Fig. 2

Single prolonged stress (SPS) affects males and females differently. a Exposure to SPS increased the acoustic startle response (ASR) in male but not in female rats. b Likewise, the dexamethasone (DEX) suppression test (DST) revealed an enhanced sensitivity to DEX only in SPS-exposed males, with DEX significantly lowering CORT levels after acute restraint stress compared to vehicle for SPS-exposed males. DEX treatment of control males failed to significantly reduce the CORT response. Surprisingly, CORT levels of SPS females after restraint stress were comparable, regardless of DEX treatment, suggesting DEX-nonsuppression, a characteristic of depression. Note that DEX lowered baseline CORT levels (0 min) in all groups, demonstrating its effectiveness in both sexes. CORT levels were significantly higher in females compared to males at both time points, as expected. c, d SPS had divergent effects on glucocorticoid receptor (GR) expression in the brain, with GR expression in the paraventricular nucleus of the hypothalamus (PVN) somewhat increased by SPS in males (P = .060) but significantly decreased in females. SPS also affected GR expression in hippocampal CA1/2, decreasing GR in males but increasing GR in females (sex*SPS interaction P = .050). GR expression in the PVN of control females was also higher compared to that of control males. e–g Surprisingly, SPS had no effect on the cFos response of males to restraint stress in the prelimbic (PrL) or infralimbic (IL) subregions of the medial prefrontal cortex (mPFC), basal lateral amygdala (BLA), nor medial amygdala (MeA), but significantly increased cFos responding of females to restraint stress in the PrL, IL, and right BLA of females. The cFos response also showed a sex difference in the mPFC, being lower in control females than control males. Data presented as mean ± SEM. Significance set at P < .05 (indicated by asterisk) for planned pairwise comparisons (Bonferroni). Refer to Additional file 1 for full statistical results