Physical exercise prevents age-related decline in precursor cell activity in the mouse dentate gyrus
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).
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Both authors contributed equally.