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Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus

Nature Neuroscience volume 10, pages 355–362 (2007)Cite this article

Abstract

Throughout adulthood, new neurons are continuously added to the dentate gyrus, a hippocampal subregion that is important in spatial learning. Whether these adult-generated granule cells become functionally integrated into memory networks is not known. We used immunohistochemical approaches to visualize the recruitment of new neurons into circuits supporting water maze memory in intact mice. We show that as new granule cells mature, they are increasingly likely to be incorporated into circuits supporting spatial memory. By the time the cells are 4 or more weeks of age, they are more likely than existing granule cells to be recruited into circuits supporting spatial memory. This preferential recruitment supports the idea that new neurons make a unique contribution to memory processing in the dentate gyrus.

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Figure 1: Age-dependent integration of new neurons into dentate gyrus circuits supporting spatial memory.
Figure 2: Induction of Arc in new neurons.
Figure 3: Age-dependent integration of new neurons into circuits supporting spatial memory does not occur in the olfactory bulb.
Figure 4: Are 1-week-old neurons transiently incorporated into dentate gyrus circuits supporting spatial memory? (a) Mice were trained either 1 week or 6 weeks following BrdU treatment, and Fos and BrdU expression was quantified after the third day of training.
Figure 5: Overlap between Fos+ and BrdU+ populations depends on the delay between BrdU treatment and training.
Figure 6: Fos expression in the dentate gyrus is correlated with memory strength.

References

  1. Aimone, J.B., Wiles, J. & Gage, F.H. Potential role for adult neurogenesis in the encoding of time in new memories. Nat. Neurosci. 9, 723–727 (2006).

    Article  CAS  Google Scholar 

  2. Cameron, H.A. & McKay, R.D. Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J. Comp. Neurol. 435, 406–417 (2001).

    Article  CAS  Google Scholar 

  3. Doetsch, F. & Hen, R. Young and excitable: the function of new neurons in the adult mammalian brain. Curr. Opin. Neurobiol. 15, 121–128 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Song, H. et al. New neurons in the adult mammalian brain: synaptogenesis and functional integration. J. Neurosci. 25, 10366–10368 (2005).

    Article  CAS  Google Scholar 

  6. Overstreet-Wadiche, L.S. & Westbrook, G.L. Functional maturation of adult-generated granule cells. Hippocampus 16, 208–215 (2006).

    Article  Google Scholar 

  7. Altman, J. & Das, G.D. Post-natal origin of microneurones in the rat brain. Nature 207, 953–956 (1965).

    Article  CAS  Google Scholar 

  8. Hastings, N.B. & Gould, E. Rapid extension of axons into the CA3 region by adult-generated granule cells. J. Comp. Neurol. 413, 146–154 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. 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).

    Article  CAS  Google Scholar 

  11. Esposito, M.S. et al. Neuronal differentiation in the adult hippocampus recapitulates embryonic development. J. Neurosci. 25, 10074–10086 (2005).

    Article  CAS  Google Scholar 

  12. Ge, S. et al. GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 439, 589–593 (2006).

    Article  CAS  Google Scholar 

  13. Tashiro, A., Sandler, V.M., Toni, N., Zhao, C. & Gage, F.H. NMDA-receptor–mediated, cell-specific integration of new neurons in adult dentate gyrus. Nature 442, 929–933 (2006).

    Article  CAS  Google Scholar 

  14. Shors, T.J. et al. Neurogenesis in the adult is involved in the formation of trace memories. Nature 410, 372–376 (2001).

    Article  CAS  Google Scholar 

  15. 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).

    Article  Google Scholar 

  16. Leuner, B., Gould, E. & Shors, T.J. Is there a link between adult neurogenesis and learning? Hippocampus 16, 216–224 (2006).

    Article  Google Scholar 

  17. 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).

    Article  CAS  Google Scholar 

  18. Dupret, D. et al. Methylazoxymethanol acetate does not fully block cell genesis in the young and aged dentate gyrus. Eur. J. Neurosci. 22, 778–783 (2005).

    Article  Google Scholar 

  19. Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809 (2003).

    Article  CAS  Google Scholar 

  20. Nowakowski, R.S., Lewin, S.B. & Miller, M.W. Bromodeoxyuridine immunohistochemical determination of the lengths of the cell cycle and the DNA-synthetic phase for an anatomically defined population. J. Neurocytol. 18, 311–318 (1989).

    Article  CAS  Google Scholar 

  21. Gage, F.H., Ray, J. & Fisher, L.J. Isolation, characterization and use of stem cells from the CNS. Annu. Rev. Neurosci. 18, 159–192 (1995).

