Skip to main content

Advertisement

Log in

Physical Activity and the Regulation of Neurogenesis in the Adult and Aging Brain

  • Original Paper
  • Published:
NeuroMolecular Medicine Aims and scope Submit manuscript

Abstract

The discovery that exercise regulates adult hippocampal neurogenesis, that is, the production of new neurons in the adult brain, was surprising news and changed quite fundamentally our view on how physical activity affects the brain. The everyday experience that not all athletes are necessarily smarter than more sedentary fellows and the scientific insight that adult hippocampal neurogenesis is actually a process that ranges on a very small scale raised important questions on the relevance of this finding. We propose that the exercise-related regulation of adult hippocampal neurogenesis is a qualitative rather than a quantitative event and that it is a particularly prominent and suggestive example of activity-dependent cellular plasticity. For rodents, the animals, in which most of this research has been done, cognition is almost inseparable from locomotion. Physical activity, especially exerted over longer periods of time, might indicate to the brain an increased chance of experience those situations rich in complexity and novelty that presumably benefit from more new neurons. We thus propose that it is not isolated physical activity that is “good for the brain”, but physical activity in the context of cognitive challenges. This would also explain why few new neurons could be beneficial for successful aging. We here review the current stage of the knowledge how this exercise-induced regulation of neurogenesis might work.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Adlard, P. A., & Cotman, C. W. (2004). Voluntary exercise protects against stress-induced decreases in brain-derived neurotrophic factor protein expression. Neuroscience, 124, 985–992.

    Article  PubMed  CAS  Google Scholar 

  • Adlard, P. A., Perreau, V. M., & Cotman, C. W. (2005). The exercise-induced expression of BDNF within the hippocampus varies across life-span. Neurobiology of Aging, 26, 511–520.

    Article  PubMed  CAS  Google Scholar 

  • Altman, J., & Das, G. D. (1965). Autoradiographic and histologic evidence of postnatal neurogenesis in rats. Journal of Comparative Neurology, 124, 319–335.

    Article  PubMed  CAS  Google Scholar 

  • Banerjee, S. B., Rajendran, R., Dias, B. G., et al. (2005). Recruitment of the Sonic hedgehog signalling cascade in electroconvulsive seizure-mediated regulation of adult rat hippocampal neurogenesis. European Journal of Neuroscience, 22, 1570–1580.

    Article  PubMed  Google Scholar 

  • Biebl, M., Cooper, C. M., Winkler, J., et al. (2000). Analysis of neurogenesis and programmed cell death reveals a self- renewing capacity in the adult rat brain. Neuroscience Letters, 291, 17–20.

    Article  PubMed  CAS  Google Scholar 

  • Bjornebekk, A., Mathe, A. A., & Brene, S. (2006). Running has differential effects on NPY, opiates, and cell proliferation in an animal model of depression and controls. Neuropsychopharmacology, 31, 256–264.

    Article  PubMed  CAS  Google Scholar 

  • Bland, B. H., & Vanderwolf, C. H. (1972). Electrical stimulation of the hippocampal formation: Behavioral and bioloectrical effects. Brain Research, 43, 89–106.

    Article  PubMed  CAS  Google Scholar 

  • Brandt, M. D., Jessberger, S., Steiner, B., et al. (2003). Transient calretinin expression defines early postmitotic step of neuronal differentiation in adult hippocampal neurogenesis of mice. Molecular and Cellular Neurosciences, 24, 603–613.

    Article  PubMed  CAS  Google Scholar 

  • Brown, J., Cooper-Kuhn, C. M., Kempermann, G., et al. (2003). Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis. European Journal of Neuroscience, 17, 2042–2046.

    Article  PubMed  Google Scholar 

  • Cameron, H. A., & McKay, R. D. (1999). Restoring production of hippocampal neurons in old age. Nature Neuroscience, 2, 894–897.

    Article  PubMed  CAS  Google Scholar 

  • Carro, E., Nunez, A., Busiguina, S., et al. (2000). Circulating insulin-like growth factor I mediates effects of exercise on the brain. Journal of Neuroscience, 20, 2926–2933.

    PubMed  CAS  Google Scholar 

  • Dobrossy, M. D., Drapeau, E., Aurousseau, C., et al. (2003). Differential effects of learning on neurogenesis: learning increases or decreases the number of newly born cells depending on their birth date. Molecular Psychiatry, 8, 974–982.

    Article  PubMed  CAS  Google Scholar 

  • D’Sa, C., & Duman, R. S. (2002). Antidepressants and neuroplasticity. Bipolar Disorders, 4, 183–194.

