Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain

Article metrics

Abstract

Neurogenesis occurs continuously in the forebrain of adult mammals, but the functional importance of adult neurogenesis is still unclear. Here, using a genetic labeling method in adult mice, we found that continuous neurogenesis results in the replacement of the majority of granule neurons in the olfactory bulb and a substantial addition of granule neurons to the hippocampal dentate gyrus. Genetic ablation of newly formed neurons in adult mice led to a gradual decrease in the number of granule cells in the olfactory bulb, inhibition of increases in the granule cell number in the dentate gyrus and impairment of behaviors in contextual and spatial memory, which are known to depend on hippocampus. These results suggest that continuous neurogenesis is required for the maintenance and reorganization of the whole interneuron system in the olfactory bulb, the modulation and refinement of the existing neuronal circuits in the dentate gyrus and the normal behaviors involved in hippocampal-dependent memory.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Tamoxifen-induced Cre recombinase activity in adult NSCs in the SVZ of the lateral ventricles of Nes-CreERT2 mice.
Figure 2: Continuous adult neurogenesis in the olfactory bulb visualized by long-term labeling of NSCs.
Figure 3: Ablation of neurogenesis decreases the number of granule cells in the olfactory bulb.
Figure 4: Similar survival of early born granule cells in oil- and tamoxifen-treated Line 5-1/NSE-DTA mice.
Figure 5: Ablation of newly formed neurons does not affect discrimination and memory of odors.
Figure 6: Continuous adult neurogenesis in the dentate gyrus visualized by long-term labeling of NSCs.
Figure 7: Ablation of neurogenesis inhibits the increase of the granule cell number in the dentate gyrus.
Figure 8: Ablation of newly formed neurons impairs retention of spatial memory.

References

  1. 1

    Alvarez-Buylla, A., Garcia-Verdugo, J.M. & Tramontin, A.D. A unified hypothesis on the lineage of neural stem cells. Nat. Rev. Neurosci. 2, 287–293 (2001).

  2. 2

    Doetsch, F. The glial identity of neural stem cells. Nat. Neurosci. 6, 1127–1134 (2003).

  3. 3

    Gage, F.H. Mammalian neural stem cells. Science 287, 1433–1438 (2000).

  4. 4

    McKay, R. Stem cell in the central nervous system. Science 276, 66–71 (1997).

  5. 5

    Temple, S. The development of neural stem cells. Nature 414, 112–117 (2001).

  6. 6

    Ming, G.L. & Song, H. Adult neurogenesis in the mammalian central nervous system. Annu. Rev. Neurosci. 28, 223–250 (2005).

  7. 7

    Rosselli-Austin, L. & Altman, J. The postnatal development of the main olfactory bulb of the rat. J. Dev. Physiol. 1, 295–313 (1979).

  8. 8

    Kaplan, M.S., McNelly, N.A. & Hinds, J.W. Population dynamics of adult-formed granule neurons of the rat olfactory bulb. J. Comp. Neurol. 239, 117–125 (1985).

  9. 9

    Biebl, M., Cooper, C.M., Winkler, J. & Kuhn, H.G. Analysis of neurogenesis and programmed cell death reveals a self-renewing capacity in the adult rat brain. Neurosci. Lett. 291, 17–20 (2000).

  10. 10

    Petreanu, L. & Alvarez-Buylla, A. Maturation and death of adult-born olfactory bulb granule neurons: role of olfaction. J. Neurosci. 22, 6106–6133 (2002).

  11. 11

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

  12. 12

    Boss, B.D., Peterson, G.M. & Cowan, M. On the number of neurons in the dentate gyrus of the rat. Brain Res. 338, 144–150 (1985).

  13. 13

    Crespo, D., Stanfield, B.B. & Cowan, W.M. Evidence that late-generated granule cells do not simply replace earlier formed neurons in the rat dentate gyrus. Exp. Brain Res. 62, 541–548 (1986).

  14. 14

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

  15. 15

    Dayer, A.G., Ford, A.A., Cleaver, K.M., Yassaee, M. & Cameron, H. Short-term and long-term survival of new neurons in the rat dentate gyrus. J. Comp. Neurol. 460, 563–572 (2003).

  16. 16

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

  17. 17

    Carleton, A., Petreanu, L.T., Lansford, R., Alvarez-Buylla, A. & Lledo, P.-M. Becoming a new neuron in the adult olfactory bulb. Nat. Neurosci. 6, 507–518 (2003).

  18. 18

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

  19. 19

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

  20. 20

    Kempermann, G., Brandon, E.P. & Gage, F.H. Environmental stimulation of 129/SvJ mice causes increased cell proliferation and neurogenesis in the adult dentate gyrus. Curr. Biol. 8, 939–942 (1998).

  21. 21

    Raber, J. et al. Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis. Radiat. Res. 162, 39–47 (2004).

  22. 22

    Shors, T.J., Townsend, D.A., Zhao, M., Kozorovitskiy, Y. & Gould, E. Neurogenesis may relate to some but not all types of hippocampal-dependent learning. Hippocampus 12, 578–584 (2002).

