Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Restoring production of hippocampal neurons in old age

Nature Neuroscience volume 2, pages 894–897 (1999)Cite this article

Abstract

The production of hippocampal granule neurons continues throughout adulthood but dramatically decreases in old age. Here we show that reducing corticosteroid levels in aged rats restored the rate of cell proliferation, resulting in increased numbers of new granule neurons. This result indicates that the neuronal precursor population in the dentate gyrus remains stable into old age, but that neurogenesis is normally slowed by high levels of corticosteroids. The findings further suggest that decreased neurogenesis may contribute to age-related memory deficits associated with high corticosteroids, and that these deficits may be reversible.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: BrdU-labeled S-phase cells (black) in the dentate gyrus (counterstained blue).
Figure 2: Quantitative analysis of cell proliferation.
Figure 3: Newly born neurons in the dentate gyrus of aged adrenalectomized rats.
Figure 4: Mean densities (number of cells per 106 μm2 cross-sectional area) of immature neurons labeled for TOAD-64 in the granule cell layer of 20-month-old (old) rats following sham operation (n = 5) or adrenalectomy (n = 4).

Similar content being viewed by others

References

  1. Vargha-Khadem, F. et al. Differential effects of early hippocampal pathology on episodic and semantic memory. Science 277, 376–380 (1997).

    Article  CAS  Google Scholar 

  2. Nilsson, L.-G., Baeckman, L., Erngrund, K. & Nyberg, L. The Betula prospective cohort study: memory, health, and aging. Aging Neuropsychol. Cognit. 4, 1–32 (1997).

    Article  Google Scholar 

  3. Sapolsky, R. M. Do glucocorticoid concentrations rise with age in the rat? Neurobiol. Aging 13, 171–174 ( 1992).

    Article  CAS  Google Scholar 

  4. Lupien, S. et al. Basal cortisol levels and cognitive deficits in human aging. J. Neurosci. 14, 2893– 2903 (1994).

    Article  CAS  Google Scholar 

  5. Lupien, S. J. et al. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nat. Neurosci. 1, 69 –73 (1998).

    Article  CAS  Google Scholar 

  6. Landfield, P. W. & Eldridge, J. C. The glucocorticoid hypothesis of age-related hippocampal neurodegeneration: role of dysregulated intraneuronal calcium. Ann. NY Acad. Sci. 746, 308–326 (1994).

    Article  CAS  Google Scholar 

  7. Porter, N. M. & Landfield, P. W. Stress hormones and brain aging: adding injury to insult? Nat. Neurosci. 1, 3–4 (1998).

    Article  CAS  Google Scholar 

  8. Cameron, H. A. & McKay, R. Stem cells and neurogenesis in the adult brain. Curr. Opin. Neurobiol. 8, 677 –680 (1998).

    Article  CAS  Google Scholar 

  9. Eriksson, P. S. et al. Neurogenesis in the adult human hippocampus. Nat. Med. 4, 1313–1317 ( 1998).

    Article  CAS  Google Scholar 

  10. Gould, E. et al. Hippocampal neurogenesis in adult Old World primates. Proc. Natl. Acad. Sci. USA 96, 5263– 5267 (1999).

    Article  CAS  Google Scholar 

  11. Seki, T. & Arai, Y. Age-related production of new granule cells in the adult dentate gyrus. Neuroreport 6, 2479–2482 (1995).

    Article  CAS  Google Scholar 

  12. 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).

    Article  CAS  Google Scholar 

  13. Gould, E., Woolley, C. S., Cameron, H. A., Daniels, D. C. & McEwen, B. S. Adrenal steroids regulate postnatal development of the rat dentate gyrus: II. Effects of glucocorticoids and mineralocorticoids on cell birth. J. Comp. Neurol. 313, 486 –493 (1991).

    Article  CAS  Google Scholar 

  14. Cameron, H. A & Gould, E. Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus. Neuroscience 61, 203–209 (1994).

    Article  CAS  Google Scholar 

  15. Gould, E., McEwen, B. S., Tanapat, P., Galea, L. A. & Fuchs, E. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J. Neurosci. 17, 2492– 2498 (1997).

    Article  CAS  Google Scholar 

  16. Gould, E., Tanapat, P., McEwen, B.S, 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 95, 3168– 3171 (1998).

    Article  CAS  Google Scholar 

  17. Cameron, H. A., Woolley, C. S., McEwen, B. S. & Gould, E. Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience 56, 337– 344 (1993).

    Article  CAS  Google Scholar 

  18. Gould, E., Woolley, C. S. & McEwen, B. S. Short-term glucocorticoid manipulations affect neuronal morphology and survival in the adult dentate gyrus. Neuroscience 37, 367–375 ( 1990).

