Activity-Dependent Regulation of the Early Phase of Adult Hippocampal Neurogenesis


New neurons are generated from neural stem cells through the neuronal progenitor cell stage at the dentate gyrus of the hippocampal formation throughout life, and contribute to higher cognitive function, such as learning and memory. Physiological conditions, such as voluntary exercise or enriched environment, or pathophysiological conditions, such as stroke or epilepsy, upregulate the generation of new neurons, but the mechanism for governing the promotion of adult neurogenesis has not been fully clarified. It has been widely accepted that the neural activities of the hippocampal circuitry regulate the generation of hippocampal new neurons. Actually, a number of neurotransmitter systems – serotoninergic, GABAergic, cholinergic, purinergic, and glutamatergic systems – are involved in the regulation of adult hippocampal neurogenesis process. In this chapter, we propose a possible involvement of activity-dependent regulation of the fate of neural stem/progenitor cells in enhanced hippocampal neurogenesis. In a series of studies, we and others have reported how hippocampal activity affects the generation of new neurons, even at the early phase of adult hippocampal neurogenesis. These findings may also contribute to the pharmaceutical enhancement of adult neurogenesis for treating neurodegenerative and psychological disorders.


Neural Stem Cell Entorhinal Cortex Adult Neurogenesis Granule Cell Layer 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.



We thank Drs. Satoshi Fukuda and Yusuke Tozuka for their discussion, comments, and the images.


