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:

Irradiation induces neural precursor-cell dysfunction

Nature Medicine volume 8, pages 955–962 (2002)Cite this article

Abstract

In both pediatric and adult patients, cranial radiation therapy causes a debilitating cognitive decline that is poorly understood and currently untreatable. This decline is characterized by hippocampal dysfunction, and seems to involve a radiation-induced decrease in postnatal hippocampal neurogenesis. Here we show that the deficit in neurogenesis reflects alterations in the microenvironment that regulates progenitor-cell fate, as well as a defect in the proliferative capacity of the neural progenitor-cell population. Not only is hippocampal neurogenesis ablated, but the remaining neural precursors adopt glial fates and transplants of non-irradiated neural precursor cells fail to differentiate into neurons in the irradiated hippocampus. The inhibition of neurogenesis is accompanied by marked alterations in the neurogenic microenvironment, including disruption of the microvascular angiogenesis associated with adult neurogenesis and a marked increase in the number and activation status of microglia within the neurogenic zone. These findings provide clear targets for future therapeutic interventions.

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: Irradiation decreases neural precursor proliferation and growth potential.
Figure 2: Irradiation alters the cell fate profile of the hippocampus.
Figure 3: Precursor cells from irradiated brains can differentiate into neurons in vitro.
Figure 4: Irradiation disrupts the neurogenic microenvironment.
Figure 5: Irradiation induces a chronic inflammatory response.
Figure 6: Irradiation disrupts the neuro-vascular relationship.

Similar content being viewed by others

References

  1. Strother, D.R. et al. Tumors of the central nervous system. in Principles and Practice of Pediatric Oncology, 4th edn. (eds. Pizzo, P.A. & Poplack, D.G.) 751–824 (Lipincott Williams and Wilkins, Philadelphia, Pennsylvania, 2002).

    Google Scholar 

  2. Surma-aho, O. et al. Adverse long-term effects of brain radiotherapy in adult low-grade glioma patients. Neurology 56, 1285–1290 (2001).

    Article  CAS  Google Scholar 

  3. Roman, D.D. & Sperduto, P.W. Neuropsychological effects of cranial radiation: Current knowledge and future directions. Int. J. Radiat. Oncol. Biol. Phys. 31, 983–998 (1995).

    Article  CAS  Google Scholar 

  4. Crossen, J.R., Garwood, D., Glatstein, E. & Neuwelt, E.A. Neurobehavioral sequelae of cranial irradiation in adults: A review of radiation-induced encephalopathy. J. Clin. Oncol. 12, 627–642 (1994).

    Article  CAS  Google Scholar 

  5. Abayomi, O.K. Pathogenesis of irradiation-induced cognitive dysfunction. Acta Oncol. 35, 659–663 (1996).

    Article  CAS  Google Scholar 

  6. Lee, P.W., Hung, B.K., Woo, E.K., Tai, P.T. & Choi, D.T. Effects of radiation therapy on neuropsychological functioning in patients with nasopharyngeal carcinoma. J. Neurol. Neurosurg. Psychiatry 52, 488–492 (1989).

    Article  CAS  Google Scholar 

  7. Hodges, H. et al. Late behavioural and neuropathological effects of local brain irradiation in the rat. Behav. Brain Res. 91, 99–114 (1998).

    Article  CAS  Google Scholar 

  8. Sienkiewicz, Z.J., Haylock, R.G. & Saunders, R.D. Prenatal irradiation and spatial memory in mice: Investigation of dose-response relationship. Int. J. Radiat. Biol. 65, 611–618 (1994).

    Article  CAS  Google Scholar 

  9. Tada, E., Parent, J.M., Lowenstein, D.H. & Fike, J.R. X-irradiation causes a prolonged reduction in cell proliferation in the dentate gyrus of adult rats. Neuroscience 99, 33–41 (2000).

    Article  CAS  Google Scholar 

  10. Peissner, W., Kocher, M., Treuer, H. & Gillardon, F. Ionizing radiation-induced apoptosis of proliferating stem cells in the dentate gyrus of the adult rat hippocampus. Brain Res. Mol. Brain Res. 71, 61–68 (1999).

    Article  CAS  Google Scholar 

  11. Parent, J.M., Tada, E., Fike, J.R. & Lowenstein, D.H. Inhibition of dentate granule cell neurogenesis with brain irradiation does not prevent seizure-induced mossy fiber synaptic reorganization in the rat. J. Neurosci. 19, 4508–4519 (1999).

    Article  CAS  Google Scholar 

  12. Snyder, J.S., Kee, N. & Wojtowicz, J.M. Effects of adult neurogenesis on synaptic plasticity in the rat dentate gyrus. J. Neurophysiol. 85, 2423–2431 (2001).

    Article  CAS  Google Scholar 

  13. 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 

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

    Article  CAS  Google Scholar 

  15. 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 

  16. Dawirs, R.R., Hildebrandt, K. & Teuchert-Noodt, G. Adult treatment with haloperidol increases dentate granule cell proliferation in the gerbil hippocampus. J. Neural Transm. 105, 317–327 (1998).

