Abstract
Previously, we found that basal corticosterone pulsatility significantly impacts the vulnerability for developing post-traumatic stress disorder (PTSD). Rats that exhibited PTSD-phenotype were characterized by blunted basal corticosterone pulsatility amplitude and a blunted corticosterone response to a stressor. This study sought to identify the mechanisms underlining both the loss of pulsatility and differences in downstream responses. Serial blood samples were collected manually via jugular vein cannula at 10-min intervals to evaluate suppression of corticosterone following methylprednisolone administration. The rats were exposed to predator scent stress (PSS) after 24 h, and behavioral responses were assessed 7 days post-exposure for retrospective classification into behavioral response groups. Brains were harvested for measurements of the glucocorticoid receptor, mineralocorticoid receptor, FK506-binding protein-51 and arginine vasopressin in specific brain regions to assess changes in hypothalamus–pituitary–adrenal axis (HPA) regulating factors. Methylprednisolone produced greater suppression of corticosterone in the PTSD-phenotype group. During the suppression, the PTSD-phenotype rats showed a significantly more pronounced pulsatile activity. In addition, the PTSD-phenotype group showed distinct changes in the ventral and dorsal CA1, dentate gyrus as well as in the paraventricular nucleus and supra-optic nucleus. These results demonstrate a pre-trauma vulnerability state that is characterized by an over-reactivity of the HPA and changes in its regulating factors.
Highlights
Glucocorticoid (GC) hormones are secreted to the bloodstream by the adrenal gland and, upon a stressful event, play a role in orchestrating the physiological and behavioral reactions essential for the restoration of homeostasis after emotional or physical stress [1,2]
A recent cohort study of post-traumatic stress disorder (PTSD) patients found heightened negative feedback of the hypothalamus–pituitary–adrenal axis (HPA) axis to dexamethasone but reduced GR lymphocyte expression [38,43]. These findings suggest that, though the picture of increased HPA reactivity is prominent in PTSD patients, the cause is more complex than an isolated GR abnormality
Even more interesting is the regionally distinct differences in MR expression, while the level of MRs was significantly lower in the dorsal hippocampus in comparison to the ventral hippocampus in the control group; these differences were more prominent in the minimal behavioral response (MBR) (‘resilient’) group, and these changes were significant and opposite in the evident by higher average amplitudes (EBR) group, showing higher levels of MR in the dorsal hippocampus compared with the ventral hippocampus, while the partial behavioral response (PBR) group showed no significant differences between areas
Summary
Glucocorticoid (GC) hormones are secreted to the bloodstream by the adrenal gland and, upon a stressful event, play a role in orchestrating the physiological and behavioral reactions essential for the restoration of homeostasis after emotional or physical stress [1,2]. 20 min post-MPST: All rats that exhibited PTSD-phenotype (4/4) demonstrated hypersuppression (51–90%) of corticosterone in response to methylprednisolone. Most rats in the PBR and MBR behavior groups suppressed corticosterone to less than 50% of pre-methylprednisolone levels (Pearson χ2 = 12.35, p < 0.0025). 40 min post-MPST: Most rats that exhibited PTSD-phenotype (3/4) suppressed corticosterone to more than 90% of pre-methylprednisolone levels, compared with 11.11% of the PBR group (1/9) and compared with 12.5% of the MBR group (1/8) (Pearson χ2 = 11.23, p < 0.025). 70 min post-MPST: All rats that exhibited PTSD-phenotype (4/4) suppressed corticosterone to more than 90% of pre-methylprednisolone levels, compared with 55.55% of the PBR group (5/9) and compared with 12.5% of the MBR group (Pearson χ2 = 11.12, p < 0.03) at the 60 min post-MPST. Taken together, impaired negative feedback regulation of the HPA function was mainly observed in the EBR group
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