2012;139:3051–62.

    CAS  PubMed  Google Scholar 

  240. 240.

    Yu DX, Di Giorgio FP, Yao J, Marchetto MC, Brennand K, Wright R, et al. Modeling hippocampal neurogenesis using human pluripotent stem cells. Stem Cell Rep. 2014;2:295–310.

    CAS  Google Scholar 

  241. 241.

    Nakagawa S, Kim JE, Lee R, Chen J, Fujioka T, Malberg J, et al. Localization of phosphorylated cAMP response element-binding protein in immature neurons of adult hippocampus. J Neurosci. 2002;22:9868–76.

    CAS  PubMed  Google Scholar 

  242. 242.

    Jagasia R, Steib K, Englberger E, Herold S, Faus-Kessler T, Saxe M, et al. GABA-cAMP response element-binding protein signaling regulates maturation and survival of newly generated neurons in the adult hippocampus. J Neurosci. 2009;29:7966–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  243. 243.

    Scobie KN, Hall BJ, Wilke SA, Klemenhagen KC, Fujii-Kuriyama Y, Ghosh A, et al. Kruppel-like factor 9 is necessary for late-phase neuronal maturation in the developing dentate gyrus and during adult hippocampal neurogenesis. J Neurosci. 2009;29:9875–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  244. 244.

    Ma DK, Jang MH, Guo JU, Kitabatake Y, Chang ML, Pow-Anpongkul N, et al. Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science. 2009;323:1074–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  245. 245.

    Zhang RR, Cui QY, Murai K, Lim YC, Smith ZD, Jin S, et al. Tet1 regulates adult hippocampal neurogenesis and cognition. Cell Stem Cell. 2013;13:237–45.

    PubMed  PubMed Central  Google Scholar 

  246. 246.

    Szulwach KE, Li X, Smrt RD, Li Y, Luo Y, Lin L, et al. Cross talk between microRNA and epigenetic regulation in adult neurogenesis. J Cell Biol. 2010;189:127–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  247. 247.

    Jin J, Kim SN, Liu X, Zhang H, Zhang C, Seo JS, et al. miR-17-92 cluster regulates adult hippocampal neurogenesis, anxiety, and depression. Cell Rep. 2016;16:1653–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  248. 248.

    Toda T, Hsu JY, Linker SB, Hu L, Schafer ST, Mertens J, et al. Nup153 interacts with Sox2 to enable bimodal gene regulation and maintenance of neural progenitor cells. Cell Stem Cell. 2017;21:618–34 e617.

    CAS  PubMed  Google Scholar 

  249. 249.

    Li X, Barkho BZ, Luo Y, Smrt RD, Santistevan NJ, Liu C, et al. Epigenetic regulation of the stem cell mitogen Fgf-2 by Mbd1 in adult neural stem/progenitor cells. J Biol Chem. 2008;283:27644–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  250. 250.

    Liu C, Teng ZQ, Santistevan NJ, Szulwach KE, Guo W, Jin P, et al. Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation and differentiation. Cell Stem Cell. 2010;6:433–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  251. 251.

    Liu C, Teng ZQ, McQuate AL, Jobe EM, Christ CC, von Hoyningen-Huene SJ, et al. An epigenetic feedback regulatory loop involving microRNA-195 and MBD1 governs neural stem cell differentiation. PLoS One. 2013;8:e51436.

    CAS  PubMed  PubMed Central  Google Scholar 

  252. 252.

    Zhao X, Ueba T, Christie BR, Barkho B, McConnell MJ, Nakashima K, et al. Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function. Proc Natl Acad Sci USA. 2003;100:6777–82.

    CAS  PubMed  Google Scholar 

  253. 253.

    Jawerka M, Colak D, Dimou L, Spiller C, Lagger S, Montgomery RL, et al. The specific role of histone deacetylase 2 in adult neurogenesis. Neuron Glia Biol. 2010;6:93–107.

    PubMed  Google Scholar 

  254. 254.

    Ballas N, Grunseich C, Lu DD, Speh JC, Mandel G. REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis. Cell. 2005;121:645–57.

    CAS  PubMed  Google Scholar 

  255. 255.

    Li H, Zhong X, Chau KF, Santistevan NJ, Guo W, Kong G, et al. Cell cycle-linked MeCP2 phosphorylation modulates adult neurogenesis involving the Notch signalling pathway. Nat Commun. 2014;5:5601.

