Integration of New Neurons into the Adult Hippocampus

  • Wei Deng
  • Chunmei Zhao
  • Fred H. GageEmail author


The hippocampus is one of the regions where continuous addition of new neurons occurs in adult mammalian brains. In this review, we describe the process of integration of newborn neurons into the neural circuitry of the hippocampus in adult rodents and discuss how hippocampal neurogenesis is regulated by the neural network activity. We further address the functional implications of adult hippocampal neurogenesis in learning and memory.


Dentate Gyrus Morris Water Maze Enrich Environment Adult Neurogenesis Hippocampal Neurogenesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid


Brain lipid-binding protein




Central nervous system




Dentate gyrus


Glial fibrillary acidic protein


Immediate early genes


Long-term potentiation


Methylazoxymethanol acetate


Morris water maze


Neuronal nuclei


Na-K-2Cl cotransporter


N-methyl-d-aspartic acid




Polysialated form of neural cell adhesion molecule


Subgranular zone


Thymidine kinase



The authors thank Jamie Simon for illustrations and Mary Lynn Gage for helpful comments. This work is supported by National Institutes of Health, Picower Foundation, Lookout Foundation, and J.S. McDonnell Foundations.


  1. Abrous DN, Koehl M, Le Moal M (2005). Adult neurogenesis: from precursors to network and physiology. Physiol Rev 85: 523–569.PubMedCrossRefGoogle Scholar
  2. Aimone JB, Wiskott L (2007). Computational modeling of adult neurogenesis. In: Gage FH, Kempermann G, Song H (eds.) Adult neurogenesis. Cold Spring Harbor Laboratory Press, Cold Spring Harbor.Google Scholar
  3. Amaral D, Lavenex P (2007). Hippocampal neuroanatomy. In: Anderson P, Morris R, Amaral D, Bliss T, O’Keefe J (eds.) The hippocampus book. Oxford University Press, Oxford.Google Scholar
  4. Bernabeu R, Sharp FR (2000). NMDA and AMPA/kainate glutamate receptors modulate dentate neurogenesis and CA3 synapsin-I in normal and ischemic hippocampus. J Cereb Blood Flow Metab 20: 1669–1680.PubMedCrossRefGoogle Scholar
  5. Brezun JM, Daszuta A (1999). Depletion in serotonin decreases neurogenesis in the dentate gyrus and the subventricular zone of adult rats. Neuroscience 89: 999–1002.PubMedCrossRefGoogle Scholar
  6. Brezun JM, Daszuta A (2000a). Serotonin may stimulate granule cell proliferation in the adult hippocampus, as observed in rats grafted with foetal raphe neurons. Eur J Neurosci 12: 391–396.PubMedCrossRefGoogle Scholar
  7. Brezun JM, Daszuta A (2000b). Serotonergic reinnervation reverses lesion-induced decreases in PSA-NCAM labeling and proliferation of hippocampal cells in adult rats. Hippocampus 10: 37–46.PubMedCrossRefGoogle Scholar
  8. Brown JP, Couillard-Despres S, Cooper-Kuhn CM et al (2003). Transient expression of doublecortin during adult neurogenesis. J Comp Neurol 467: 1–10.PubMedCrossRefGoogle Scholar
  9. Bruel-Jungerman E, Laroche S, Rampon C (2005). New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment. Eur J Neurosci 21: 513–521.PubMedCrossRefGoogle Scholar
  10. Bruel-Jungerman E, Davis S, Rampon C et al (2006). Long-term potentiation enhances neurogenesis in the adult dentate gyrus. J Neurosci 26: 5888–5893.PubMedCrossRefGoogle Scholar
  11. Bursztajn S, Falls WA, Berman SA et al (2007). Cell proliferation in the brains of NMDAR NR1 transgenic mice. Brain Res 1172: 10–20.PubMedCrossRefGoogle Scholar
  12. Cameron HA, McEwen BS, Gould E (1995). Regulation of adult neurogenesis by excitatory input and NMDA receptor activation in the dentate gyrus. J Neurosci 15: 4687–4692.PubMedGoogle Scholar