    Article  PubMed  CAS  Google Scholar 

  • Encinas, J. M., Vaahtokari, A., & Enikolopov, G. (2006). Fluoxetine targets early progenitor cells in the adult brain. Proceedings of the National Academy of Sciences of the United States of America, 103, 8233–8238.

    Article  PubMed  CAS  Google Scholar 

  • Eriksson, P. S., Perfilieva, E., Bjork-Eriksson, T., et al. (1998). Neurogenesis in the adult human hippocampus. Nature Medicine, 4, 1313–1317.

    Article  PubMed  CAS  Google Scholar 

  • Ernst, C., Olson, A. K., Pinel, J. P., et al. (2006). Antidepressant effects of exercise: Evidence for an adult-neurogenesis hypothesis? Journal of Psychiatry & Neuroscience, 31, 84–92.

    Google Scholar 

  • Fabel, K., Fabel, K., Tam, B., et al. (2003a). VEGF is necessary for exercise-induced adult hippocampal neurogenesis. European Journal of Neuroscience, 18, 2803–2812.

    Article  PubMed  Google Scholar 

  • Fabel, K., Toda, H., & Palmer, T. (2003b). Copernican stem cells: regulatory constellations in adult hippocampal neurogenesis. Journal of Cellular Biochemistry, 88, 41–50.

    Article  PubMed  CAS  Google Scholar 

  • Fediuc, S., Campbell, J. E., & Riddell, M. C. (2006). Effect of voluntary wheel running on circadian corticosterone release and on HPA axis responsiveness to restraint stress in Sprague-Dawley rats. Journal of Applied Physiology, 100, 1867–1875.

    Article  PubMed  CAS  Google Scholar 

  • Filippov, V., Kronenberg, G., Pivneva, T., et al. (2003). Subpopulation of nestin-expressing progenitor cells in the adult murine hippocampus shows electrophysiological and morphological characteristics of astrocytes. Molecular and Cellular Neurosciences, 23, 373–382.

    Article  PubMed  CAS  Google Scholar 

  • Garcia, A., Steiner, B., Kronenberg, G., et al. (2004). Age-dependent expression of glucocorticoid- and mineralocorticoid receptors on neural precursor cell populations in the adult murine hippocampus. Aging Cell, 3, 363–371.

    Article  PubMed  CAS  Google Scholar 

  • Gomez-Merino, D., Bequet, F., Berthelot, M., et al. (2001). Site-dependent effects of an acute intensive exercise on extracellular 5-HT and 5-HIAA levels in rat brain. Neuroscience Letters, 301, 143–146.

    Article  PubMed  CAS  Google Scholar 

  • Gomez-Pinilla, F., Dao, L., & So, V. (1997). Physical exercise induces FGF-2 and its mRNA in the hippocampus. Brain Research, 764, 1–8.

    Article  PubMed  CAS  Google Scholar 

  • Gould, E., Beylin, A., Tanapat, P., et al. (1999). Learning enhances adult neurogenesis in the hippoampal formation. Nature Neuroscience, 2, 260–265.

    Article  PubMed  CAS  Google Scholar 

  • Heiss, J. D., Papavassiliou, E., Merrill, M. J., et al. (1996). Mechanism of dexamethasone suppression of brain tumor-associated vascular permeability in rats. Involvement of the glucocorticoid receptor and vascular permeability factor. Journal of Clinical Investigation, 98, 1400–1408.

    Article  PubMed  CAS  Google Scholar 

  • Huang, T. L., Lee, C. T., & Liu, Y. L. (2007). Serum brain-derived neurotrophic factor levels in patients with major depression: Effects of antidepressants. Journal of Psychiatric Research. Ahead of print, PMID: 17585940.

  • Huttmann, K., Sadgrove, M., Wallraff, A., et al. (2003). Seizures preferentially stimulate proliferation of radial glia-like astrocytes in the adult dentate gyrus: functional and immunocytochemical analysis. European Journal of Neuroscience, 18, 2769–2778.

    Article  PubMed  Google Scholar 

  • Ivy, A. S., Rodriguez, F. G., Garcia, C., et al. (2003). Noradrenergic and serotonergic blockade inhibits BDNF mRNA activation following exercise and antidepressant. Pharmacology Biochemistry and Behavior, 75, 81–88.

    Article  CAS  Google Scholar 

  • Jessberger, S., Romer, B., Babu, H., et al. (2005). Seizures induce proliferation and dispersion of doublecortin-positive hippocampal progenitor cells. Experimental Neurology, 196, 342–351.

