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The role of adult hippocampal neurogenesis in brain health and disease

Molecular Psychiatry (2018) | Download Citation

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.

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References

  1. 1.

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

  2. 2.

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

  3. 3.

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

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  17. 17.

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

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  25. 25.

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

  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.

  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.

  28. 28.

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

  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.

  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.

  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.

  32. 32.

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

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  42. 42.

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

  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.

  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.

  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.

  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.

  47. 47.

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

  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.

  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.

  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.

  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.

  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.

  54. 54.

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

  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.

  56. 56.

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

  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.

  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.

  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.

  60. 60.

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

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  78. 78.

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

  79. 79.

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

  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.

  81. 81.

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

  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.

  83. 83.

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

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  93. 93.

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

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  141. 141.

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

  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

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  150. 150.

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

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  194. 194.

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

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  266. 266.

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

  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.

  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.

  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.

  270. 270.

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

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

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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.

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  1. These authors contributed equally: Tomohisa Toda, Sarah Parylak.

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  1. Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA

    • Tomohisa Toda
    • , Sarah L. Parylak
    • , Sara B. Linker
    •  & Fred H. Gage

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The authors declare that they have no conflict of interest.

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Correspondence to Fred H. Gage.

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https://doi.org/10.1038/s41380-018-0036-2