    Article  CAS  Google Scholar 

  22. Guzowski, J.F. et al. Mapping behaviorally relevant neural circuits with immediate-early gene expression. Curr. Opin. Neurobiol. 15, 599–606 (2005).

    Article  CAS  Google Scholar 

  23. Teixeira, C.M., Pomedli, S.R., Maei, H.R., Kee, N. & Frankland, P.W. Involvement of the anterior cingulate cortex in the expression of remote spatial memory. J. Neurosci. 26, 7555–7564 (2006).

    Article  Google Scholar 

  24. Kim, J.J. & Fanselow, M.S. Modality-specific retrograde amnesia of fear. Science 256, 675–677 (1992).

    Article  CAS  Google Scholar 

  25. Takehara, K., Kawahara, S. & Kirino, Y. Time-dependent reorganization of the brain components underlying memory retention in trace eyeblink conditioning. J. Neurosci. 23, 9897–9905 (2003).

    Article  CAS  Google Scholar 

  26. Clark, R.E., Broadbent, N.J. & Squire, L.R. Hippocampus and remote spatial memory in rats. Hippocampus 15, 260–272 (2005).

    Article  Google Scholar 

  27. Martin, S.J., de Hoz, L. & Morris, R.G. Retrograde amnesia: neither partial nor complete hippocampal lesions in rats result in preferential sparing of remote spatial memory, even after reminding. Neuropsychologia 43, 609–624 (2005).

    Article  Google Scholar 

  28. McNaughton, B.L., Barnes, C.A., Meltzer, J. & Sutherland, R.J. Hippocampal granule cells are necessary for normal spatial learning but not for spatially-selective pyramidal cell discharge. Exp. Brain Res. 76, 485–496 (1989).

    Article  CAS  Google Scholar 

  29. Gould, E., Beylin, A., Tanapat, P., Reeves, A. & Shors, T.J. Learning enhances adult neurogenesis in the hippocampal formation. Nat. Neurosci. 2, 260–265 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  31. van Praag, H., Kempermann, G. & Gage, F.H. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat. Neurosci. 2, 266–270 (1999).

    Article  CAS  Google Scholar 

  32. Kempermann, G., Kuhn, H.G. & Gage, F.H. Experience-induced neurogenesis in the senescent dentate gyrus. J. Neurosci. 18, 3206–3212 (1998).

    Article  CAS  Google Scholar 

  33. 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).

    Article  CAS  Google Scholar 

  34. Schmidt-Hieber, C., Jonas, P. & Bischofberger, J. Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature 429, 184–187 (2004).

    Article  CAS  Google Scholar 

  35. Wang, S., Scott, B.W. & Wojtowicz, J.M. Heterogenous properties of dentate granule neurons in the adult rat. J. Neurobiol. 42, 248–257 (2000).

    Article  CAS  Google Scholar 

  36. Chawla, M.K. et al. Sparse, environmentally selective expression of Arc RNA in the upper blade of the rodent fascia dentata by brief spatial experience. Hippocampus 15, 579–586 (2005).

    Article  CAS  Google Scholar 

  37. Guzowski, J.F. et al. Recent behavioral history modifies coupling between cell activity and Arc gene transcription in hippocampal CA1 neurons. Proc. Natl. Acad. Sci. USA 103, 1077–1082 (2006).

    Article  CAS  Google Scholar 

  38. Zhang, W.P., Guzowski, J.F. & Thomas, S.A. Mapping neuronal activation and the influence of adrenergic signaling during contextual memory retrieval. Learn. Mem. 12, 239–247 (2005).

    Article  Google Scholar 

  39. Lois, C. & Alvarez-Buylla, A. Long-distance neuronal migration in the adult mammalian brain. Science 264, 1145–1148 (1994).

    Article  CAS  Google Scholar 

  40. Giese, K.P., Fedorov, N.B., Filipkowski, R.K. & Silva, A.J. Autophosphorylation at Thr286 of the alpha calcium-calmodulin kinase II in LTP and learning. Science 279, 870–873 (1998).

    Article  CAS  Google Scholar 

  41. Jung, M.W. & McNaughton, B.L. Spatial selectivity of unit activity in the hippocampal granular layer. Hippocampus 3, 165–182 (1993).

    Article  CAS  Google Scholar 

  42. Bruel-Jungerman, E., Davis, S., Rampon, C. & Laroche, S. Long-term potentiation enhances neurogenesis in the adult dentate gyrus. J. Neurosci. 26, 5888–5893 (2006).