  13. Chun SK, Sun W, Park JJ et al (2006). Enhanced proliferation of progenitor cells following long-term potentiation induction in the rat dentate gyrus. Neurobiol Learn Mem 86: 322–329.PubMedCrossRefGoogle Scholar
  14. Cooper-Kuhn CM, Winkler J, Kuhn HG (2004). Decreased neurogenesis after cholinergic forebrain lesion in the adult rat. J Neurosci Res 77: 155–165.PubMedCrossRefGoogle Scholar
  15. Dupret D, Montaron MF, Drapeau E et al (2005). Methylazoxymethanol acetate does not fully block cell genesis in the young and aged dentate gyrus. Eur J Neurosci 22: 778–783.PubMedCrossRefGoogle Scholar
  16. Dupret D, Fabre A, Dobrossy MD et al (2007). Spatial learning depends on both the addition and removal of new hippocampal neurons. PLoS Biol 5: e214.PubMedCrossRefGoogle Scholar
  17. Esposito MS, Piatti VC, Laplagne DA et al (2005). Neuronal differentiation in the adult hippocampus recapitulates embryonic development. J Neurosci 25: 10074–10086.PubMedCrossRefGoogle Scholar
  18. Feng R, Rampon C, Tang YP et al (2001). Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces. Neuron 32: 911–926.PubMedCrossRefGoogle Scholar
  19. Fontana X, Nacher J, Soriano E et al (2006). Cell proliferation in the adult hippocampal formation of rodents and its modulation by entorhinal and fimbria-fornix afferents. Cereb Cortex 16: 301–312.PubMedCrossRefGoogle Scholar
  20. Garcia AD, Doan NB, Imura T et al (2004). GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain. Nat Neurosci 7: 1233–1241.PubMedCrossRefGoogle Scholar
  21. Ge S, Goh EL, Sailor KA et al (2006). GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 439: 589–593.PubMedCrossRefGoogle Scholar
  22. Ge S, Yang CH, Hsu KS et al (2007). A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain. Neuron 54: 559–566.PubMedCrossRefGoogle Scholar
  23. Gong C, Wang TW, Huang HS et al (2007). Reelin regulates neuronal progenitor migration in intact and epileptic hippocampus. J Neurosci 27: 1803–1811.PubMedCrossRefGoogle Scholar
  24. Gould E, Beylin A, Tanapat P et al (1999). Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci 2: 260–265.PubMedCrossRefGoogle Scholar
  25. Hoglinger GU, Rizk P, Muriel MP et al (2004). Dopamine depletion impairs precursor cell proliferation in Parkinson disease. Nat Neurosci 7: 726–735.PubMedCrossRefGoogle Scholar
  26. Jessberger S, Kempermann G (2003). Adult-born hippocampal neurons mature into activity-dependent responsiveness. Eur J Neurosci 18: 2707–2712.PubMedCrossRefGoogle Scholar
  27. Jessberger S, Zhao C, Toni N et al (2007). Seizure-associated, aberrant neurogenesis in adult rats characterized with retrovirus-mediated cell labeling. J Neurosci 27: 9400–9407.PubMedCrossRefGoogle Scholar
  28. Joo JY, Kim BW, Lee JS et al (2007). Activation of NMDA receptors increases proliferation and differentiation of hippocampal neural progenitor cells. J Cell Sci 120: 1358–1370.PubMedCrossRefGoogle Scholar
  29. Kee N, Teixeira CM, Wang AH et al (2007). Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat Neurosci 10: 355–362.PubMedCrossRefGoogle Scholar
  30. Kempermann G, Gage FH (2002). Genetic determinants of adult hippocampal neurogenesis correlate with acquisition, but not probe trial performance, in the water maze task. Eur J Neurosci 16: 129–136.PubMedCrossRefGoogle Scholar
  31. Kempermann G, Kuhn HG, Gage FH (1997a). More hippocampal neurons in adult mice living in an enriched environment. Nature 386: 493–495.PubMedCrossRefGoogle Scholar
  32. Kempermann G, Kuhn HG, Gage FH (1997b). Genetic influence on neurogenesis in the dentate gyrus of adult mice. Proc Natl Acad Sci USA 94: 10409–10414.PubMedCrossRefGoogle Scholar