    Article  CAS  Google Scholar 

  19. Cameron, H. A. & Gould, E. Distinct populations of cells in the adult dentate gyrus undergo mitosis or apoptosis in response to adrenalectomy. J. Comp. Neurol. 369, 56–63 (1996).

    Article  CAS  Google Scholar 

  20. Sloviter, R. S., Dean, E. & Neubort, S. Electron microscopic analysis of adrenalectomy-induced hippocampal granule cell degeneration in the rat apoptosis in the adult central nervous system. J. Comp. Neurol. 330, 337 –351 (1993).

    Article  CAS  Google Scholar 

  21. Bye, N. & Nichols, N. R. Adrenalectomy-induced apoptosis and glial responsiveness during ageing. Neuroreport 9, 1179–1184 (1998).

    Article  CAS  Google Scholar 

  22. Minturn, J. E., Geschwind, D. H., Fryer, H. J. & Hockfield, S. Early postmitotic neurons transiently express TOAD-64, a neural specific protein. J. Comp. Neurol. 355, 369– 379 (1995).

    Article  CAS  Google Scholar 

  23. Seress, L. & Pokorny, J. Structure of the granular layer of the rat dentate gyrus. A light microscopic and Golgi study. J. Anat. 133, 181–195 ( 1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Debus, E., Weber, K. & Osborn, M. Monoclonal antibodies specific for glial fibrillary acidic (GFA) protein and for each of the neurofilament triplet polypeptides. Differentiation 25, 193–203 (1983).

    Article  CAS  Google Scholar 

  25. Kosaka, T. & Hama, K. Three-dimensional structure of astrocytes in the rat dentate gyrus. J. Comp. Neurol. 249, 242–260 (1986).

    Article  CAS  Google Scholar 

  26. Gould, E. & Tanapat, P. Lesion-induced proliferation of neuronal progenitors in the dentate gyrus of the adult rat. Neuroscience 80, 427–436 ( 1997).

    Article  CAS  Google Scholar 

  27. Gould, E., Cameron, H. A., Daniels, D. C., Woolley, C. S. & McEwen, B. S. Adrenal hormones suppress cell division in the adult rat dentate gyrus. J. Neurosci. 12, 3642–3650 (1992).

    Article  CAS  Google Scholar 

  28. 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 

  29. 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 

  30. West, M. J. Regionally specific loss of neurons in the aging human hippocampus. Neurobiol. Aging 14, 287–293 (1993).

    Article  CAS  Google Scholar 

  31. Rapp, P. R. & Gallagher, M. Preserved neuron number in the hippocampus of aged rats with spatial learning deficits. Proc. Natl. Acad. Sci. USA 93, 9926–9930 (1996).

    Article  CAS  Google Scholar 

  32. Woolley, C. S., Gould, E. & McEwen, B. S. Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res. 531, 225–231 (1990).

    Article  CAS  Google Scholar 

  33. Watanabe, Y., Gould, E., Cameron, H. A., Daniels, D. C. & McEwen, B. S. Phenytoin prevents stress- and corticosterone-induced damage of CA3 pyramidal neurons. Hippocampus 2, 431–436 ( 1992).

    Article  CAS  Google Scholar 

  34. Magarinos, A. M., Deslandes, A. & McEwen, B. S. Effects of antidepressants and benzodiazepine treatments on the dendritic structure of CA3 pyramidal neurons after chronic stress. Eur. J. Pharmacol. 371, 113– 122 (1999).

    Article  CAS  Google Scholar 

  35. Magarinos, A. M. & McEwen, B. S. Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: involvement of glucocorticoid secretion and excitatory amino acid receptors. Neuroscience 69, 89–98 (1995).

    Article  CAS  Google Scholar 

  36. Liu, Y. B., Lio, P. A., Pasternak, J. F. & Trommer, B. L. Developmental changes in membrane properties and postsynaptic currents of granule cells in rat dentate gyrus. J. Neurophysiol. 76, 1074–1088 (1996).

    Article  CAS  Google Scholar 

  37. West, M. J. New stereological methods for counting neurons. Neurobiol. Aging 14, 275–285 ( 1993).

    Article  CAS  Google Scholar 

  38. Guillery, R. W. & Herrup, K. Quantification without pontification: Choosing a method for counting objects in sectioned tissues. J. Comp. Neurol. 386, 2– 7 (1997).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Susan Hockfield for her gift of TOAD-64 antisera and Farnaz Yassaee and Bechien Wu for their technical assistance.

Author information

Authors and Affiliations

  1. Laboratory of Molecular Biology, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Heather A. Cameron & Ronald D. G. McKay

Authors
  1. Heather A. Cameron
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ronald D. G. McKay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Heather A. Cameron.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cameron, H., McKay, R. Restoring production of hippocampal neurons in old age. Nat Neurosci 2, 894–897 (1999). https://doi.org/10.1038/13197

Download citation

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/13197

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing