%0 Journal Article
%T PERK inhibitor (ISRIB) improves depression-like behavior by inhibitions of HPA-axis over-activation in mice exposed to chronic restraint stress.
%A Luhong L
%A Zhou HM
%A Tang XH
%A Chen J
%A Zhang AM
%A Zhou CL
%A Li SY
%A Wen Yu C
%A Liyan H
%A Xiang YY
%A Yang X
%J Behav Brain Res
%V 0
%N 0
%D 2024 Jun 26
%M 38942086
%F 3.352
%R 10.1016/j.bbr.2024.115122
%X 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.