Exposure to early stressful events increases susceptibility to post-traumatic stress disorder (PTSD) in adulthood, in which the hypothalamic-pituitary-adrenal (HPA) axis plays a crucial role. Studies have found that environmental enrichment (EE) mitigates the detrimental outcomes of early adversity. However, the HPA-related mechanism remains unclear. In this study, we used the single prolonged stress (SPS) paradigm to explore the long-term effects of early adolescent stress on behavior, HPA axis activity, as well as expression levels of the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), corticotropin-releasing hormone receptor 1 (CRF1R) and CRF2R in the hypothalamus and hippocampus. Meanwhile, the protective effects of EE intervention were examined. We found that adult male rats exposed to adolescent stress showed reduced locomotor activity, increased anxiety-like behaviors, enhanced contextual fear memory, elevated basal plasma ACTH levels, and enhanced HPA negative feedback inhibition, as indicated by decreased plasma ACTH levels in the dexamethasone suppression test (DST). Furthermore, EE normalized the behavioral abnormalities and enhanced HPA negative feedback in stressed rats, possibly through down-regulating GR expression in the hippocampus and hypothalamus. These findings suggested that EE could ameliorate adolescent stress-induced PTSD-like behaviors and aberrant reprogramming of the HPA axis, reducing the risk of developing PTSD in adulthood.

暴露于早期压力事件会增加成年后对创伤后应激障碍 (PTSD) 的易感性，其中下丘脑-垂体-肾上腺 (HPA) 轴起着至关重要的作用。研究发现，丰富环境 (EE) 可以减轻早期逆境的不利后果。然而，HPA 相关机制仍不清楚。在这项研究中，我们使用单一长期压力 (SPS) 范式来探索青少年早期压力对行为、HPA 轴活动以及糖皮质激素受体 (GR)、盐皮质激素受体 (MR) 表达水平的长期影响, 下丘脑和海马中的促肾上腺皮质激素释放激素受体 1 (CRF1R) 和 CRF2R。同时，检查了EE干预的保护作用。我们发现暴露于青春期压力的成年雄性大鼠表现出运动活动减少、焦虑样行为增加、情境恐惧记忆增强、基础血浆 ACTH 水平升高和 HPA 负反馈抑制增强，如地塞米松抑制中血浆 ACTH 水平降低所示测试（夏令时）。此外，EE 使应激大鼠的行为异常正常化并增强了 HPA 负反馈，可能是通过下调海马和下丘脑中的 GR 表达。这些发现表明，EE 可以改善青少年压力引起的 PTSD 样行为和 HPA 轴的异常重编程，从而降低成年后患 PTSD 的风险。和增强的 HPA 负反馈抑制，如地塞米松抑制试验 (DST) 中血浆 ACTH 水平降低所示。此外，EE 使应激大鼠的行为异常正常化并增强了 HPA 负反馈，可能是通过下调海马和下丘脑中的 GR 表达。这些发现表明，EE 可以改善青少年压力引起的 PTSD 样行为和 HPA 轴的异常重编程，从而降低成年后患 PTSD 的风险。和增强的 HPA 负反馈抑制，如地塞米松抑制试验 (DST) 中血浆 ACTH 水平降低所示。此外，EE 使应激大鼠的行为异常正常化并增强了 HPA 负反馈，可能是通过下调海马和下丘脑中的 GR 表达。这些发现表明，EE 可以改善青少年压力引起的 PTSD 样行为和 HPA 轴的异常重编程，从而降低成年后患 PTSD 的风险。