Stress-related neuropsychiatric disorders are often accompanied by dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. In patients suffering from post-traumatic stress disorder (PTSD),... Show moreStress-related neuropsychiatric disorders are often accompanied by dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. In patients suffering from post-traumatic stress disorder (PTSD), increased sensitivity of glucocorticoid negative feedback has regularly been observed. The single prolonged stress (SPS) paradigm was developed to model increased negative feedback and other aspects of PTSD in rats. In this study, we used a setup that precluded the evaluation of negative feedback but rather served to test the hypothesis of the enhanced glucocorticoid receptor (GR) signaling in higher brain areas. We injected corticosterone or vehicle 7 days after SPS and evaluated plasma corticosterone, as well as gene expression in the dorsal hippocampus and amygdala. We observed a strikingly rapid change in the expression of established GR target genes (t = 30 min) only in the SPS group on exogenous corticosterone injection. Our results extend the notion of increased GR sensitivity in PTSD to include transcriptional responses in the hippocampus. Show less
Ding, J.L.; Chen, X.Z.; Silva, M.S. da; Lingeman, J.; Han, F.; Meijer, O.C. 2020
The Single Prolonged Stress protocol is considered a model for PTSD, as it induces long lasting changes in rat behaviour and endocrine regulation. Previous work demonstrated that some of these... Show moreThe Single Prolonged Stress protocol is considered a model for PTSD, as it induces long lasting changes in rat behaviour and endocrine regulation. Previous work demonstrated that some of these changes can be prevented by treatment with the glucocorticoid receptor antagonist RU486, administered a week after the stressor. The current study evaluated the effects of an earlier intervention with RU486, as evaluated 1 week after SPS-exposure. Most RU486 effects occurred independent of prior stress, except for the reversal of a stress-induced increase in locomotor behaviour. The accompanying changes in gene expression depended on gene, brain region, and time. DNA methylation of the robustly down-regulated Fkbp5 gene was dissociated of changes in mRNA expression. The findings reinforce the long term effects of GR antagonist treatment, but also emphasize the need to evaluate changes over time to allow the identification of robust correlates between gene expression and behavioural/endocrine outcome of stressful experiences. Show less
