The effects of exercise and stress on the survival and maturation of adult-generated granule cells - PubMed (original) (raw)

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

Jason S Snyder et al. Hippocampus. 2009 Oct.

Abstract

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.

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Figures

Figure 1

Figure 1

Markers used to measure adult neurogenesis. a) Cobalt-enhanced DAB immunohistochemistry against proliferating cell nuclear antigen (PCNA) was used to identify proliferating precursor cells (dark gray/black). Arrows on inset photo indicate clusters of 4 and 2 cells from left to right. b) Cobalt-enhanced DAB immunohistochemistry against bromodeoxyuridine (BrdU) was used to identify young neurons born two days prior to treatment onset (dark gray/black against purple nuclear counterstain). Arrows on inset photo indicate BrdU+ cells. c) Fluorescent immunohistochemistry against Arc (red), an activity-dependent immediate-early gene, was used to determine whether cells of known age, labeled by BrdU (green) were activated by seizures. The neuron-specific antibody NeuN (white alone or blue in composite) was used to exclude non-neuronal cells from the analysis. Image shows two 21-day-old neurons, one expressing Arc following seizure (arrow) and one showing Arc staining below the threshold (arrowhead). d) Fluorescent immunohistochemistry against zif268 (red), another activity-dependent immediate-early gene, was also used to determine whether BrdU+/NeuN+ neurons of specific ages were activated by seizures. Image shows a 21-day-old neuron staining for zif268 after seizure (arrow) and a second BrdU+ neuron with zif268 staining below the detection criteria (arrowhead). Scale bars = 100 μm for large brightfield images and 10 μm for brightfield insets and fluorescent images. GCL, granule cell layer.

Figure 2

Figure 2

Effects of stress and running on proliferation and survival. a) Experimental timelines (see methods for details). b) Twelve days of running significantly increased proliferating cell number, an effect that was no longer significant after 19 days of running. c) Both running and restraint stress enhanced the survival of new neurons to 14 days of age. Only running enhanced survival of new neurons to 21 days of age. *p<0.05 versus control at the same time point.

Figure 3

Figure 3

Running accelerates the maturation of adult-generated neurons. a) Seizure-induced expression of the immediate-early gene Arc. Running significantly increased the proportion of 21-day-old neurons capable of expressing Arc. b) Seizure-induced expression of the immediate-early gene zif268. Neither stress nor running significantly affected the proportion of young neurons capable of expressing zif268. **p<0.01 compared with control at the same time point.

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