  1. Abrous DN, Koehl M, Le Moal M (2005) Adult neurogenesis: from precursors to network and physiology. Physiol Rev 85:523–569PubMedCrossRefGoogle Scholar
  2. Airan RD, Meltzer LA, Roy M et al (2007) High-speed imaging reveals neurophysiological links to behavior in an animal model of depression. Science 317:819–823PubMedCrossRefGoogle Scholar
  3. Aizawa K, Ageyama N, Terao K, Hisatsune T (2011) Primate-specific alterations in neural stem/progenitor cells in the aged hippocampus. Neurobiol Aging, doi: 10.1016/j.neurobiolaging.32:140–150 (2011).12.011, onlineGoogle Scholar
  4. Altman J, Das GD (1965) Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 124:319–335PubMedCrossRefGoogle Scholar
  5. Altman J, Das GD (1967) Postnatal neurogenesis in the guinea-pig. Nature 214:1098–1101CrossRefGoogle Scholar
  6. 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, New York, p 37–114Google Scholar
  7. Bland BH (1986) The physiology and pharmacology of hippocampal formation theta rhythms. Prog Neurobiol 26:1–54CrossRefGoogle Scholar
  8. Bordey A, Sontheimer H (2000) Ion channel expression by astrocytes in situ: comparison of different CNS regions. Glia 30:27–38PubMedCrossRefGoogle Scholar
  9. Bruel-Jungerman E, Davis S, Rampon C et al (2006) Long-term potentiation enhances neurogenesis in the adult dentate gyrus. J Neurosci 26:5888–5893PubMedCrossRefGoogle Scholar
  10. Buzsáki G (2002) Theta oscillations in the hippocampus. Neuron 33:325–340PubMedCrossRefGoogle Scholar
  11. Buzsáki G (2006) Rhythms of the brain. Oxford University Press, New YorkCrossRefGoogle 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 15:4687–4692PubMedGoogle 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 86:322–329PubMedCrossRefGoogle Scholar
  14. Cornwell BR, Johnson LL, Holroyd T et al (2008) Human hippocampal and parahippocampal theta during goal-directed spatial navigation predicts performance on a virtual Morris water maze. J Neurosci 28:5983–5990PubMedCrossRefGoogle Scholar
  15. Deisseroth K, Singla S, Toda H et al (2004) Excitation-neurogenesis coupling in adult neural stem/progenitor cells. Neuron 42:535–552PubMedCrossRefGoogle Scholar
  16. Döbrössy MD, Drapeau E, Aurousseau C et al (2003) Differential effects of learning on neurogenesis: learning increases or decreases the number of newly born cells depending on their birth date. Mol Psychiatry 8:974–982PubMedCrossRefGoogle Scholar
  17. Dupret D, Fabre A, Döbrössy MD et al (2007) Spatial learning depends on both the addition and removal of new hippocampal neurons. PLoS Biol 5:e214PubMedCrossRefGoogle Scholar
  18. Dupret D, Revest JM, Koehl M et al (2008) Spatial relational memory requires hippocampal adult neurogenesis. PLoS One 3:e1959PubMedCrossRefGoogle Scholar
  19. Eriksson PS, Perfilieva E, Bjork-Eriksson T et al (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:1313–1317PubMedCrossRefGoogle Scholar
  20. Esposito MS, Piatti VC, Laplagne DA et al (2005) Neuronal differentiation in the adult hippocampus recapitulates embryonic development. J Neurosci 25:10074–10086PubMedCrossRefGoogle Scholar
  21. Fabel K, Tam B, Kaufer D et al (2003) VEGF is necessary for exercise-induced adult hippocampal neurogenesis. Eur J Neurosci 18:2803–2812PubMedCrossRefGoogle Scholar
  22. Filippov V, Kronenberg G, Pivneva T et al (2003) Subpopulation of nestin-expressing progenitor cells in the adult murine hippocampus shows electrophysiological and morphological characteristics of astrocytes. Mol Cell Neurosci 23:373–382PubMedCrossRefGoogle Scholar
  23. Freund TF, Buzsáki G (1996) Interneurons of the hippocampus. Hippocampus 6:347–470PubMedCrossRefGoogle Scholar
  24. Fukuda S, Kato F, Tozuka Y et al (2003) Two distinct subpopulations of nestin-positive cells in adult mouse dentate gyrus. J Neurosci 23:9357–9366PubMedGoogle Scholar
  25. Ge S, Goh EL, Sailor KA et al (2006) GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 439:589–593CrossRefGoogle Scholar
  26. 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 24:559–566CrossRefGoogle Scholar
  27. Gould E, Tanapat P, McEwen BS et al (1998) Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc Natl Acad Sci USA 95:3168–3171PubMedCrossRefGoogle Scholar
