Suppressed proliferation and apoptotic changes in the rat dentate gyrus after acute and chronic stress are reversible

Abstract

Acute stress suppresses new cell birth in the hippocampus in several species. Relatively little is known, however, on how chronic stress affects the turnover, i.e. proliferation and apoptosis, of the rat dentate gyrus (DG) cells, and whether the stress effects are lasting. We investigated how 3 weeks of chronic unpredictable stress would influence the structural dynamic plasticity of the rat DG, and studied newborn cell proliferation, survival, apoptosis, volume and cell number in 10-week-old animals. To study lasting effects, another group of animals was allowed to recover for 3 weeks. Based on two independent parameters, bromodeoxyuridine (BrdU) and Ki-67 immunocytochemistry, our results show that both chronic and acute stress decrease new cell proliferation rate. The reduced proliferation after acute stress normalized within 24 h. Interestingly, chronically stressed animals showed recovery after 3 weeks, albeit with still fewer proliferating cells than controls. Apoptosis, by contrast, increased after acute but decreased after chronic stress. These results demonstrate that, although chronic stress suppresses proliferation and apoptosis, 3 weeks of recovery again normalized most of these alterations. This may have important implications for our understanding of the reversibility of stress-related hippocampal volume changes, such as occur, for example, in depression.

Repeated Unpredictable Stress and Antidepressants Differentially Regulate Expression of the Bcl-2 Family of Apoptotic Genes in Rat Cortical, Hippocampal, and Limbic Brain Structures

“…Stress increased the number of apoptotic cells in the temporal cortex, but decreased it in the hippocampal pyramidal cell layers (Lucassen et al, 2001a). Particularly, within the hippocampus, there is a close association between apoptosis and neurogenesis and the precise balance drives the continuous turnover of cells in this region (Biebl et al, 2000;Heine et al, 2004). Besides slowing down neurogenesis, stress and steroid hormones temporally reduce the dentate cell turnover, by modulating the ongoing rate of apoptosis (Lucassen et al, 2006;Czeh and Lucassen, 2007).…”

Hippocampal neuroplasticity induced by early-life stress: Functional and molecular aspects

“…Whereas the effects of stress on hippocampal structure and function in adults may be profound, they are generally reversible [92,57,114]. The reasons are unclear, but may stem from the fact that the adult brain has been fully 'programmed,' as far as gene expression levels or 'set-points' are concerned.…”

“…However, the glucocorticoid stress hormones as well as glutamatemediated excitotoxicity have been shown to contribute to these effects [71,95]. More recently, other molecules and signaling cascades have been found to contribute to the dendritic remodeling evoked by stress, including tissue plasminogen activator [110].Whereas the effects of stress on hippocampal structure and function in adults may be profound, they are generally reversible [92,57,114]. The reasons are unclear, but may stem from the fact that the adult brain has been fully 'programmed,' as far as gene expression levels or 'set-points' are concerned.…”

Regulation of Structural Plasticity and Neurogenesis during Stress and Diabetes; Protective Effects of Glucocorticoid Receptor Antagonists

“…After acute stress, a reduction in proliferation was paralleled by increased numbers of apoptotic cells, yet no distinction was made between apoptosis of newborn or mature cells. Following chronic stress, both proliferation and apoptosis were reduced, parallel to increases in the cell cycle inhibitor p27Kip1, indicating that more cells had entered cell cycle arrest and that the granule cell turnover had thus slowed down [26, 46].…”

“…After acute stress, a reduction in proliferation was paralleled by increased numbers of apoptotic cells, yet no distinction was made between apoptosis of newborn or mature cells. Following chronic stress, both proliferation and apoptosis were reduced, parallel to increases in the cell cycle inhibitor p27Kip1, indicating that more cells had entered cell cycle arrest and that the granule cell turnover had thus slowed down [26, 46].The exact underlying cellular mechanisms mediating the inhibitory effect of stress are unknown. The adrenal GC hormones have been pointed out as key players in this process and both GR as well as NMDA receptors have been identified on early progenitor cells [47, 48].…”