The effects of exercise and stress on the survival and maturation of adult-generated granule cells.

Stress strongly inhibits proliferation of granule cell precursors in the adult dentate gyrus, whereas voluntary running has the opposite effect. Few studies, however, have examined the possible effects of these environmental manipulations on the maturation and survival of young granule cells. We examined the number of surviving granule cells and the proportion of young neurons that were functionally mature, as defined by seizure-induced immediate-early gene (IEG) expression, in 14- and 21-day-old granule cells in mice that were given access to a running wheel, restrained daily for 2 h, or given no treatment during this period. Treatments began 2 days after BrdU injection, to isolate effects on survival from those on cell proliferation. We found a large increase in granule cell survival in running mice when compared with controls at both time points. In addition, running increased the proportion of granule cells expressing the IEG Arc in response to seizures, suggesting that it speeds incorporation into circuits, i.e., functional maturation. Stressed mice showed no change in Arc expression, compared with control animals, but, surprisingly, showed a transient increase in survival of 14-day-old granule cells, which was gone 7 days later. Examination of cell proliferation, using the endogenous mitotic marker PCNA showed an increase in cell proliferation after 12 days of running but not after 19 days of running. The number of proliferating cells was unchanged 24 h after the 12th or 19th episode of daily restraint stress. These findings demonstrate that running has strong effects on survival and maturation of young granule cells as well as their birth and that stress can have positive but short-lived effects on granule cell survival. Published 2009 Wiley-Liss, Inc. Copyright 2008 Wiley-Liss, Inc.