As the cerebellar molecular stress response is understudied, we assessed protein expression levels of hypothalamic-pituitary-adrenal (HPA) axis regulators and neurostructural markers in the cerebellum of a male PTSD mouse model and of unstressed vs. stressed male FK506 binding protein 51 (Fkbp5) knockout (KO) vs. wildtype mice. We explored the translatability of our findings in the Fkbp5 KO model to the situation in humans by correlating mRNA levels of candidates with those of FKBP5 in two whole transcriptome datasets of post-mortem human cerebellum and in blood of unstressed and stressed humans. Fkbp5 deletion rescued the stress-induced loss in hippocampal, prefrontal cortical, and, possibly, also cerebellar FKBP52 expression and modulated post-stress cerebellar expression levels of the glucocorticoid receptor (GR) and possibly (trend) also of glial fibrillary acidic protein (GFAP). Accordingly, expression levels of genes encoding for these three genes correlated with those of FKBP5 in human post-mortem cerebellum, while other neurostructural markers were not related to Fkbp5 either in mouse or human cerebellum. Also, gene expression levels of the two immunophilins correlated inversely in the blood of unstressed and stressed humans. We found transient changes in FKBP52 and persistent changes in GR and GFAP in the cerebellum of PTSD-like mice. Altogether, upon elucidating the cerebellar stress response we found first evidence for a novel facet of HPA axis regulation, i.e., the ability of FKBP51 to modulate the expression of its antagonist FKBP52 in the mouse and, speculatively, also in the human brain and blood and, moreover, detected long-term single stress-induced changes in expression of cerebellar HPA axis regulators and neurostructural markers of which some might contribute to the role of the cerebellum in fear extinction.

由于对小脑分子应激反应的研究不足，我们评估了雄性 PTSD 小鼠模型和未受压与受压的雄性 FK506 结合蛋白 51 ( Fkbp5 ) 敲除 (KO) 与野生型小鼠。我们通过将候选者的 mRNA 水平与FKBP5 的mRNA 水平相关联，在死后人类小脑的两个完整转录组数据集中以及无压力和压力人类的血液中，探索了我们在Fkbp5 KO 模型中的发现对人类情况的可译性。Fkbp5缺失挽救了海马、前额叶皮层以及可能还有小脑 FKBP52 表达的压力诱导的损失，并调节了糖皮质激素受体 (GR) 和可能（趋势）还有神经胶质纤维酸性蛋白 (GFAP) 的压力后小脑表达水平. 因此，编码这三个基因的基因的表达水平与人死后小脑中FKBP5 的表达水平相关，而其他神经结构标志物与Fkbp5 无关。在小鼠或人小脑中。此外，两种亲免素的基因表达水平在无压力和压力人的血液中呈负相关。我们发现 PTSD 样小鼠小脑中 FKBP52 的瞬时变化和 GR 和 GFAP 的持续变化。总之，在阐明小脑应激反应后，我们发现了 HPA 轴调节新方面的第一个证据，即 FKBP51 在小鼠中调节其拮抗剂 FKBP52 表达的能力，推测也在人脑和血液中，此外，检测到长期单一压力引起的小脑 HPA 轴调节因子和神经结构标志物的表达变化，其中一些可能有助于小脑在恐惧消退中的作用。