Abstract：
Stressful life event is closely associated with depression, thus strategies that blunt or prevent the negative effect stress on the brain might benefits for the treatment of depression. Although previous study showed the role of protein kinase R (PKR)-like ER kinase (PERK) in inflammation related depression, its involvement in the neuropathology of chronic stress induced depression is still unknown. We tried to explore whether block the PERK pathway would alleviate the animals\' depression-like behavior induced by chronic restraint stress (CRS) and investigate the underlying mechanism. The CRS-exposed mice exhibited depression-like behavior, including anhedonia in the sucrose preference test (SPT), and increased immobility time in tail suspension test (TST) and forced swim test (FST). ISRIB administration for 2 weeks significantly improved the depression-like behavior in male mice exposed to CRS,which was manifested by markedly increasing the sucrose preference and reducing the immobility time in the FST and TST. However, we observed that exposure to the same dose of ISRIB in CRS female mice only showed improved anhedonia-like deficits,leaving un-altered improvement in the FST and TST. Mechanically, we found thatISRIB reversed the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, indicatingby decreased levels of serum corticosterone, reduced hippocampal glucocorticoidreceptor (GR) expression and expression of FosB in hypothalamic paraventricularnucleus (PVN), which was accompanied by preserved hippocampal neurogenesis. Thepresent findings further expand the potential role of ER stress in depression andprovide important details for a therapeutic path forward for PERK inhibitors in mood disorders.
摘要：
生活压力事件与抑郁密切相关,因此，钝化或防止压力对大脑的负面影响的策略可能有利于抑郁症的治疗。尽管先前的研究表明蛋白激酶R（PKR）样ER激酶（PERK）在炎症相关性抑郁症中的作用，其参与慢性应激性抑郁症的神经病理学尚不清楚。我们试图探索阻断PERK通路是否会减轻慢性束缚应激（CRS）引起的动物抑郁样行为，并探讨其潜在机制。暴露于CRS的小鼠表现出抑郁样行为，包括蔗糖偏好测试(SPT)中的快感缺乏症，尾悬吊试验（TST）和强迫游泳试验（FST）的不动时间增加。ISRIB给药2周显着改善了暴露于CRS的雄性小鼠的抑郁样行为，这表现在FST和TST中显着增加了蔗糖的偏好并减少了不动时间。然而,我们观察到，在CRS雌性小鼠中暴露于相同剂量的ISRIB仅显示出改善的快感缺乏样缺陷，在FST和TST中留下不变的改进。机械上,我们发现ISRIB逆转了下丘脑-垂体-肾上腺（HPA）轴的过度活动，血清皮质酮水平下降，海马糖皮质激素受体（GR）的表达和下丘脑脑室旁核（PVN）中FosB的表达减少，伴随着保留的海马神经发生。本研究结果进一步扩展了ER应激在抑郁症中的潜在作用，并为PERK抑制剂在情绪障碍中的治疗路径提供了重要细节。