  33. Kempermann G, Kuhn HG, Gage FH (1998). Experience-induced neurogenesis in the senescent dentate gyrus. J Neurosci 18: 3206–3212.PubMedGoogle Scholar
  34. Kempermann G, Gast D, Gage FH (2002). Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment. Ann Neurol 52: 135–143.PubMedCrossRefGoogle Scholar
  35. Klempin F, Kempermann G (2007). Adult hippocampal neurogenesis and aging. Eur Arch Psychiatry Clin Neurosci 257: 271–280.PubMedCrossRefGoogle Scholar
  36. Kubik S, Miyashita T, Guzowski JF (2007). Using immediate-early genes to map hippocampal subregional functions. Learn Mem 14: 758–770.PubMedCrossRefGoogle Scholar
  37. Kulkarni VA, Jha S, Vaidya VA (2002). Depletion of norepinephrine decreases the proliferation, but does not influence the survival and differentiation, of granule cell progenitors in the adult rat hippocampus. Eur J Neurosci 16: 2008–2012.PubMedCrossRefGoogle Scholar
  38. Laplagne DA, Esposito MS, Piatti VC et al (2006). Functional convergence of neurons generated in the developing and adult hippocampus. PLoS Biol 4: e409.PubMedCrossRefGoogle Scholar
  39. Laplagne DA, Kamienkowski JE, Esposito MS et al (2007). Similar GABAergic inputs in dentate granule cells born during embryonic and adult neurogenesis. Eur J Neurosci 25: 2973–2981.PubMedCrossRefGoogle Scholar
  40. Leuner B, Waddell J, Gould E et al (2006). Temporal discontiguity is neither necessary nor sufficient for learning-induced effects on adult neurogenesis. J Neurosci 26: 13437–13442.PubMedCrossRefGoogle Scholar
  41. Madsen TM, Treschow A, Bengzon J et al (2000). Increased neurogenesis in a model of electroconvulsive therapy. Biol Psychiatry 47: 1043–1049.PubMedCrossRefGoogle Scholar
  42. Madsen TM, Kristjansen PE, Bolwig TG et al (2003). Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat. Neuroscience 119: 635–642.PubMedCrossRefGoogle Scholar
  43. Magavi SS, Mitchell BD, Szentirmai O et al (2005). Adult-born and preexisting olfactory granule neurons undergo distinct experience-dependent modifications of their olfactory responses in vivo. J Neurosci 25: 10729–10739.PubMedCrossRefGoogle Scholar
  44. Malberg JE, Eisch AJ, Nestler EJ et al (2000). Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 20: 9104–9110.PubMedGoogle Scholar
  45. Marques-Mari AI, Nacher J, Crespo C et al (2007). Loss of input from the mossy cells blocks maturation of newly generated granule cells. Hippocampus 17: 510–524.PubMedCrossRefGoogle Scholar
  46. Meshi D, Drew MR, Saxe M et al (2006). Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment. Nat Neurosci 9: 729–731.PubMedCrossRefGoogle Scholar
  47. Mohapel P, Leanza G, Kokaia M et al (2005). Forebrain acetylcholine regulates adult hippocampal neurogenesis and learning. Neurobiol Aging 26: 939–946.PubMedCrossRefGoogle Scholar
  48. Monje ML, Toda H, Palmer TD (2003). Inflammatory blockade restores adult hippocampal neurogenesis. Science 302: 1760–1765.PubMedCrossRefGoogle Scholar
  49. Nacher J, McEwen BS (2006). The role of N-methyl-D-asparate receptors in neurogenesis. Hippocampus 16: 267–270.PubMedCrossRefGoogle Scholar
  50. Nacher J, Rosell DR, Alonso-Llosa G et al (2001). NMDA receptor antagonist treatment induces a long-lasting increase in the number of proliferating cells, PSA-NCAM-immunoreactive granule neurons and radial glia in the adult rat dentate gyrus. Eur J Neurosci 13: 512–520.PubMedCrossRefGoogle Scholar
  51. Nacher J, Alonso-Llosa G, Rosell DR et al (2003). NMDA receptor antagonist treatment increases the production of new neurons in the aged rat hippocampus. Neurobiol Aging 24: 273–284.PubMedCrossRefGoogle Scholar
  52. Nacher J, Varea E, Miguel Blasco-Ibanez J et al (2007). N-methyl-d-aspartate receptor expression during adult neurogenesis in the rat dentate gyrus. Neuroscience 144: 855–864.PubMedCrossRefGoogle Scholar