  28. Gould E, Beylin A, Tanapat P et al (1999) Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci 2:260–265PubMedCrossRefGoogle Scholar
  29. Green JD, Arduini A (1954) Hippocampal electrical activity in arousal. J Neurophysiol 17:533–557PubMedGoogle Scholar
  30. Hattiangady B, Shetty AK (2008) Aging does not alter the number or phenotype of putative stem/progenitor cells in the neurogenic region of the hippocampus. Neurobiol Aging 29:129–147PubMedCrossRefGoogle Scholar
  31. Ide Y, Fujiyama F, Okamoto-Furuta K, Tamamaki N, Kaneko T, Hisatsune T (2008) Rapid integration of young newborn dentate gyrus granule cells in the adult hippocampal circuitry. Eur J Neurosci 28:2381–2392PubMedCrossRefGoogle Scholar
  32. Itou Y, Nochi R, Kuribayashi H, Saito Y, Hisatsune T (2011) Cholinergic activation of hippocampal neural stem cells in aged dentate gyrus. Hippocampus 21:446–459Google Scholar
  33. Jin K, Minami M, Lan JQ et al (2001) Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proc Natl Acad Sci USA 98:4710–4715PubMedCrossRefGoogle Scholar
  34. Jung R, Kornmullar A (1938) Eine methodik der ableitung lokalisierter potential schwankingen aus subcorticalen hirnyebieten. Arch Psychiat Neruenkr 109:1–30CrossRefGoogle Scholar
  35. Kahana MJ, Sekuler R, Caplan JB et al (1999) Human theta oscillations exhibit task dependence during virtual maze navigation. Nature 24:781–784CrossRefGoogle Scholar
  36. Kaneko N, Okano H, Sawamoto K (2006) Role of the cholinergic system in regulating survival of newborn neurons in the adult mouse dentate gyrus and olfactory bulb. Genes Cells 11:1145–1159PubMedCrossRefGoogle Scholar
  37. Kaplan MS, Bell DH (1984) Mitotic neuroblasts in the 9-day-old and 11-month-old rodent hippocampus. J Neurosci 4:1429–1441PubMedGoogle Scholar
  38. Kaplan MS, Hinds JW (1977) Neurogenesis in the adult rat: electron microscopic analysis of light radioautographs. Science 197:1092–1094PubMedCrossRefGoogle Scholar
  39. 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 10:355–362PubMedCrossRefGoogle Scholar
  40. Kempermann G, Kuhn HG, Gage FH (1997) Genetic influence on neurogenesis in the dentate gyrus of adult mice. Proc Natl Acad Sci USA 94:10409–10414PubMedCrossRefGoogle Scholar
  41. Kempermann G, Brandon EP, Gage FH (1998) Environmental stimulation of 129/SvJ mice causes increased cell proliferation and neurogenesis in the adult dentate gyrus. Curr Biol 8:939–942PubMedCrossRefGoogle Scholar
  42. Kempermann G, Jessberger S, Steiner B et al (2004) Milestones of neuronal development in the adult hippocampus. Trends Neurosci 27:447–452PubMedCrossRefGoogle Scholar
  43. Koketsu D, Furuichi Y, Maeda, M et al (2006) Increased number of new neurons in the olfactory bulb and hippocampus of adult non-human primates after focal ischemia. Exp Neurol 199:92–102PubMedCrossRefGoogle Scholar
  44. Kornack DR, Rakic P (1999) Continuation of neurogenesis in the hippocampus of the adult macaque monkey. Proc Natl Acad Sci USA 96:5768–5773PubMedCrossRefGoogle Scholar
  45. Kramis R, Vanderwolf CH, Bland BH (1975) Two types of hippocampal rhythmical slow activity in both the rabbit and the rat: relations to behavior and effects of atropine, diethyl ether, urethane, and pentobarbital. Exp Neurol 49:58–85PubMedCrossRefGoogle Scholar
  46. Kressin K, Kuprijanova E, Jabs R et al (1995) Developmental regulation of Na+ and K+ conductances in glial cells of mouse hippocampal brain slices. Glia 15:173–187PubMedCrossRefGoogle Scholar
  47. Lawson VH, Bland BH (1993) The role of the septohippocampal pathway in the regulation of hippocampal field activity and behavior: analysis by the intraseptal microinfusion of carbachol, atropine, and procaine. Exp Neurol 120:132–144PubMedCrossRefGoogle Scholar
  48. Matsuyama S, Nei K, Tanaka C (1997) Regulation of GABA release via NMDA and 5-HT1A receptors in guinea pig dentate gyrus. Brain Res 761:105–112PubMedCrossRefGoogle Scholar
  49. Matthias K, Kirchhoff F, Seifert G et al (2003) Segregated expression of AMPA-type glutamate receptors and glutamate transporters defines distinct astrocyte populations in the mouse hippocampus. J Neurosci 23:1750–1758PubMedGoogle Scholar
