Effects Of Chronic Stress On Depressive-like Behaviors And JMJD3 Expression In The Prefrontal Cortex And Hippocampus Of C57BL/6 And Ob/ob Mice

Background:Depression is a serious psychological disorder that causes enormous social and economic costs in the worldwide.Patients with depression are often accompanied by the activation of immune system and increased levels of inflammatory cytokines.Obesity is a worldwide health problem,and also considered as a low-grade inflammatory state of the body.Studies have found that obese individuals are more likely to suffer from depression,but its possible mechanism has not been specifically illuminated.Microglia cells play an important role in neuroinflammatory responses,which its activation is regulated by epigenetic modifications.Trimethylation at lysine 27 of histone-H3(H3K27me3)is a histone modification associated with transcriptional repression,and the Jumonji domain protein 3(JMJD3)is its specific histone demethylase that catalyzes H3K27me3 demethylation.JMJD3 can be directly induced by nuclear transcription factor-KappaB(NF-?B),which promotes the expression of inflammatory related genes through H3K27me3 demethylation,and its upregulation may be limited by adiponectin(APN).However,the role of JMJD3 in susceptibility to neuroinflammation and depression in obesity has not been clarified.Objectives:1.To investigate the effects of chronic stress on anxiety and depressive-like behaviors and spatial learning and memory ability,neuroinflammation state and JMJD3 expression in obese and normal weight mice.2.To elucidate the role of JMJD3 in chronic stress-induced depression and increased susceptibility to depression in obesity,and whether JMJD3 inhibitors GSK-J4 improve depressive-like behaviors and neuroinflammation due to chronic stress.Materials and methods:1.Thirty male C57BL/6 mice and thirty ob/ob mice(8 weeks old)were randomly divided into the control group and the chronic unpredictable mild stress(CUMS)group.Four weeks of CUMS procedure were used to establish the animal model with depression.Sucrose preference test(SPT),tail suspension test(TST)and open field test(OFT)were used to detect and anxiety-and depressive-like behaviors.2.The CUMS group of C57BL/6 mice and ob/ob mice were randomly divided into the CUMS group and the CUMS+GSK-J4 group after behavioral tests.The CUMS group continued to undergo 2-week CUMS modeling procedure,and the CUMS+GSK-J4 group received a daily intraperitoneal injection of GSK-J4 before receiving stress stimulation for 2 weeks.SPT,TST,OFT and Morris water maze(MWM)test were used to detect anxiety-and depressive-like behaviors and spatial learning and memory impairment after CUMS and GSK-J4 injection.3.Microglial activation was detected by Immunofluorescence.4.The expressions of pro-inflammatory cytokines,NF-?B in the prefrontal cortex(PFC)and hippocampus(HIP)and adiponectin levels in serum and PFC,HIP were detected by enzyme-linked immunosorbent assay(ELISA).5.The expressions of JMJD3 and H3K27me3 in PFC and HIP were detected by western blotting.Results:CUMS led to anxiety-and depressive-like behaviors and memory impairment,and microglial activation,increased expressions of pro-inflammatory cytokines,NF-?B and JMJD3,decreased expression of H3K27me3 in the PFC and HIP in C57BL/6 mice and ob/ob mice.More severer behavioral abnormalities and memory impairment,more pronounced levels of microglial activation,over-expression of pro-inflammatory cytokines and NF-?B and decreased H3K27me3 levels were shown in ob/ob mice compared with C57BL/6 mice.Moreover,CUMS also decreased APN levels in the serum and brain tissues of ob/ob mice.However,JMJD3 inhibitor GSK-J4 could alleviate the above alterations.Conclusions:Chronic stress leads to the increase of JMJD3 expression in the PFC and HIP and a marked depressive-like behavior and neuroinflammatory state in obese mice.JMJD3 might be involved in the increased susceptibility to depressive-like behaviors and neuroinflammation in obese mice by demethylation of H3K27me3,and APN may be involved in this process by reducing the combination of Enhancer of zeste homolog 2(EZH2)and H3K27me3.The role of JMJD3 in severer inflammatory state in the comorbidity of obesity and depression was considered.