  53. Okuyama N, Takagi N, Kawai T et al (2004). Phosphorylation of extracellular-regulating kinase in NMDA receptor antagonist-induced newly generated neurons in the adult rat dentate gyrus. J Neurochem 88: 717–725.PubMedCrossRefGoogle Scholar
  54. Overstreet LS, Hentges ST, Bumaschny VF et al (2004). A transgenic marker for newly born granule cells in dentate gyrus. J Neurosci 24: 3251–3259.PubMedCrossRefGoogle Scholar
  55. Overstreet Wadiche L, Bromberg DA, Bensen AL et al (2005). GABAergic signaling to newborn neurons in dentate gyrus. J Neurophysiol 94: 4528–4532.PubMedCrossRefGoogle Scholar
  56. Overstreet-Wadiche LS, Bromberg DA, Bensen AL et al (2006). Seizures accelerate functional integration of adult-generated granule cells. J Neurosci 26: 4095–4103.PubMedCrossRefGoogle Scholar
  57. Parent JM, Yu TW, Leibowitz RT et al (1997). Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci 17: 3727–3738.PubMedGoogle Scholar
  58. Parent JM, Janumpalli S, McNamara JO et al (1998). Increased dentate granule cell neurogenesis following amygdala kindling in the adult rat. Neurosci Lett 247: 9–12.PubMedCrossRefGoogle Scholar
  59. Parent JM, Elliott RC, Pleasure SJ et al (2006). Aberrant seizure-induced neurogenesis in experimental temporal lobe epilepsy. Ann Neurol 59: 81–91.PubMedCrossRefGoogle Scholar
  60. Raber J, Rola R, LeFevour A et al (2004). Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis. Radiat Res 162: 39–47.PubMedCrossRefGoogle Scholar
  61. Ramirez-Amaya V, Marrone DF, Gage FH et al (2006). Integration of new neurons into functional neural networks. J Neurosci 26: 12237–12241.PubMedCrossRefGoogle Scholar
  62. Rola R, Raber J, Rizk A et al (2004). Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice. Exp Neurol 188: 316–330.PubMedCrossRefGoogle Scholar
  63. Saxe MD, Battaglia F, Wang JW et al (2006). Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc Natl Acad Sci USA 103: 17501–17506.PubMedCrossRefGoogle Scholar
  64. Saxe MD, Malleret G, Vronskaya S et al (2007). Paradoxical influence of hippocampal neurogenesis on working memory. Proc Natl Acad Sci USA 104: 4642–4646.PubMedCrossRefGoogle Scholar
  65. Schmidt-Hieber C, Jonas P, Bischofberger J (2004). Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature 429: 184–187.PubMedCrossRefGoogle Scholar
  66. Seki T, Namba T, Mochizuki H et al (2007). Clustering, migration, and neurite formation of neural precursor cells in the adult rat hippocampus. J Comp Neurol 502: 275–290.PubMedCrossRefGoogle Scholar
  67. Shapiro LA, Upadhyaya P, Ribak CE (2007). Spatiotemporal profile of dendritic outgrowth from newly born granule cells in the adult rat dentate gyrus. Brain Res 1149: 30–37.PubMedCrossRefGoogle Scholar
  68. Shors TJ (2004). Learning during stressful times. Learn Mem 11: 137–144.PubMedCrossRefGoogle Scholar
  69. Shors TJ, Miesegaes G, Beylin A et al (2001). Neurogenesis in the adult is involved in the formation of trace memories. Nature 410: 372–376.PubMedCrossRefGoogle Scholar
  70. Shors TJ, Townsend DA, Zhao M et al (2002). Neurogenesis may relate to some but not all types of hippocampal-dependent learning. Hippocampus 12: 578–584.PubMedCrossRefGoogle Scholar
  71. Sisti HM, Glass AL, Shors TJ (2007). Neurogenesis and the spacing effect: learning over time enhances memory and the survival of new neurons. Learn Mem 14: 368–375.PubMedCrossRefGoogle Scholar
  72. Snyder JS, Hong NS, McDonald RJ et al (2005). A role for adult neurogenesis in spatial long-term memory. Neuroscience 130: 843–852.PubMedCrossRefGoogle Scholar
