Elsevier

Neurobiology of Aging

Volume 27, Issue 10, October 2006, Pages 1505-1513
Neurobiology of Aging

Physical exercise prevents age-related decline in precursor cell activity in the mouse dentate gyrus

https://doi.org/10.1016/j.neurobiolaging.2005.09.016Get rights and content

Abstract

Physical activity induces adult hippocampal neurogenesis. We here show that the acute up-regulating effect of voluntary wheel running on precursor cell proliferation decreases with continued exercise, but that continued exercise reduces the age-dependent decline in adult neurogenesis. Cell proliferation peaked at 3 days of running. After 32 days of exercise this response returned to baseline. Running-induced proliferation of transiently amplifying progenitor cells led to a consecutive increase in the number of more mature cells. Increasing age reduced adult neurogenesis at 9 months to 50% of the value at 6 weeks and to 17% at the age of 2 years. At both 1 and 2 years, precursor cell divisions remained inducible by physical activity. Exercise from 3 to 9 months of age significantly reduced the age-dependent decline in cell proliferation but (presumably in the absence of additional stimuli) did not maintain net neurogenesis at levels corresponding to a younger age. We propose that physical activity might contribute to successful aging by increasing the potential for neurogenesis represented by the pool of proliferating precursor cells.

Introduction

Physical activity is perceived as “good for the brain” [13], [14] and to engage in physical exercise is associated with a reduced risk of developing neurodegenerative disorders such as Alzheimer's disease [62]. The cellular mechanisms underlying this benefit of physical activity are hardly known. It is tempting to speculate that the effect of physical activity on adult hippocampal neurogenesis might explain part of this phenomenon. Adult neurogenesis strongly decreases with increasing age in laboratory and wild-living rodents [5], [7], [10], [39], [44] and an important question is, how few new cells in old age might still make a relevant functional contribution. At present, the function of new neurons in the adult and aging hippocampus remains unresolved, although several theories exist [17], [40].

Adult neurogenesis strongly decreases with age [10], [44]. More precisely, both precursor cell proliferation and the relative number of neurons among the progeny of neural precursors decrease in older age [39]. One hypothesis is that this age-related decline is a consequence of elevated corticosterone levels, because adrenalectomy was largely able to reverse it [10]. We have found that reduced levels of adult hippocampal neurogenesis in old age are strongly up-regulated after exposure to complex environments [39]. This suggests that the decreased resources for neurogenesis can still be recruited in old age, possibly when unexpected functional challenges occur. We have also found that prolonged exposure to environmental complexity maintains adult hippocampal neurogenesis at a “younger” level [34]. A change in behavior thus exerts profound and sustained effects on cellular plasticity in the aging hippocampus. This finding prompted us to further investigate the possible mechanisms by which the potential for cellular plasticity is controlled in the aging hippocampus.

Physical activity strongly induces adult neurogenesis [59] by increasing precursor cell proliferation [41], [43]. We hypothesized that besides the acute induction of precursor cell proliferation, voluntary physical activity might have additional effects on adult hippocampal neurogenesis on later stages of neuronal maturation.

We designed the present study in order to investigate (1) duration effects in the activity-induced regulation of adult neurogenesis, (2) the question, whether only cell proliferation or additionally other stages of neuronal development would be influenced by physical activity, (3) how aging affected the activity-dependent regulation of adult neurogenesis, and (4) whether long-term exercise would increase the potential for adult hippocampal neurogenesis, consistent with the idea that physical activity maintains hippocampal plasticity and function into old age.

Section snippets

Animals and experimental design

The experimental design is outlined in Table 1. Male C57BL/6 mice were obtained from Charles River and were kept at an ambient temperature of 22 ± 1 °C. Animals were housed together with two animals per cage (Experiment 1) or 3–5 animals per cage (Experiments 3 and 4) in standard laboratory cages on a 12 h light/dark schedule with ad libitum access to laboratory chow and tap water. In the physical activity condition, cages contained stainless steel running wheels (diameter 24 cm; Tecniplast,

Effects of exercise on progenitor cell proliferation follow an inverted u-shape

Our first question was whether the pro-proliferative effect of voluntary wheel running is transient (Experiment 1). Mice with access to a running wheel for 3, 10 and 32 days received one single injection of BrdU on the last day of their training and were histologically examined the next day (N = 8; for controls without access to the running wheel N = 12). All animals were 74 days old on the day of perfusion. Exercise started at different intervals before this time point, because age itself exerts a

Discussion

In the present study we show that continued physical activity maintains a stimulating effect on adult hippocampal neurogenesis but also that the quality of this effect changes over time.

