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Depression is a leading cause of mortality and morbidity worldwide and results from a combination of genetic and environmental risk factors.Electroacupuncture (EA) is an ancient and effective antidepressant strategy.However, the exactly mechanism of EA on depression is poorly understood.Here, we observed the effect of EA on depressive-like behaviors induced by chronic unpredictable stress (CUS).We also investigated the pathological changes in hippocampus after the CUS and EA treatment.The experiments were performed on 40 male Sprauge-Dawley (SD) rats.At the beginning of chronic unpredictable stress (CUS), the rats were randomly divided into four groups: Normal (n=10), Model (CUS, n=10), CUS+ EA (n=10), CUS + Sham EA (n=10).During CUS, rats were submitted once every two days to the following stressors for a total of ten weeks: food and water deprivation (24h), inversion of light / dark cycle (24h), cold water swimming (4 ℃ for 5 min), intermittent illumination (24h).In order to prevent habituation and maintain the aspect of unpredictability, each week stressors and stressor sequences took place at different times.Then EA and sham EA treatments were given to depressive rat once daily for 4 weeks from the 7th week of the CUS procedure.During this period, rats belong to Normal group were left undisturbed in their home cages with the exception of behavioral tests.The depressive-like behaviors were evaluated in the open field test (OPT), forced swimming test (FST) at the weekend of the 6th week and after the entire paradigm.After exposed to 6 or 10 weeks of CUS, the rats displayed significant depressive-like behaviors (i.e., decreased struggling time in FST (## p < 0.01), decreased rearing and total distance in OFT (##P < 0.01, #p < 0.05)).And, 4 weeks of EA treatment can significant alleviate CUS-induced depressive-like behaviors (i.e., increased struggling time in FST (* p < 0.05), increased rearing and total distance in OPT (* P < 0.05, * P < 0.05).Similarly, after exposure to 10 weeks of CUS, the protein and mRNA level of P2XR7 (***p < 0.001) and Iba-1(*** p < 0.001) in CUS rats significantly exceeded that in normal rats.And, the protein level of GFAP (*** p < 0.01) decreased in hippocampus in model rats.The NLRP3 inflammasome were more assembled, and the matured proinflammatory cytokines, such as, interleukin-1beta significantly increased in hippocampus of CUS rats.Moreover, EA treatment can significantly reverse CUS-induced up-regulation of P2XR7 (### p < 0.001), Iba-1(### p < 0.001) and the decrease of GFAP (# p < 0.05).Simultaneously, the assembled NLRP3 inflammasome and the matured interleukin-1 beta of EA group were decreased significantly in compared with that of Sham-EA group.In conclusion, CUS can induce significant depressive-like behaviors and up-regulation the P2XR7, proliferation of microglia and atrophy of astrocyte in rats.Further, EA can significant reverse depressive-like behaviors and alleviate the pathological changes in hippocampus of rats in the CUS model of depression.These findings may give the inspiration to the elucidation of the etiology of depression.