Journal of Molecular Neuroscience

, Volume 15, Issue 2, pp 99–108 | Cite as

Dietary restriction increases the number of newly generated neural cells, and induces BDNF expression, in the dentate gyrus of rats

  • Jaewon Lee
  • Wenzhen Duan
  • Jeffrey M. Long
  • Donald K. Ingram
  • Mark P. MattsonEmail author


The adult brain contains neural stem cells that are capable of proliferating, differentiating into neurons or glia, and then either surviving or dying. This process of neural-cell production (neurogenesis) in the dentate gyrus of the hippocampus is responsive to brain injury, and both mental and physical activity. We now report that neurogenesis in the dentate gyrus can also be modified by diet. Previous studies have shown that dietary restriction (DR) can suppress agerelated deficits in learning and memory, and can increase resistance of neurons to degeneration in experimental models of neurodegenerative disorders. We found that maintenance of adult rats on a DR regimen results in a significant increase in the numbers of newly produced neural cells in the dentate gyrus of the hippocampus, as determined by stereologic analysis of cells labeled with the DNA precursor analog bromodeoxyuridine. The increase in neurogenesis in rats maintained on DR appears to result from decreased death of newly produced cells, rather than from increased cell proliferation. We further show that the expression of brain-derived neurotrophic factor, a trophic factor recently associated with neurogenesis, is increased in hippocampal cells of rats maintained on DR. Our data are the first evidence that diet can affect the process of neurogenesis, as well as the first evidence that diet can affect neurotrophic factor production. These findings provide insight into the mechanisms whereby diet impacts on brain plasticity, aging and neurodegenerative disorders.

Index Entries

Aging Alzheimer’s disease bromodeoxyuridine caloric restriction hippocampus stem cells stereology 