    Article  CAS  Google Scholar 

  43. Jessberger, S. & Kempermann, G. Adult-born hippocampal neurons mature into activity-dependent responsiveness. Eur. J. Neurosci. 18, 2707–2712 (2003).

    Article  Google Scholar 

  44. Ramirez-Amaya, V., Marrone, D.F., Gage, F.H., Worley, P.F. & Barnes, C.A. Integration of new neurons into functional neural networks. J. Neurosci. 26, 12237–12241 (2006).

    Article  CAS  Google Scholar 

  45. Frankland, P.W. & Bontempi, B. The organization of recent and remote memories. Nat. Rev. Neurosci. 6, 119–130 (2005).

    Article  CAS  Google Scholar 

  46. Overstreet-Wadiche, L.S., Bensen, A.L. & Westbrook, G.L. Delayed development of adult-generated granule cells in dentate gyrus. J. Neurosci. 26, 2326–2334 (2006).

    Article  CAS  Google Scholar 

  47. Becker, S. A computational principle for hippocampal learning and neurogenesis. Hippocampus 15, 722–738 (2005).

    Article  Google Scholar 

  48. Wiskott, L., Rasch, M.J. & Kempermann, G. A functional hypothesis for adult hippocampal neurogenesis: avoidance of catastrophic interference in the dentate gyrus. Hippocampus 16, 329–343 (2006).

    Article  Google Scholar 

  49. Magavi, S.S., Mitchell, B.D., Szentirmai, O., Carter, B.S. & Macklis, J.D. Adult-born and preexisting olfactory granule neurons undergo distinct experience-dependent modifications of their olfactory responses in vivo. J. Neurosci. 25, 10729–10739 (2005).

    Article  CAS  Google Scholar 

  50. Coggeshall, R.E. & Lekan, H.A. Methods for determining numbers of cells and synapses: a case for more uniform standards of review. J. Comp. Neurol. 364, 6–15 (1996).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank S. Josselyn for comments on this manuscript. This work was supported by grants from the Canadian Institutes of Health Research and the EJLB Foundation (P.W.F.). N.K. and A.H.W. were supported by Hospital for Sick Children Restracomp awards. C.M.T. received support from the Graduate Program in Areas of Basic and Applied Biology and the Portuguese Foundation for Science and Technology.

Author information

Author notes

  1. Nohjin Kee and Cátia M Teixeira: These authors contributed equally to this work.

Authors and Affiliations

  1. Program in Neurosciences and Mental Health, The Hospital for Sick Children, 555 University Avenue, Toronto, M5G 1X8, Ontario, Canada

    Nohjin Kee, Cátia M Teixeira, Afra H Wang & Paul W Frankland

  2. Department of Physiology, University of Toronto, Toronto, M5S 1A8, Ontario, Canada

    Nohjin Kee, Cátia M Teixeira & Paul W Frankland

  3. Institute of Medical Science, University of Toronto, Toronto, M5S 1A8, Ontario, Canada

    Nohjin Kee, Cátia M Teixeira, Afra H Wang & Paul W Frankland

  4. Graduate Program in Areas of Basic and Applied Biology, Universidade do Porto, Porto, 4050-465, Portugal

    Cátia M Teixeira

Authors
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Contributions

P.W.F., N.K. and C.M.T. conceived the experiments. C.M.T., P.W.F. and A.H.W. conducted the water maze studies, N.K. and C.M.T. conducted the immunohistochemistry and quantification and C.M.T. conducted the statistical analyses. PW.F. supervised the project and wrote the paper.

Corresponding author

Correspondence to Paul W Frankland.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Induction of Fos and Arc is limited to neurons following behavior testing. (PDF 662 kb)

Supplementary Fig. 2

Induction of Fos in the dentate gyrus neurons following water maze training and testing. (PDF 62 kb)

Supplementary Fig. 3

Performance of mice across multiple probe tests. (PDF 66 kb)

Supplementary Fig. 4

Preferential recruitment of adult-generated neurons from the innermost layers of the dentate gyrus into spatial memory networks. (PDF 72 kb)

Supplementary Fig. 5

Vast majority of BrdU+ cells are neuronal 10 weeks following BrdU treatment. (PDF 465 kb)

Supplementary Fig. 6

Induction of Arc in BrdU+ cells. (PDF 437 kb)

Supplementary Fig. 7

One-week-old granule cells are not transiently recruited into spatial memory networks. (PDF 151 kb)

Supplementary Results (PDF 158 kb)

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Kee, N., Teixeira, C., Wang, A. et al. Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat Neurosci 10, 355–362 (2007). https://doi.org/10.1038/nn1847

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