    CAS  PubMed  PubMed Central  Google Scholar 

  256. 256.

    Tsujimura K, Irie K, Nakashima H, Egashira Y, Fukao Y, Fujiwara M, et al. miR-199a links MeCP2 with mTOR signaling and its dysregulation leads to Rett syndrome phenotypes. Cell Rep. 2015;12:1887–901.

    CAS  PubMed  Google Scholar 

  257. 257.

    Smrt RD, Eaves-Egenes J, Barkho BZ, Santistevan NJ, Zhao C, Aimone JB, et al. Mecp2 deficiency leads to delayed maturation and altered gene expression in hippocampal neurons. Neurobiol Dis. 2007;27:77–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  258. 258.

    Han J, Kim HJ, Schafer ST, Paquola A, Clemenson GD, Toda T, et al. Functional implications of miR-19 in the migration of newborn neurons in the adult brain. Neuron. 2016;91:79–89.

    CAS  PubMed  Google Scholar 

  259. 259.

    Magill ST, Cambronne XA, Luikart BW, Lioy DT, Leighton BH, Westbrook GL, et al. microRNA-132 regulates dendritic growth and arborization of newborn neurons in the adult hippocampus. Proc Natl Acad Sci USA. 2010;107:20382–7.

    CAS  PubMed  Google Scholar 

  260. 260.

    Song J, Zhong C, Bonaguidi MA, Sun GJ, Hsu D, Gu Y, et al. Neuronal circuitry mechanism regulating adult quiescent neural stem-cell fate decision. Nature. 2012;489:150–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  261. 261.

    Song J, Sun J, Moss J, Wen Z, Sun GJ, Hsu D, et al. Parvalbumin interneurons mediate neuronal circuitry-neurogenesis coupling in the adult hippocampus. Nat Neurosci. 2013;16:1728–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  262. 262.

    Dumitru I, Neitz A, Alfonso J, Monyer H. Diazepam binding inhibitor promotes stem cell expansion controlling environment-dependent neurogenesis. Neuron. 2017;94:125–37 e125.

    CAS  PubMed  Google Scholar 

  263. 263.

    Giachino C, Barz M, Tchorz JS, Tome M, Gassmann M, Bischofberger J, et al. GABA suppresses neurogenesis in the adult hippocampus through GABAB receptors. Development. 2014;141:83–90.

    CAS  PubMed  Google Scholar 

  264. 264.

    Tozuka Y, Fukuda S, Namba T, Seki T, Hisatsune T. GABAergic excitation promotes neuronal differentiation in adult hippocampal progenitor cells. Neuron. 2005;47:803–15.

    CAS  PubMed  Google Scholar 

  265. 265.

    Deisseroth K, Singla S, Toda H, Monje M, Palmer TD, Malenka RC. Excitation-neurogenesis coupling in adult neural stem/progenitor cells. Neuron. 2004;42:535–52.

    CAS  PubMed  Google Scholar 

  266. 266.

    Park JH, Enikolopov G. Transient elevation of adult hippocampal neurogenesis after dopamine depletion. Exp Neurol. 2010;222:267–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  267. 267.

    Jhaveri DJ, O’Keeffe I, Robinson GJ, Zhao QY, Zhang ZH, Nink V, et al. Purification of neural precursor cells reveals the presence of distinct, stimulus-specific subpopulations of quiescent precursors in the adult mouse hippocampus. J Neurosci. 2015;35:8132–44.

    CAS  PubMed  Google Scholar 

  268. 268.

    Cooper-Kuhn CM, Winkler J, Kuhn HG. Decreased neurogenesis after cholinergic forebrain lesion in the adult rat. J Neurosci Res. 2004;77:155–65.

    CAS  PubMed  Google Scholar 

  269. 269.

    Harrist A, Beech RD, King SL, Zanardi A, Cleary MA, Caldarone BJ, et al. Alteration of hippocampal cell proliferation in mice lacking the beta 2 subunit of the neuronal nicotinic acetylcholine receptor. Synapse. 2004;54:200–6.

    CAS  PubMed  Google Scholar 

  270. 270.

    Mohapel P, Leanza G, Kokaia M, Lindvall O. Forebrain acetylcholine regulates adult hippocampal neurogenesis and learning. Neurobiol Aging. 2005;26:939–46.