    Article  CAS  Google Scholar 

  17. Leventhal, C., Rafii, S., Rafii, D., Shahar, A. & Goldman, S.A. Endothelial trophic support of neuronal production and recruitment from the adult mammalian subependyma. Mol. Cell Neurosci. 13, 450–464 (1999).

    Article  CAS  Google Scholar 

  18. Vallieres, L., Campbell, I.L., Gage, F.H. & Sawchenko, P.E. Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J. Neurosci. 22, 486–492 (2002).

    Article  CAS  Google Scholar 

  19. Calvo, W., Hopewell, J.W., Reinhold, H.S. & Yeung, T.K. Time- and dose-related changes in the white matter of the rat brain after single doses of X rays. Br. J. Radiol. 61, 1043–1052 (1988).

    Article  CAS  Google Scholar 

  20. Sheline, G.E., Wara, W.M. & Smith, V. Therapeutic irradiation and brain injury. Int. J. Radiat. Oncol. Biol. Phys. 6, 1215–1228 (1980).

    Article  CAS  Google Scholar 

  21. Pezner, R.D. & Archambeau, J.O. Brain tolerance unit: A method to estimate risk of radiation brain injury for various dose schedules. Int. J. Radiat. Oncol. Biol. Phys. 7, 397–402 (1981).

    Article  CAS  Google Scholar 

  22. Marks, J.E., Baglan, R.J., Prassad, S.C. & Blank, W.F. Cerebral radionecrosis: Incidence and risk in relation to dose, time, fractionation and volume. Int. J. Radiat. Oncol. Biol. Phys. 7, 243–252 (1981).

    Article  CAS  Google Scholar 

  23. Palmer, T.D., Willhoite, A.R. & Gage, F.H. Vascular niche for adult hippocampal neurogenesis. J. Comp Neurol. 425, 479–494 (2000).

    Article  CAS  Google Scholar 

  24. Gundersen, H.J. et al. The new stereological tools: Dissector, fractionator, nucleator and point sampled intercepts and their use in pathological research and diagnosis. APMIS 96, 857–881 (1988).

    Article  CAS  Google Scholar 

  25. 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 

  26. Gage, F.H. et al. Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc. Natl. Acad. Sci. USA 92, 11879–11883 (1995).

    Article  CAS  Google Scholar 

  27. Suhonen, J.O., Peterson, D.A., Ray, J. & Gage, F.H. Differentiation of adult hippocampus-derived progenitors into olfactory neurons in vivo. Nature 383, 624–627 (1996).

    Article  CAS  Google Scholar 

  28. Hong, J.H. et al. Induction of acute phase gene expression by brain irradiation. Int. J. Radiat. Oncol. Biol. Phys. 33, 619–626 (1995).

    Article  CAS  Google Scholar 

  29. Heyser, C.J., Masliah, E., Samimi, A., Campbell, I.L. & Gold, L.H. Progressive decline in avoidance learning paralleled by inflammatory neurodegeneration in transgenic mice expressing interleukin 6 in the brain. Proc. Natl. Acad. Sci. USA 94, 1500–1505 (1997).

    Article  CAS  Google Scholar 

  30. Louissaint, A., Rao, S., Leventhal, C. & Goldman, S.A. Coordinated interaction of neurogenesis and angiogenesis in the adult songbird brain. Neuron 34, 945–960 (2002).

    Article  CAS  Google Scholar 

  31. Lim, D.A. et al. Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron 28, 713–726 (2000).

    Article  CAS  Google Scholar 

  32. Seaberg, R.M. & van der Kooy, D. Adult rodent neurogenic regions: the ventricular subependyma contains neural stem cells, but the dentate gyrus contains restricted progenitors. J. Neurosci. 22, 1784–1793 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank W. Stallcup for the NG2 antibody; B.E. Hoyte for help with the manuscript graphics; R. Malenka for the use of the Pritzker Foundation confocal microscope; D. Morhardt and D. Schaal for help in preparing the manuscript; and M. Brown, L. Fajardo and P. Fisher for valuable insights. This work was supported by grants MH20016-05 from the National Institute of Mental Health, R01CA76141 from the National Cancer Institute, R21NS40088 from the National Institute for Neurological Disorders and Stroke and Palmer Lab Startup funds from the Department of Neurosurgery, Stanford University.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Stanford University, Stanford, California, USA

    Michelle L. Monje & Theo D. Palmer

  2. Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA

    Shinichiro Mizumatsu & John R. Fike

Authors
  1. Michelle L. Monje
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shinichiro Mizumatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John R. Fike
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Theo D. Palmer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Theo D. Palmer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Monje, M., Mizumatsu, S., Fike, J. et al. Irradiation induces neural precursor-cell dysfunction. Nat Med 8, 955–962 (2002). https://doi.org/10.1038/nm749

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm749

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