Stress-Induced Epigenetic Changes in Hippocampal Mkp-1 Promote Persistent Depressive Behaviors
| Autor: | Jung-Eun Lee, Pyung Lim Han, Juli Choi, Hye-Jin Kwon |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Restraint Physical Neuroscience (miscellaneous) Down-Regulation Histone Deacetylase 2 Biology Hippocampal formation Depsides Hippocampus Cell Line Epigenesis Genetic 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Animals Chronic stress Epigenetics Phosphorylation Cyclic AMP Response Element-Binding Protein SUV39H1 Behavior Animal Histone deacetylase 2 Depression Stress induced Dual Specificity Phosphatase 1 Methyltransferases Stress adaptation Up-Regulation Mice Inbred C57BL PPAR gamma Repressor Proteins 030104 developmental biology Neurology Cinnamates Chronic Disease Neuroscience 030217 neurology & neurosurgery Homeostasis Stress Psychological |
| Zdroj: | Molecular neurobiology. 56(12) |
| ISSN: | 1559-1182 |
| Popis: | Chronic stress induces persistent depressive behaviors. Stress-induced transcriptional alteration over the homeostatic range in stress hormone-sensitive brain regions is believed to underlie long-lasting depressive behaviors. However, the detailed mechanisms by which chronic stress causes those adaptive changes are not clearly understood. In the present study, we investigated whether epigenetic changes regulate stress-induced depressive behaviors. We found that chronic stress in mice downregulates the epigenetic factors HDAC2 and SUV39H1 in the hippocampus. A series of follow-up analyses including ChIP assay and siRNA-mediated functional analyses reveal that glucocorticoids released by stress cumulatively increase Mkp-1 expression in the hippocampus, and increased Mkp-1 then debilitates p-CREB and PPARγ, which in turn suppress the epigenetic factors HDAC2 and SUV39H1. Furthermore, HDAC2 and SUV39H1 normally suppress the transcription of the Mkp-1, and therefore the reduced expression of HDAC2 and SUV39H1 increases Mkp-1 expression. Accordingly, repeated stress progressively strengthens a vicious cycle of the Mkp-1 signaling cascade that facilitates depressive behaviors. These results suggest that the hippocampal stress adaptation system comprising HDAC2/SUV39H1-regulated Mkp-1 signaling network determines the vulnerability to chronic stress and the maintenance of depressive behaviors. |
| Databáze: | OpenAIRE |
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