Sustained physical activity kept precursor cell divisions at a level corresponding to a much younger age and prevented the age-dependent decline in the precursor cell-based potential for adult hippocampal neurogenesis. This increased potential did not, however, translate into a prolonged induction of net

Acknowledgements

We would like to thank Irene Thun, Ruth Zarmstorff, and Silke Kurths for their technical support. The present work was funded by Deutsche Forschungsgemeinschaft (DFG).

References (63)

  • V. Filippov et al.

    Subpopulation of nestin-expressing progenitor cells in the adult murine hippocampus shows electrophysiological and morphological characteristics of astrocytes

    Mol Cell Neurosci

    (2003)
  • F. Gomez-Pinilla et al.

    Physical exercise induces FGF-2 and its mRNA in the hippocampus

    Brain Res

    (1997)
  • F. Gomez-Pinilla et al.

    Spatial learning and physical activity contribute to the induction of fibroblast growth factor: neural substrates for increased cognition associated with exercise

    Neuroscience

    (1998)
  • E. Gould et al.

    Neurogenesis in adulthood: a possible role in learning

    Trends Cogn Sci

    (1999)
  • V.M. Heine et al.

    Prominent decline of newborn cell proliferation, differentiation, and apoptosis in the aging dentate gyrus, in absence of an age-related hypothalamus-pituitary-adrenal axis activation

    Neurobiol Aging

    (2004)
  • G. Kempermann et al.

    Milestones of neuronal development in the adult hippocampus

    Trends Neurosci

    (2004)
  • Y.P. Kim et al.

    Age-dependence of the effect of treadmill exercise on cell proliferation in the dentate gyrus of rats

    Neurosci Lett

    (2004)
  • T. Kitamura et al.

    Enhancement of neurogenesis by running wheel exercises is suppressed in mice lacking NMDA receptor epsilon 1 subunit

    Neurosci Res

    (2003)
  • A. Makatsori et al.

    Voluntary wheel running modulates glutamate receptor subunit gene expression and stress hormone release in Lewis rats

    Psychoneuroendocrinology

    (2003)
  • M.A. Aberg et al.

    Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus

    J Neurosci

    (2000)
  • J. Altman et al.

    Autoradiographic and histologic evidence of postnatal neurogenesis in rats

    J Comp Neurol

    (1965)
  • I. Amrein et al.

    Marked species and age-dependent differences in cell proliferation and neurogenesis in the hippocampus of wild-living rodents

    Hippocampus

    (2004)
  • H.A. Cameron et al.

    Restoring production of hippocampal neurons in old age

    Nat Neurosci

    (1999)
  • H.A. Cameron et al.

    Adrenal steroids and N-methyl-D-aspartate receptor activation regulate neurogenesis in the dentate gyrus of adult rats through a common pathway

    Neuroscience

    (1998)
  • E. Carro et al.

    Circulating insulin-like growth factor I mediates effects of exercise on the brain

    J Neurosci

    (2000)
  • S.J. Colcombe et al.

    Cardiovascular fitness, cortical plasticity, and aging

    Proc Natl Acad Sci USA

    (2004)
  • S. Couillard-Despres et al.

    Doublecortin expression levels in adult brain reflect neurogenesis

    Eur J Neurosci

    (2005)
  • K. Fabel et al.

    VEGF is necessary for exercise-induced adult hippocampal neurogenesis

    Eur J Neurosci

    (2003)
  • S. Fukuda et al.

    Two distinct subpopulations of nestin-positive cells in adult mouse dentate gyrus

    J Neurosci

    (2003)
  • A. Garcia et al.

    Age-dependent expression of glucocorticoid- and mineralocorticoid receptors on neural precursor cell populations in the adult murine hippocampus

    Aging Cell

    (2004)
  • E. Gould et al.

    Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation

    J Neurosci

    (1997)
  • Cited by (363)

    View all citing articles on Scopus
    1

    Both authors contributed equally.

    View full text