    CAS  PubMed  Google Scholar 

  271. 271.

    Dominguez-Escriba L, Hernandez-Rabaza V, Soriano-Navarro M, Barcia JA, Romero FJ, Garcia-Verdugo JM, et al. Chronic cocaine exposure impairs progenitor proliferation but spares survival and maturation of neural precursors in adult rat dentate gyrus. Eur J Neurosci. 2006;24:586–94.

    CAS  PubMed  Google Scholar 

  272. 272.

    Overstreet Wadiche L, Bromberg DA, Bensen AL, Westbrook GL. GABAergic signaling to newborn neurons in dentate gyrus. J Neurophysiol. 2005;94:4528–32.

    PubMed  Google Scholar 

  273. 273.

    Vivar C, Potter MC, Choi J, Lee JY, Stringer TP, Callaway EM, et al. Monosynaptic inputs to new neurons in the dentate gyrus. Nat Commun. 2012;3:1107.

    PubMed  PubMed Central  Google Scholar 

  274. 274.

    Toni N, Teng EM, Bushong EA, Aimone JB, Zhao C, Consiglio A, et al. Synapse formation on neurons born in the adult hippocampus. Nat Neurosci. 2007;10:727–34.

    CAS  PubMed  Google Scholar 

  275. 275.

    Sultan S, Li L, Moss J, Petrelli F, Casse F, Gebara E, et al. Synaptic Integration of Adult-Born Hippocampal Neurons Is Locally Controlled by Astrocytes. Neuron. 2015;88:957–72.

    CAS  PubMed  Google Scholar 

  276. 276.

    Kaneko N, Okano H, Sawamoto K. Role of the cholinergic system in regulating survival of newborn neurons in the adult mouse dentate gyrus and olfactory bulb. Genes Cells. 2006;11:1145–59.

    CAS  PubMed  Google Scholar 

  277. 277.

    Campbell NR, Fernandes CC, Halff AW, Berg DK. Endogenous signaling through alpha7-containing nicotinic receptors promotes maturation and integration of adult-born neurons in the hippocampus. J Neurosci. 2010;30:8734–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  278. 278.

    Mu Y, Zhao C, Gage FH. Dopaminergic modulation of cortical inputs during maturation of adult-born dentate granule cells. J Neurosci. 2011;31:4113–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  279. 279.

    Meshi D, Drew MR, Saxe M, Ansorge MS, David D, Santarelli L, et al. Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment. Nat Neurosci. 2006;9:729–31.

    CAS  PubMed  Google Scholar 

  280. 280.

    Wang W, Pan YW, Zou J, Li T, Abel GM, Palmiter RD, et al. Genetic activation of ERK5 MAP kinase enhances adult neurogenesis and extends hippocampus-dependent long-term memory. J Neurosci. 2014;34:2130-47.

    CAS  PubMed  Google Scholar 

  281. 281.

    Zou J, Wang W, Pan YW, Abel GM, Storm DR, Xia Z. Conditional inhibition of adult neurogenesis by inducible and targeted deletion of ERK5 MAP kinase is not associated with anxiety/depression-like behaviors. eNeuro. 2015;2:ENEURO.0014-14.2015.

  282. 282.

    Zhuo JM, Tseng HA, Desai M, Bucklin ME, Mohammed AI, Robinson NT, et al. Young adult born neurons enhance hippocampal dependent performance via influences on bilateral networks. Elife. 2016;5:e22429.

Download references

Acknowledgements

We thank M. L. Gage for comments on the manuscript, V. Mertens for the illustrations and Dr. Abed Al Fattah Mansour for discussion. This work was supported by NIH R01 MH095741, NIH U01 MH106882, The G. Harold and Leila Y. Mathers Charitable Foundation, The Leona M. and Harry B. Helmsley Charitable Trust (grant #2012-PG-MED00), Annette C. Merle-Smith, JPB Foundation and The McKnight Foundation. T.T. was supported by JSPS and the Kanae Foundation.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Fred H. Gage.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Toda, T., Parylak, S.L., Linker, S.B. et al. The role of adult hippocampal neurogenesis in brain health and disease. Mol Psychiatry 24, 67–87 (2019). https://doi.org/10.1038/s41380-018-0036-2

Download citation

Further reading

Search

Quick links