Prolonged voluntary wheel-running stimulates neural precursors in the hippocampus and forebrain of adult CD1 mice.

Voluntary wheel-running induces a rapid increase in proliferation and neurogenesis by neural precursors present in the adult rodent hippocampus. In contrast, the responses of hippocampal and other central nervous system neural precursors following longer periods of voluntary physical activity are unclear and are an issue of potential relevance to physical rehabilitation programs. We investigated the effects of a prolonged, 6-week voluntary wheel-running paradigm on neural precursors of the CD1 mouse hippocampus and forebrain. Examination of the hippocampus following 6 weeks of running revealed two to three times as many newly born neurons and 60% more proliferating cells when compared with standard-housed control mice. Among running mice, the number of newly born neurons correlated with the total running distance. To establish the effects of wheel-running on hippocampal precursors dividing during later stages of the prolonged running regime, BrdU was administered after 3 weeks of running and the BrdU-retaining cells were analyzed 18 days later. Quantifications revealed that the effects of wheel-running were maintained in late-stage proliferating cells, as running mice had two to three times as many BrdU-retaining cells within the hippocampal dentate gyrus, and these yielded greater proportions of both mature neurons and proliferative cells. The effects of prolonged wheel-running were also detected beyond the hippocampus. Unlike short-term wheel-running, prolonged wheel-running was associated with higher numbers of proliferating cells within the ventral forebrain subventricular region, a site of age-associated decreases in neural precursor proliferation and neurogenesis. Collectively, these findings indicate that (i) prolonged voluntary wheel-running maintains an increased level of hippocampal neurogenesis whose magnitude is linked to total running performance, and (ii) that it influences multiple neural precursor populations of the adult mouse brain.

Bednarczyk MR ，Aumont A ，Décary S ，Bergeron R ，Fernandes KJ ... -  《-》

Physical exercise leads to rapid adaptations in hippocampal vasculature: temporal dynamics and relationship to cell proliferation and neurogenesis.

Increased levels of angiogenesis and neurogenesis possibly mediate the beneficial effects of physical activity on hippocampal plasticity. This study was designed to investigate the temporal dynamics of exercise-induced changes in hippocampal angiogenesis and cell proliferation. Mice were housed with a running wheel for 1, 3, or 10 days. Analysis of glucose transporter Glut1-positive vessel density showed a significant increase after 3 days of wheel running. Cell proliferation in the dentate gyrus showed a trend towards an increase after 3 days of running and was significantly elevated after 10 days of physical exercise. Ten days of wheel running resulted in a near-significant increase in the number of immature neurons, as determined by a doublecortin (DCX) staining. In the second part of the study, the persistence of the exercise-induced changes in angiogenesis and cell proliferation was determined. The running wheel was removed from the cage after 10 days of physical activity. Glut-1 positive vessel density and hippocampal cell proliferation were determined 1 and 6 days after removal of the wheel. Both parameters had returned to baseline 24 h after cessation of physical activity. The near-significant increase in the number of DCX-positive immature neurons persisted for at least 6 days, indicating that new neurons formed during the period of increased physical activity had survived. Together these experiments show that the hippocampus displays a remarkable angiogenic and neurogenic plasticity and rapidly responds to changes in physical activity.

Van der Borght K ，Kóbor-Nyakas DE ，Klauke K ，Eggen BJ ，Nyakas C ，Van der Zee EA ，Meerlo P ... -  《-》

Adult hippocampal neurogenesis and voluntary running activity: circadian and dose-dependent effects.

Running activity increases cell proliferation and neurogenesis in the dentate gyrus of adult mice. The present experiment was designed to investigate whether the effect of activity on adult neurogenesis is dependent on the time of day (circadian phase) and the amount of activity. Mice received restricted access to a running wheel (0, 1, or 3 hr) at one of three times of day: the middle of the light phase (i.e., when mice are normally inactive), dark onset (i.e., when mice begin their nocturnal activity), and the middle of the dark period (i.e., when mice are in the middle of their active period). Cell proliferation and net neurogenesis were assessed after incorporation of the thymidine analog bromodeoxyuridine (BrdU) and immunohistochemical detection of BrdU and neuronal markers. Running activity significantly increased cell proliferation, cell survival, and total number of new neurons only in animals with 3 hr of wheel access during the middle of the dark period. Although activity was positively correlated with increased neurogenesis at all time points, the effects were not statistically significant in animals with wheel access at the beginning of the dark period or during the middle of the light period. These data suggest that the influence of exercise on cell proliferation and neurogenesis is modulated by both circadian phase and the amount of daily exercise, thus providing new insight into the complex relationship between physiological and behavioral factors that can mediate adult neuroplasticity.

Holmes MM ，Galea LA ，Mistlberger RE ，Kempermann G ... -  《JOURNAL OF NEUROSCIENCE RESEARCH》

Physical exercise increases Notch activity, proliferation and cell cycle exit of type-3 progenitor cells in adult hippocampal neurogenesis.

In adult hippocampal neurogenesis of mice, the proliferation of precursor cells can be stimulated by voluntary exercise (wheel-running). Physical activity has an additional effect on late progenitor cells (type-3) by promoting cell survival and further maturation. Notch1 is a key regulator of various steps in neuronal development, including the inhibition of cell cycle exit and neuronal differentiation of neural stem cells, as well as promoting the survival and dendritic branching of newborn neurons. We here report that physical activity increased the proportion and absolute number of doublecortin(+) (DCX) type-2b and type-3 progenitor cells that showed an activated Notch1 pathway. In contrast, the fraction of dividing cells with nuclear Notch intracellular domain expression indicating an activated Notch pathway was not affected by physical exercise. We used double labeling with two halogenated thymidine analogs, iododeoxyuridine and chlorodeoxyuridine, to distinguish between cell cycle exit and continued division at the progenitor cell level. After 7 days of physical exercise, the proliferative activity of precursor cells was increased, whereas the proportion of type-2b/3 cells re-entering S-phase was reduced. Consistent with this observation, the proportion of DCX(+) cells that expressed the marker of postmitotic immature granule cells (calretinin) was enhanced. Running promotes both the proliferation and cell cycle exit of DCX(+) type-3 precursors, possibly by preferentially stimulating a last neurogenic cell division. These pro-proliferative effects are independent of Notch1, whereas the running-induced survival and cell cycle exit of type-3 progenitor cells might by mediated by Notch1 activity.

Brandt MD ，Maass A ，Kempermann G ，Storch A ... -  《-》

Stress differentially regulates the effects of voluntary exercise on cell proliferation in the dentate gyrus of mice.

It has been well-established that cell proliferation and neurogenesis in the adult mouse dentate gyrus (DG) can be regulated by voluntary exercise. Recent evidence has suggested that the effects of voluntary exercise can in turn be influenced by environmental factors that regulate the amount of stress an animal is exposed to. In this study, we use bromodeoxyuridine and proliferating cell nuclear antigen immunohistochemistry to show that voluntary exercise produces a significant increase in cell proliferation in the adult mouse DG in both isolated and socially housed mice. This effect on proliferation translates into an increase in neurogenesis and neuronal branching of new neurons in the mice that exercised. Although social condition did not regulate proliferation in young adult mice, an effect of social housing could be observed in mice exposed to acute restraint stress. Surprisingly, only exercising mice housed in isolated conditions showed an increase in cellular proliferation following restraint stress, whereas socially housed, exercising mice, failed to show a significant increase in proliferation. These findings indicate that social housing may increase the effects of any stressful episodes on hippocampal neurogenesis in the mouse DG.

Kannangara TS ，Webber A ，Gil-Mohapel J ，Christie BR ... -  《-》