The Effect Of Chronic Stress On Postoperative Cognitive Function And Neuroinflammation In Adult Rats

Objective: Accumulated evidence indicates that stress sensitizes neuroinflammatory responses to a subsequent peripheral immune challenge.The present study investigated whether chronic unpredictable stress(C US)aggravated surgery-induced sickness behavior and neuroinflammatory processes via glucocorticoids secretion in the adult brain.Methods: Sprague-Dawley adult male rats(12-14 weeks old)were randomly divided into a total of six groups: control group,CUS group,RU486 group,surgery group,CUS+surgery group,and RU486+CUS+surgery group,36 rats in CUS group and 30 rats in each other groups.Rats in CUS group were exposed to 14-day CUS and the rats in RU486+CUS+surgery group were subjected to partial hepatectomy 24 h after the last stress session.The rats in RU486+CUS+surgery group were pretreated with an antagonist of the glucocorticoids(GCs)receptor RU486(30 mg/kg,i.p.)1 h prior to stress exposure.The behavioral change was evaluated with an open field test and elevated plus-maze test on postoperative days 1,3 and 7;The hippocampal cytokines interleukin(IL)-1?,IL-6 and brain derived neurotrophic factor(BDNF)were measured by western blot;Immunohistochemistry was used to detect the expression of microglial M1 phenotype marker(Iba)-1;Real-time PCR was used to detect the expression of microglial M2 phenotype marker Arg1 m RNA and CD200 m RNA.Concentrations of GCs in plasma were quantified by using an enzyme-linked immunoassay(ELISA).Results: CUS decreased the bodyweight of stressed rats.Chronic stress aggravates the sickness behavior caused by surgical trauma: The total distance and the time in the central area were shorter in the CUS+Surgery group compared with that in the Surgery group in the open field test.The percentage of time spent and the number of enries in the open arms were shorter in the CUS+Surgery group compared with that in the Surgery group in the elevated plus-maze test.CUS exaggerated surgery-induced neuroinflammatory responses in the hippocampus :Exposure to CUS alone failed to alter the levels of pro-inflammatory cytokines in the brain.However,CUS exaggerated surgery-induced pro-inflammatory cytokines expression(e.g.IL-1? and IL-6)on postoperative day 3.CUS upregulated surgery-induced microglial Iba-1expression and reduced the m RNA levels of M2 phenotype marker Arg1: Compared to the naive controls,CUS failed to alter the expression of Iba-1 and m RNA levels of Arg1 in the hippocampus.Higher levels of Iba-1 and lower levels of Arg1 m RNA were observed in the animals of CUS+surgery group compared with those of the surgery group.Pretreatment with RU486 blocked the effects of CUS on surgery-induced Iba-1 upregulation and downregulation of Arg1 expression in the hippocampus.CUS exaggerated surgical trauma-induced decrease of levels of BDNF and CD200 m RNA in the adult brain:In the CUS+Surgery group,CUS decreased the level of CD200 m RNA and BDNF on postoperative days 1 and 3.The pretreatment of RU486 reduces the potential role of CUS in the reduction of CD200 and BDNF caused by surgical trauma.Exposure to CUS resulted in a significant increase in plasma GCs compared to the rats in the control group at 24,48 h after the last session of stress.The levels of GCs returned to baseline 96 h post-stress.Conclusion: Chronic unpredictable stress enhanced surgery-induced sickness behavior and neuroinflammatory responses.Stress-induced GCs played a pivotal role in enhancing surgery-induced neuroinflammatory processes by modulation of microglia functions,which was partially blunted with pretreatment of RU486.