    Article  PubMed  CAS  Google Scholar 

  • Johnson, R. A., & Mitchell, G. S. (2003). Exercise-induced changes in hippocampal brain-derived neurotrophic factor and neurotrophin-3: Effects of rat strain. Brain Research, 983, 108–114.

    Article  PubMed  CAS  Google Scholar 

  • Kempermann, G. (2002). Why new neurons? Possible functions for adult hippocampal neurogenesis. Journal of Neuroscience, 22, 635–638.

    PubMed  CAS  Google Scholar 

  • Kempermann, G., Chesler, E. J., Lu, L., et al. (2006). Natural variation and genetic covariance in adult hippocampal neurogenesis. Proceedings of the National Academy of Sciences of the United States of America, 103, 780–785.

    Article  PubMed  CAS  Google Scholar 

  • Kempermann, G., Gast, D., Kronenberg, G., et al. (2003). Early determination and long-term persistence of adult-generated new neurons in the hippocampus of mice. Development, 130, 391–399.

    Article  PubMed  CAS  Google Scholar 

  • Kempermann, G., Jessberger, S., Steiner, B., et al. (2004). Milestones of neuronal development in the adult hippocampus. Trends in Neurosciences, 27, 447–452.

    Article  PubMed  CAS  Google Scholar 

  • Kim, Y. P., Kim, H., Shin, M. S., et al. (2004). Age-dependence of the effect of treadmill exercise on cell proliferation in the dentate gyrus of rats. Neuroscience Letters, 355, 152–154.

    Article  PubMed  CAS  Google Scholar 

  • Klempin, F., & Kempermann, G. (2007). Adult hippocampal neurogenesis and aging. European Archives of Psychiatry and Clinical Neuroscience, 257, 271–280.

    Article  PubMed  Google Scholar 

  • Kronenberg, G., Bick-Sander, A., Bunk, E., et al. (2006). Physical exercise prevents age-related decline in precursor cell activity in the mouse dentate gyrus. Neurobiology of Aging, 27, 1505–1513.

    Article  PubMed  Google Scholar 

  • Kronenberg, G., Reuter, K., Steiner, B., et al. (2003). Subpopulations of proliferating cells of the adult hippocampus respond differently to physiologic neurogenic stimuli. Journal of Comparative Neurology, 467, 455–463.

    Article  PubMed  Google Scholar 

  • Kuhn, H. G., Biebl, M., Wilhelm, D., et al. (2005). Increased generation of granule cells in adult Bcl-2-overexpressing mice: A role for cell death during continued hippocampal neurogenesis. European Journal of Neuroscience, 22, 1907–1915.

    Article  PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Kunze, A., Grass, S., Witte, O. W., et al. (2006). Proliferative response of distinct hippocampal progenitor cell populations after cortical infarcts in the adult brain. Neurobiology of Disease, 21, 324–332.

    Article  PubMed  CAS  Google Scholar 

  • Lawlor, D. A., & Hopker, S. W. (2001). The effectiveness of exercise as an intervention in the management of depression: Systematic review and meta-regression analysis of randomised controlled trials. British Medical Journal, 322, 763–767.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Lucassen, P. J., Fuchs, E., & Czeh, B. (2004). Antidepressant treatment with tianeptine reduces apoptosis in the hippocampal dentate gyrus and temporal cortex. Biological Psychiatry, 55, 789–796.

    Article  PubMed  CAS  Google Scholar 

  • Malberg, J. E., Eisch, A. J., Nestler, E. J., et al. (2000). Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Journal of Neuroscience, 20, 9104–9110.

    PubMed  CAS  Google Scholar 

  • Mercier, F., Kitasako, J. T., & Hatton, G. I. (2002). Anatomy of the brain neurogenic zones revisited: Fractones and the fibroblast/macrophage network. Journal of Comparative Neurology, 451, 170–188.

    Article  PubMed  Google Scholar 

  • Nauck, M., Karakiulakis, G., Perruchoud, A. P., et al. (1998). Corticosteroids inhibit the expression of the vascular endothelial growth factor gene in human vascular smooth muscle cells. European Journal of Clinical Pharmacology, 341, 309–315.

    Article  CAS  Google Scholar 

  • O’Keefe, J. (1976). Place units in the hippocampus of the freely moving rat. Experimental Neurology, 51, 78–109.

    Article  PubMed  CAS  Google Scholar 

  • Palmer, T. D., Willhoite, A. R., & Gage, F. H. (2000). Vascular niche for adult hippocampal neurogenesis. Journal of Comparative Neurology, 425, 479–494.