  73. Tashiro A, Zhao C, Gage FH (2006). Retrovirus-mediated single-cell gene knockout technique in adult newborn neurons in vivo. Nat Protoc 1: 3049–3055.PubMedCrossRefGoogle Scholar
  74. Tashiro A, Makino H, Gage FH (2007). Experience-specific functional modification of the dentate gyrus through adult neurogenesis: a critical period during an immature stage. J Neurosci 27: 3252–3259.PubMedCrossRefGoogle Scholar
  75. Toni N, Teng EM, Bushong EA et al (2007). Synapse formation on neurons born in the adult hippocampus. Nat Neurosci 10: 727–734.PubMedCrossRefGoogle Scholar
  76. Toni N, Laplagne DA, Zhao C et al (2008). Neurons born in the adult dentate gyrus form functional synapses with target cells. Nat Neurosci 11: 901–907.PubMedCrossRefGoogle Scholar
  77. Tozuka Y, Fukuda S, Namba T et al (2005). GABAergic excitation promotes neuronal differentiation in adult hippocampal progenitor cells. Neuron 47: 803–815.PubMedCrossRefGoogle Scholar
  78. Van der Borght K, Mulder J, Keijser JN et al (2005). Input from the medial septum regulates adult hippocampal neurogenesis. Brain Res Bull 67: 117–125.PubMedCrossRefGoogle Scholar
  79. van Praag H, Christie BR, Sejnowski TJ et al (1999). Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci USA 96: 13427–13431.PubMedCrossRefGoogle Scholar
  80. van Praag H, Schinder AF, Christie BR et al (2002). Functional neurogenesis in the adult hippocampus. Nature 415: 1030–1034.PubMedCrossRefGoogle Scholar
  81. van Praag H, Shubert T, Zhao C et al (2005). Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci 25: 8680–8685.PubMedCrossRefGoogle Scholar
  82. Walter C, Murphy BL, Pun RY et al (2007). Pilocarpine-induced seizures cause selective time-dependent changes to adult-generated hippocampal dentate granule cells. J Neurosci 27: 7541–7552.PubMedCrossRefGoogle Scholar
  83. Winocur G, Wojtowicz JM, Sekeres M et al (2006). Inhibition of neurogenesis interferes with hippocampus-dependent memory function. Hippocampus 16: 296–304.PubMedCrossRefGoogle Scholar
  84. Wojtowicz JM (2006). Irradiation as an experimental tool in studies of adult neurogenesis. Hippocampus 16: 261–266.PubMedCrossRefGoogle Scholar
  85. Yamaguchi M, Mori K (2005). Critical period for sensory experience-dependent survival of newly generated granule cells in the adult mouse olfactory bulb. Proc Natl Acad Sci USA 102: 9697–9702.PubMedCrossRefGoogle Scholar
  86. Yoshimizu T, Chaki S (2004). Increased cell proliferation in the adult mouse hippocampus following chronic administration of group II metabotropic glutamate receptor antagonist, MGS0039. Biochem Biophys Res Commun 315: 493–496.PubMedCrossRefGoogle Scholar
  87. Zhang CL, Zou Y, He W et al (2008). A role for adult TLX-positive neural stem cells in learning and behaviour. Nature 451: 1004–1007.PubMedCrossRefGoogle Scholar
  88. Zhao X, Ueba T, Christie BR et al (2003). Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function. Proc Natl Acad Sci USA 100: 6777–6782.PubMedCrossRefGoogle Scholar
  89. Zhao C, Teng EM, Summers RG, Jr. et al (2006). Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J Neurosci 26: 3–11.PubMedCrossRefGoogle Scholar
  90. Zhao M, Li D, Shimazu K et al (2007). Fibroblast growth factor receptor-1 is required for long-term potentiation, memory consolidation, and neurogenesis. Biol Psychiatry 62: 381–390.PubMedCrossRefGoogle Scholar
  91. Zhao C, Deng W, Gage FH (2008). Mechanisms and functional implications of adult neurogenesis. Cell 132: 645–660.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2011

Authors and Affiliations

  1. 1.Laboratory of GeneticsSalk Institute for Biological StudiesLa JollaUSA

Personalised recommendations