The Role Of The Dynamic Changes In Hippocampal Microglia In Alcohol-induced Depression-like Behaviors In Mice

Objective To study the role of alcohol-triggered dynamic changes in hippocampal microglia in depression formation.Methods The adolescent and adult C57BL6/J male mice were employed in this study.The immunofluorescence was used to detect the changes in microglial numbers and morphology,as well as microglial proliferation and apoptosis in the hippocampus.Real-time quantitative PCR was used to measure the changes in Iba-1 m RNA levels in hippocampal DG.The behavioral tests were used to evaluate the influence of lipopolysaccharide(LPS)and macrophage-colony stimulating factor(M-CSF)on adolescent or adult alcohol exposure-induced depression-like behaviors in mice.The microglia inhibitor minocycline or the microglia depletor PLX3397 was used to investigate whether the microglia mediate the antidepressant effect of LPS and M-CSF in alcohol exposure models.Results(1)Both intermittent alcohol exposure(AIE)and adult alcohol exposure induced depression-like behaviors in mice,and reduced microglial cell numbers,branched process length,cell body area,and Iba-1 m RNA levels in hippocampal DG;(2)microglia activators,such as LPS and M-CSF,reversed AIE-or adult alcohol exposure-induced(a)reductions in hippocampal microglial numbers,(b)increases in immobility time in the tail suspension test(TST)and forced swim test(FST),and(c)decreases in sucrose preference in the sucrose preference Abstract test(SPT),and those effects of LPS and M-CSF were associated with hippocampal microglia activation,as minocycline,an inhibitor of microgla,and PLX3397,an depletor of microglia,prevented the antidepressant effect of LPS and M-CSF in alcohol exposure models;(3)the AIE and adult alcohol exposure-induced depression-like behaviors in mice were associated with the earlier activation and apoptosis of microglia in the hippocampus,as(a)1 day of alcohol exposure induced microglia activation,while 5 days of alcohol exposure induced microglia apoptosis in hippocampal DG in adolescent and adult mice,(b)inhibition of th earlier activation of hippocampal microglia by minocycline pretreatment prevented the short-term alcohol exposure-induced microglial activation and apoptosis,as well as the AIE-or adult alcohol exposure-induced decrease in hippocampal microglial numbers.Conclusions(1)Both AIE and adult alcohol exposure induce depression-like behavior in mice,which is associated with the decrease in microglial numbers in hippocampal DG;(2)microglia activation can reverse AIE or adult alcohol exposure-induced depression-like behaviors in mice;(3)the AIE-or adult alcohol exposure-induced decrease in hippocampal microglia is positively associated with the alcohol-induced early activation and apoptosis of microglia in the hippocampus,and inhibition of the early activation of hippocampal microglia can reverse the AIE-or adult alcohol exposure-induced depression-like behaviors in mice as well as the AIE-or adult alcohol exposure-induced decrease in hippocampal microglia.