  23. 23

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

  24. 24

    Silva, A.J. et al. Mutant mice and neuroscience: recommendations concerning genetic background. Neuron 19, 755–759 (1997).

  25. 25

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

  26. 26

    Balordi, F. & Fishell, G. Mosaic removal of hedgehog signaling in the adult SVZ reveals that the residual wild-type stem cells have a limited capacity for self-renewal. J. Neurosci. 27, 14248–14259 (2007).

  27. 27

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

  28. 28

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

  29. 29

    Parras, C.M. et al. Mash1 specifies neurons and oligodendrocytes in the postnatal brain. EMBO J. 23, 4495–4505 (2004).

  30. 30

    Lemasson, M., Saghatelyan, A., Olivo-Marin, J.-C. & Lledo, P.-M. Neonatal and adult neurogenesis provide two distinct populations of newborn neurons to the mouse olfactory bulb. J. Neurosci. 25, 6816–6825 (2005).

  31. 31

    Kobayakawa, K. et al. Innate versus learned odour processing in the mouse olfactory bulb. Nature 450, 503–508 (2007).

  32. 32

    Ahn, S. & Joyner, A.L. In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog. Nature 437, 894–897 (2005).

  33. 33

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

  34. 34

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

  35. 35

    Kempermann, G., Kuhn, H.G. & Gage, F.H. More hippocampal neurons in adult mice living in an enriched environment. Nature 386, 493–495 (1997).

  36. 36

    Snyder, J.S., Hong, N.S., McDonald, R.J. & Wojtowicz, J.M. A role for adult neurogenesis in spatial long-term memory. Neuroscience 130, 843–852 (2005).

  37. 37

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

  38. 38

    Lledo, P.M., Alonso, M. & Grubb, M.S. Adult neurogenesis and functional plasticity in neuronal circuits. Nat. Rev. Neurosci. 7, 179–193 (2006).

  39. 39

    Winner, B., Cooper-Kuhn, C.M., Aigner, R., Winkler, J. & Kuhn, H.G. Long-term survival and cell death of newly generated neurons in the adult rat olfactory bulb. Eur. J. Neurosci. 16, 1681–1689 (2002).

  40. 40

    Alonso, M. et al. Olfactory discrimination learning increases the survival of adult-born neurons in the olfactory bulb. J. Neurosci. 26, 10508–10513 (2006).

  41. 41

    Yamaguchi, M. & Mori, K. 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 (2005).

  42. 42

    Dusek, J.A. & Eichenbaum, H. The hippocampus and memory for orderly stimulus relations. Proc. Natl. Acad. Sci. USA 94, 7109–7114 (1997).

  43. 43

    Gheusi, G. et al. Importance of newly generated neurons in the adult olfactory bulb for odor discrimination. Proc. Natl. Acad. Sci. USA 97, 1823–1828 (2000).

  44. 44

    Bruce, H.M. An exteroceptive block to pregnancy in the mouse. Nature 184, 105 (1959).

  45. 45

    Kaplan, M.S. Neurogenesis in the 3-month-old rat visual cortex. J. Comp. Neurol. 195, 323–338 (1981).

  46. 46

    Magavi, S.S., Leavitt, B.R. & Macklis, J.D. Induction of neurogenesis in the neocortex of adult mice. Nature 405, 951–955 (2000).

  47. 47

    Jackson, E.L. et al. PDGFRα-positive B cells are neural stem cells in the adult SVZ that form glioma-like growths in response to increased PDGF signaling. Neuron 51, 187–199 (2006).

  48. 48

    Soriano, P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat. Genet. 21, 70–71 (1999).

  49. 49

    Srinivas, S. et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1, 4 (2001).

  50. 50

    Novak, A., Guo, C., Yang, W., Nagy, A. & Lobe, C.G. Z/EG, a double reporter mouse line that expresses enhanced green fluorescent protein upon Cre-mediated excision. Genesis 28, 147–155 (2000).

Download references

Acknowledgements

We thank P. Soriano, F. Costantini and C. Lobe for materials, and K. Nakanishi, N. Tsunekawa, M. Hayashi, M. Fujioka, H. Kohda and K. Okamoto-Furuta for technical help. This work was supported by Grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan. I.I. was supported by the 21st Century Center of Excellence Program of the Ministry of Education, Culture, Sports, Science and Technology of Japan and Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists.

Author information

I.I. conducted the experiments. I.I., M.S., M.Y. and K.M. carried out analysis on odorant discrimination and memory. I.I., K.T. and T.M. performed analysis on other behavioral tests. T.I. and S.I. provided the NSE-DTA mice. T.O. and R.K. supervised the project. I.I. and R.K. wrote the manuscript.

Correspondence to Ryoichiro Kageyama.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–13, Supplementary Tables 1–5 and Supplementary Methods (PDF 2613 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Imayoshi, I., Sakamoto, M., Ohtsuka, T. et al. Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. Nat Neurosci 11, 1153–1161 (2008) doi:10.1038/nn.2185

Download citation

Further reading