Based On FMRI To Explore The Molecular Connotation Of IDO1 Regulating Mouse Liver Depression Syndrome And The Intervention Mechanism Of Jiawei Xiaoyao San Granules

BackgroundChinese medicine has unique advantages in regulating the mental and neuropsychiatric diseases such as liver depression syndrome.For example,Jiawei Xiaoyao San Granules are commonly used in clinical treatment of liver depression syndrome caused by various pathogeny,but the mechanism is unknown.Indoleamine 2,3-dioxygenase 1(IDO1),the first enzyme involved in the tryptophan(TRP)-kynurenine(K YN),is the pivotal mechanism of the pathogenesis of liver depression syndrome.However,whether it participates in the regulatory mechanism of Jiawei Xiaoyao San granules in intervention of liver depression syndrome remains to be studied.ObjectiveBased on brain fMRI,we investigated the molecular content of IDO1 in the regulation of CUMS-induced liver depression syndrome in mice and the intervention mechanism of Modified Xiaoyao San Granules.To find new targets for effective prevention and regulation of liver depression syndromes,and to provide basic research basis for clinical application of Jiawei Xiaoyao San Granules.MethodsIn this study,we first replicated the mouse model of liver depression syndrome by CUMS program and used Jiawei Xiaoyao San Granules to intervene.Then,we used fMRI to analyze the effect of Jiawei Xiaoyao San Granules on ALFF.In addition,we analyzed the IDO1 levels in mouse brain regions by LC-MS/MS analysis,western blot(WB),qPCR,and immunofluorescence staining.Moreover,we confirmed whether or not the dorsal raphe nuclei(DRN)is an important brain regions for IDO1 regulation of liver depression syndrome through stereotactic injection techniques.Finally,we explored the mechanism of Jiawei Xiaoyao San Granules in the treatment of liver depression syndromes by analyzing IDO1 function of the DRN,hippocampal BDNF levels and neurogenesis.Data were analyzed using SPSS 20.0 software and the results were expressed as X ± SEM.P<0.05 was considered statistically significant.Results:In the study,we had successfully established animal liver depression syndrome model.We found that,in the serum of CUMS mice,TRP and 5-HT levels decreased,KYN and QUIN levels increased,KYN/TRP values increased and 5-HT/TRP values decreased.Moreover,a high-level expression of IDO1 in the DRN of liver depression syndrome mice.However,after injection of INCB024360 into DRN,the behavioral of liver depression syndrome mice could be improved,and IDO1 was reduced.Therefore,we hypothesized that the DRN was an important brain region for IDO1 to regulate liver depression syndrome.In addition,Jiawei Xiaoyao San Granules could reduces depression-like behavior and the level of IDOl in the DRN of CUMS mice.Amazingly,ALFF of brain function in mice could improved by Jiawei Xiaoyao San Granules.Finally,we also found that it increased the level of BDNF in hippocampus and promoted the hippocampal neurogenesis.Conclusion:Our results indicate that Jiawei Xiaoyao San Granules,maybe as an IDO1 inhibitor,restrains the activity of IDO1 in the DRN.It inhibits the activity of IDO1 in DRN and increases the concentration of 5-HT in the synaptic cleft.Furthermore,Jiawei Xiaoyao San Granules can increase BDNF levels and promote neurogenesis in hippocampal neurons through the CAMP-PKA-CREB-BDNF pathway.In other words,Jiawei Xiaoyao San Granules,improving brain function activity,is an effective medicine for treating liver depression syndrome.This study confirmed the presence of IDO1 overexpressing pathological conditions in mice with liver depression syndrome.We proposed that DRN is an important brain region for IDO1 regulation of liver depression syndrome,which provides a new target for the development of new drugs.Moreover,our study was the first to perform BOLD-fMRI analysis of mice after intervention of Modified Xiaoyao San Granules.Originally,it provided a preliminary study basis for the study of liver depression syndrome and related brain regions.Finally,this study primarily described the mechanism by which Jiawei Xiaoyao San Granules interfered with liver depression syndrome by regulating the IDO1 level of the DRN,providing a direct basis for clinical.