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  1. Ballarin M., Ernfors P., Lindefors N., and Persson H. (1991) Hippocampal damage and kainic acid injection induce a rapid increase in mRNA for BDNF and NGF in the rat brain. Exp. Neurol. 114, 35–43.PubMedCrossRefGoogle Scholar
  2. Bruce-Keller A. J., Umberger G., McFall R., and Mattson M. P. (1999) Food restriction reduces brain damage and improves behavioral outcome following excitotoxic and metabolic insults. Ann. Neurol. 45, 8–15.PubMedCrossRefGoogle Scholar
  3. Cameron H. A., Hazel T. G., and McKay R. D. (1998) Regulation of neurogenesis by growth factors and neurotransmitters. J. Neurobiol. 36, 287–306.PubMedCrossRefGoogle Scholar
  4. Cheng B. and Mattson M. P. (1994) NT-3 and BDNF protect CNS neurons against metabolic/excitotoxic insults. Brain Res. 640, 56–67.PubMedCrossRefGoogle Scholar
  5. Cheng Y., Gidday J. M., Yan Q., Shah A. R., and Holtzman D. M. (1997) Marked age-dependent neuroprotection by brain-derived neurotrophic factor against neonatal hypoxic-ischemic brain injury. Ann. Neurol. 41, 521–529.PubMedCrossRefGoogle Scholar
  6. Duan W. and Mattson M. P. (1999) Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson’s disease. J. Neurosci. Res. 57, 195–206.PubMedCrossRefGoogle Scholar
  7. Finch C. E. and Morgan T. E. (1997) Food restriction and brain aging, in The Aging Brain, Mattson M. P. and Geddes J. W., eds., JAI Press. Adv. Cell Aging Gerontol. 2, 279–297.CrossRefGoogle Scholar
  8. Gage F. H., Kempermann G., Palmer T. D., Peterson D. A., and Ray J. (1998) Multipotent progenitor cells in the adult dentate gyrus. J. Neurobiol. 36, 249–266.PubMedCrossRefGoogle Scholar
  9. Gage F. H. (2000) Mammalian neural stem cells. Science 287, 1433–1438.PubMedCrossRefGoogle Scholar
  10. Goodrick C. L., Ingram D. K., Reynolds M. A., Freeman J. R., and Cider N. L. (1983) Differential effects of intermittent feeding and voluntary exercise on body weight and lifespan in adult rats. J. Gerontol. 38, 36–45.PubMedGoogle Scholar
  11. Gundersen H. J. G. and Jensen E. B. (1987) The efficiency of systematic sampling in stereology and its prediction. J. Micros. 147, 229–263.Google Scholar
  12. Hetman M., Kanning K., Cavanaugh J. E., and Xia Z. (1999) Neuroprotection by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase. J. Biol. Chem. 274, 22,569–22,580.CrossRefGoogle Scholar
  13. Idrobo F., Nandy K., Mostofsky D. I., Blatt L., and Nandy L. (1987) Dietary restriction: effects on radial maze learning and lipofuscin pigment deposition in the hippocampus and frontal cortex. Arch. Gerontol. Geriatr. 6, 355–362.PubMedCrossRefGoogle Scholar
  14. Ingram D. K., Weindruch R., Spangler E. L., Freeman J. R., and Walford R. L. (1987) Dietary restriction benefits learning and motor performance of aged mice. J. Gerontol. 42, 78–81.PubMedGoogle Scholar
  15. Kempermann G., Kuhn H. G., and Gage F. H. (1997) More hippocampal neurons in adult mice living in an enriched environment. Nature 386, 493–495.PubMedCrossRefGoogle Scholar
  16. Lee S., Williamson J., Lothman E. W., Szele F. G., Chesselet M. F., Von Hagen S., et al. (1997) Early induction of mRNA for calbindin-D28k and BDNF but not NT-3 in rat hippocampus after kainic acid treatment. Mol. Brain Res. 47, 183–194.PubMedCrossRefGoogle Scholar
  17. Lee J., Bruce-Keller A. J., Kruman I., Chan S. L., and Mattson M. P. (1999) 2-deoxy-D-glucose protects hippocampal neurons against excitotoxic and oxidative injury: involvement of stress proteins. J. Neurosci. Res. 57, 48–61.PubMedCrossRefGoogle Scholar
  18. Levine E. S., Dreyfus C. F., Black I. B., and Plummer M. R. (1995) Brain-derived neurotrophic factor rapidly enhances synaptic transmission in hippocampal neurons via postsynaptic tyrosine kinase receptors. Proc. Natl. Acad. Sci. USA 92, 8074–8077.PubMedCrossRefGoogle Scholar
  19. Lindvall O., Ernfors P., Bengzon J., Kokaia Z., Smith M. L., Siesjo B. K., and Persson H. (1992) Differential regulation of mRNAs for nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 in the adult rat brain following cerebral ischemia and hypoglycemic coma. Proc. Natl. Acad. Sci. USA 89, 648–652.PubMedCrossRefGoogle Scholar
  20. Liu J., Solway K., Messing R. O., and Sharp F. R. (1998) Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J. Neurosci. 18, 7768–7778.PubMedGoogle Scholar
  21. Logroscino G., Marder K., Cote L., Tang M. X., Shea S., and Mayeux R. (1996) Dietary lipids and antioxidants in Parkinson’s disease: a population-based, case-control study. Ann. Neurol. 39, 89–94.PubMedCrossRefGoogle Scholar
