Several intracellular pathways that contribute to the adaptation or maladaptation to environmental challenges mediate the vulnerability and resilience to chronic stress. The activity of the hypothalamic-pituitary-adrenal (HPA) axis is fundamental for the proper maintenance of brain processes, and it is related to the functionality of the isoform alfa and beta of the glucocorticoid receptor (Gr), the primary regulator of HPA axis. Among the downstream effectors of the axis, the scaffolding protein RACK1 covers an important role in regulating synaptic activity and mediates the transcription of the neurotrophin Bdnf. Hence, by employing the chronic mild stress (CMS) paradigm, we studied the role of the Grβ-RACK1-Bdnf signaling in the different susceptibility to chronic stress exposure. We found that resilience to two weeks of CMS is paralleled by the activation of this pathway in the ventral hippocampus, the hippocampal subregion involved in the modulation of stress response. Moreover, the results we obtained in vitro by exposing SH-SY5Y cells to cortisol support the data we found in vivo. The results obtained add novel critical information about the link among Gr, RACK1 and Bdnf and the resilience to chronic stress, suggesting novel targets for the treatment of stress-related disorders, including depression.

一些有助于适应或适应不良环境挑战的细胞内途径介导了对慢性压力的脆弱性和恢复力。下丘脑-垂体-肾上腺 (HPA) 轴的活动对于大脑过程的正常维持至关重要，并且与糖皮质激素受体 (Gr) 的同工型 α 和 β 的功能相关，糖皮质激素受体 (Gr) 是 HPA 轴的主要调节剂。在轴的下游效应器中，支架蛋白 RACK1 在调节突触活性和介导神经营养蛋白 Bdnf 的转录中发挥着重要作用。因此，通过采用慢性轻度应激（CMS）范式，我们研究了 Grβ-RACK1-Bdnf 信号在慢性应激暴露的不同易感性中的作用。我们发现，对两周 CMS 的恢复能力与腹侧海马中该通路的激活是平行的，腹侧海马是参与调节应激反应的海马亚区域。此外，我们通过将 SH-SY5Y 细胞暴露于皮质醇而在体外获得的结果支持了我们在体内发现的数据。获得的结果增加了关于 Gr、RACK1 和 Bdnf 之间的联系以及慢性压力恢复能力的新的关键信息，提示了治疗包括抑郁症在内的压力相关疾病的新目标。