    Article  PubMed  CAS  Google Scholar 

  • Park, E., Chan, O., Li, Q., et al. (2005). Changes in basal hypothalamo-pituitary-adrenal activity during exercise training are centrally mediated. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 289, 1360–1371.

    Google Scholar 

  • Plumpe, T., Ehninger, D., Steiner, B., et al. (2006). Variability of doublecortin-associated dendrite maturation in adult hippocampal neurogenesis is independent of the regulation of precursor cell proliferation. BMC Neuroscience, 7, 77.

    Article  PubMed  CAS  Google Scholar 

  • Pozniak, C. D., & Pleasure, S. J. (2006). A tale of two signals: Wnt and Hedgehog in dentate neurogenesis. Science’s STKE, 5.

  • Rochefort, C., Gheusi, G., Vincent, J. D., et al. (2002). Enriched odor exposure increases the number of newborn neurons in the adult olfactory bulb and improves odor memory. Journal of Neuroscience, 22, 2679–2689.

    PubMed  CAS  Google Scholar 

  • Russo-Neustadt, A., Beard, R. C., & Cotman, C. W. (1999). Exercise, antidepressant medications, and enhanced brain derived neurotrophic factor expression. Neuropsychopharmacology, 21, 679–682.

    Article  PubMed  CAS  Google Scholar 

  • Samorajski, T., Rolsten, C., Przykorska, A., et al. (1987). Voluntary wheel running exercise and monoamine levels in brain, heart and adrenal glands of aging mice. Experimental Gerontology, 22, 421–431.

    Article  PubMed  CAS  Google Scholar 

  • Santarelli, L., Saxe, M., Gross, C., et al. (2003). Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science, 301, 805–809.

    Article  PubMed  CAS  Google Scholar 

  • Schanzer, A., Wachs, F. P., Wilhelm, D., et al. (2004). Direct stimulation of adult neural stem cells in vitro and neurogenesis in vivo by vascular endothelial growth factor. Brain Pathology, 14, 237–248.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Soares, D. D., Coimbra, C. C., & Marubayashi, U. (2007). Tryptophan-induced central fatigue in exercising rats is related to serotonin content in preoptic area. Neuroscience Letters, 415, 274–278.

    Article  PubMed  CAS  Google Scholar 

  • Steiner, B., Klempin, F., Wang, L., et al. (2006). Type-2 cells as link between glial and neuronal lineage in adult hippocampal neurogenesis. Glia, 54, 805–814.

    Article  PubMed  Google Scholar 

  • Steiner, B., Kronenberg, G., Jessberger, S., et al. (2004). Differential regulation of gliogenesis in the context of adult hippocampal neurogenesis in mice. Glia, 46, 41–52.

    Article  PubMed  Google Scholar 

  • Stranahan, A. M., Khalil, D., & Gould, E. (2006). Social isolation delays the positive effects of running on adult neurogenesis. Nature Neuroscience, 9, 526–533.

    Article  PubMed  CAS  Google Scholar 

  • Trejo, J. L., Carro, E., & Torres-Aleman, I. (2001). Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. Journal of Neuroscience, 21, 1628–1634.

    PubMed  CAS  Google Scholar 

  • Uda, M., Ishido, M., Kami, K., et al. (2006). Effects of chronic treadmill running on neurogenesis in the dentate gyrus of the hippocampus of adult rat. Brain Research, 1104, 64–72.

    Article  PubMed  CAS  Google Scholar 

  • Van Praag, H., Christie, B. R., Sejnowski, T. J., et al. (1999a). Running enhances neurogenesis, learning and long-term potentiation in mice. Proceedings of the National Academy of Sciences of the United States of America, 96, 13427–13431.

    Article  PubMed  Google Scholar 

  • Van Praag, H., Kempermann, G., & Gage, F. H. (1999b). Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nature Neuroscience, 2, 266–270.

    Article  PubMed  Google Scholar 

  • Videbech, P., & Ravnkilde, B. (2004). Hippocampal volume and depression: a meta-analysis of MRI studies. American Journal of Psychiatry, 161, 1957–1966.

    Article  PubMed  Google Scholar 

  • Zheng, H., Liu, Y., Li, W., et al. (2006). Beneficial effects of exercise and its molecular mechanisms on depression in rats. Behavioural Brain Research, 168, 47–55.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gerd Kempermann.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fabel, K., Kempermann, G. Physical Activity and the Regulation of Neurogenesis in the Adult and Aging Brain. Neuromol Med 10, 59–66 (2008). https://doi.org/10.1007/s12017-008-8031-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12017-008-8031-4

Keywords

Navigation