  22. Long J. M., Kalehua A. N., Muth N. J., Hengemihle J. M., Jucker M., Calhoun M. E., et al. (1998) Stereological estimation of total microglia number in mouse hippocampus. J. Neurosci. Meth. 84, 101–108.CrossRefGoogle Scholar
  23. Lowenstein D. H. and Arsenault L. (1996) The effects of growth factors on the survival and differentiation of cultured dentate gyrus neurons. J. Neurosci. 16, 1759–1769.PubMedGoogle Scholar
  24. Luskin M. B. (1998) Neuroblasts of the postnatal mammalian forebrain: their phenotype and fate. J. Neurobiol. 36, 221–233.PubMedCrossRefGoogle Scholar
  25. Mattson M. P., Lovell M. A., Furukawa K., and Markesbery W. R. (1995) Neurotrophic factors attenuate glutamate-induced accumulation of peroxides, elevation of intracellular Ca2+ concentration, and neurotoxicity and increase antioxidant enzyme activities in hippocampal neurons. J. Neurochem. 65, 1740–1751.PubMedCrossRefGoogle Scholar
  26. Mattson M. P. (2000) Impact of dietary restriction on brain aging and neurodegenerative disorders: emerging findings from experimental and epidemiological studies. Anti-Aging Med. 2, 331–336.Google Scholar
  27. Mayeux R., Costa R., Bell K., Merchant C., Tung M. X., and Jacobs D. (1999) Reduced risk of Alzheimer’s disease among individuals with low calorie intake. Neurology 59, S296-S297.Google Scholar
  28. Minichiello L., Korte M., Wolfer D., Kuhn R., Unsicker K., Cestari V., et al. (1999) Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 24, 401–414.PubMedCrossRefGoogle Scholar
  29. Nilsson M., Perfilieva E., Johansson U., Orwar O., and Eriksson P. S. (1999) Enriched environment increases neurogenesis in the adult rat dentate gyrus and improves spatial memory. J. Neurobiol. 39, 569–578.PubMedCrossRefGoogle Scholar
  30. Parent J. M., Yu T. W., Leibowitz R. T., Geschwind D. H., Sloviter R. S., and Lowenstein D. H. (1997) Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J. Neurosci. 17, 3727–3738.PubMedGoogle Scholar
  31. Seroogy K. B. and Herman J. P. (1997) In situ hybridization approaches to the study of the nervous system, in Neurochemistry: A Practical Approach, 2nd ed., Turner A. J. and Bachelard H. S., eds, Oxford University Press, Oxford, pp. 121–150.Google Scholar
  32. Sohal R. S. and Weindruch R. (1996) Oxidative stress, caloric restriction, and aging. Science 273, 59–63.PubMedCrossRefGoogle Scholar
  33. Stewart J., Mitchell J., and Kalant N. (1989) The effects of life-long food restriction on spatial memory in young and aged Fischer 344 rats measured in the eight-arm radial and the Morris water mazes. Neurobiol. Aging 10, 669–675.PubMedCrossRefGoogle Scholar
  34. van Praag H., Kempermann G., and Gage F. H. (1999) Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nature Neurosci. 2, 266–270.PubMedCrossRefGoogle Scholar
  35. Wachsman J. T. (1996) The beneficial effects of dietary restriction: reduced oxidative damage and enhanced apoptosis. Mutat. Res. 350, 25–34.PubMedGoogle Scholar
  36. Weindruch R and Walford R. L. (1988) The Retardation of Aging and Disease by Dietary Restriction. Charles C. Thomas, Springfield, IL, p. 436.Google Scholar
  37. West M. J. (1993) New stereological methods for counting neurons. Neurobiol. Aging 14, 275–285.PubMedCrossRefGoogle Scholar
  38. Young D., Lawlor P. A., Leone P., Dragunow M., and During M. J. (1999) Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective. Nature Med. 5, 448–453.PubMedCrossRefGoogle Scholar
  39. Yu Z. F. and Mattson M. P. (1999) Dietary restriction and 2-deoxyglucose administration reduce focal ischemic brain damage and improve behavioral outcome: evidence for a preconditioning mechanism. J. Neurosci. Res. 57, 830–839.PubMedCrossRefGoogle Scholar
  40. Zhu H., Guo Q., and Mattson M. P. (1999) Dietary restriction protects hippocampal neurons against the death-promoting action of a presenilin-1 mutation. Brain Res. 842, 224–229.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2001

Authors and Affiliations

  • Jaewon Lee
    • 1
    • 2
  • Wenzhen Duan
    • 1
  • Jeffrey M. Long
    • 1
  • Donald K. Ingram
    • 1
  • Mark P. Mattson
    • 1
    • 2
    Email author
  1. 1.Laboratory of Neurosciences, Gerontology Research CenterNational Institute on AgingBaltimore
  2. 2.Sanders-Brown Center on Aging and Department of Anatomy and NeurobiologyUniversity of KentuckyLexington

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