Exposure to prolonged, unpredictable stress leads to glucocorticoids-mediated long-lasting neuroendocrine abnormalities associated with emotional and cognitive impairments. Excessive levels of serum glucocorticoids (cortisol in humans, corticosterone in rodents) contribute notably to deficits in working memory (WM), a task which heavily relies on functional interactions between the medial prefrontal cortex (PFC) and the dorsal hippocampus (dHPC). However, it is unknown whether stress-induced increases in plasma corticosterone mirror corticosterone levels in specific brain regions critical for WM. After a 6 week-UCMS exposure, C57BL/6 J male mice exhibited increased anxiety- and depressive-like behaviors when measured one week later and displayed WM impairments timely associated with increased plasma corticosterone response. In chronically stressed mice, basal phosphorylated/activated CREB (pCREB) was markedly increased in the PFC and the CA1 area of the dHPC and WM testing did not elicit any further increase in pCREB in the two regions. Using microdialysis samples from freely-moving mice, we found that WM testing co-occurred with a rapid and sustained increase in corticosterone response in the PFC while there was a late, non-significant rise of corticosterone in the dHPC. The results also show that non-stressed mice injected with corticosterone (2 mg/kg i.p.) before WM testing displayed behavioral and molecular alterations similar to those observed in stressed animals while a pre-WM testing metyrapone injection (35 mg/kg i.p.), a corticosterone synthesis inhibitor, prevented the effects of UCMS exposure. Overall, the abnormal regional increase of corticosterone concentrations mainly in the PFC emerges as a key factor of enduring WM dysfunctions in UCMS-treated animals.

长时间暴露于不可预测的压力下会导致糖皮质激素介导的持久性神经内分泌异常，与情绪和认知障碍有关。血清糖皮质激素水平过高（人类中的皮质醇，啮齿动物中的皮质酮）显着地导致了工作记忆（WM）的不足，这项工作在很大程度上依赖于内侧前额叶皮层（PFC）和背侧海马（dHPC）之间的功能性相互作用。但是，尚不清楚应激引起的血浆皮质酮水平的增加是否反映了对WM至关重要的特定大脑区域皮质酮水平的升高。6周后-UCMS暴露后，一周后测量，C57BL / 6 J雄性小鼠表现出增加的焦虑和抑郁样行为，并表现出与血浆皮质类固醇激素反应增强相关的WM损伤。在慢性应激的小鼠中，PFC中的基础磷酸化/激活的CREB（pCREB）明显增加，而dHPC和WM测试的CA1区域并未引起这两个区域中pCREB的任何进一步增加。使用来自自由移动的小鼠的微透析样品，我们发现WM测试同时发生在PFC中皮质酮反应迅速且持续增加的同时，而dHPC中皮质酮的晚期，无明显升高。结果还表明，非应激小鼠注射了皮质酮（2 mg / kg ipUCMS暴露。总体而言，主要在PFC中皮质类固醇浓度的异常区域增加已成为忍受UCMS治疗的动物中持久性WM功能障碍的关键因素。