  50. Mohapel P, Leanza G, Kokaia M et al (2005) Forebrain acetylcholine regulates adult hippocampal neurogenesis and learning. Neurobiol Aging 26:939–946PubMedCrossRefGoogle Scholar
  51. 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 13:512–520PubMedCrossRefGoogle Scholar
  52. O’Keefe (2007) Hippocampal neurophysiology in the behaving animal. In: Andersen P, Morris R, Amaral D, et al (eds) The hippocampus book. Oxford University Press, New YorkGoogle Scholar
  53. Olariu A, Cleaver KM, Shore LE et al (2005) A natural form of learning can increase and decrease the survival of new neurons in the dentate gyrus. Hippocampus 15:750–762PubMedCrossRefGoogle Scholar
  54. Pereira AC, Huddleston DE, Brickman AM et al (2007) An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci USA 104:5638–5643PubMedCrossRefGoogle Scholar
  55. Santarelli L, Saxe M, Gross C et al (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301:805–809PubMedCrossRefGoogle Scholar
  56. Saxe MD, Battaglia F, Wang J et al (2006) Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc Natl Acad Sci USA 103:17501–17506PubMedCrossRefGoogle Scholar
  57. Seri B, Garcia-Verdugo JM, McEwen BS et al (2001) Astrocytes give rise to new neurons in the adult mammalian hippocampus. J Neurosci 21:7153–7160PubMedGoogle Scholar
  58. Shors TJ, Miesegaes G, Beylin A et al (2001) Neurogenesis in the adult is involved in the formation of trace memories. Nature 410:372–376CrossRefGoogle Scholar
  59. Steiner B, Klempin F, Wang L et al (2006) Type-2 cells as link between glial and neuronal lineage in adult hippocampal neurogenesis. Glia 54:805–814PubMedCrossRefGoogle Scholar
  60. Suh H, Consiglio A, Ray J et al (2007) In vivo fate analysis reveals the multipotent and self-renewal capacities of Sox2(+) neural stem cells in the adult hippocampus. Cell Stem Cell 1:515–528PubMedCrossRefGoogle Scholar
  61. Tashiro A, Sandler VM, Toni N et al (2006) NMDA-receptor-mediated, cell-specific integration of new neurons in adult dentate gyrus. Nature 442:929–933CrossRefGoogle Scholar
  62. Tonchev AB, Yamashima T, Zhao L et al (2003) Proliferation of neural and neuronal progenitors after global brain ischemia in young adult macaque monkeys. Mol Cell Neurosci 23:292–301PubMedCrossRefGoogle Scholar
  63. Toni N, Teng EM, Bushong EA et al (2007) Synapse formation on neurons born in the adult hippocampus. Nat Neurosci 10:727–734PubMedCrossRefGoogle Scholar
  64. Tozuka Y, Fukuda S, Namba T et al (2005) GABAergic excitation promotes neuronal differentiation in adult hippocampal progenitor cells. Neuron 47:803–815PubMedCrossRefGoogle Scholar
  65. van Praag H, Kempermann G, Gage FH (1999) Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 2:266–270PubMedCrossRefGoogle Scholar
  66. van Praag H, Schinder AF, Christie BR et al (2002) Functional neurogenesis in the adult hippocampus. Nature 415:1030–1034CrossRefGoogle Scholar
  67. Vanderwolf CH (1969) Hippocampal electrical activity and voluntary movement in the rat. Electroencephalogr Clin Neurophysiol 26:407–418PubMedCrossRefGoogle Scholar
  68. Wang LP, Kempermann G, Kettenmann H (2005) A subpopulation of precursor cells in the mouse dentate gyrus receives synaptic GABAergic input. Mol Cell Neurosci 29:181–189PubMedCrossRefGoogle Scholar
  69. Yamaguchi M, Saito H, Suzuki M et al (2000) Visualization of neurogenesis in the central nervous system using nestin promoter-GFP transgenic mice. Neuroreport 26:1991–1996CrossRefGoogle Scholar
  70. Yoshimura S, Takagi Y, Harada J et al (2001) FGF-2 regulation of neurogenesis in adult hippocampus after brain injury. Proc Natl Acad Sci USA 98:5874–5879PubMedCrossRefGoogle Scholar
  71. Zhang CL, Zou Y, He W et al (2008) A role for adult TLX-positive neural stem cells in learning and behaviour. Nature 451:1004–1007CrossRefGoogle Scholar
  72. 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 26:3–11PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2011

Authors and Affiliations

  1. 1.Department of Integrated BiosciencesThe University of TokyoKashiwaJapan

Personalised recommendations