Preliminary Exploration Of Brain Region-specific Metabolic Phenotyping In Depression Research

BACKGROUNDDepression is a major mental disorder disease that cause huge harm to human.It is the main cause of global disease and disability burden.According to the WHO(2017)report,depression has become the leading cause of disability globally,and affected about 322 million individuals worldwide.One of the key issues in studying the mechanisms of antidepressant action and the depression pathogenesis is to select the core brain regions that play a central role.At present,domestic and foreign scholars focus on a single specific brain region to carry out research on the pathogenesis of depression.A large number of studies have shown that the changes of depression-related molecules mainly occur in the prefrontal cortex and hippocampus in the depression model,and the hippocampus and the prefrontal lobe have different transcriptome responses to antidepressants.Therefore,comparing the metabolic networks of the two functional brain regions of the hippocampus and the prefrontal cortex in responding to the antidepressants and stress,and analyzing the association of mechanisms in the microbiota-gut-liver-brain axis,are helpful to provide new ideas for the study of depression and offer important mechanistic insights into the therapeutic actions.OBJECTIVEIn view of the hippocampus and the prefrontal cortex may play an entirely different role in the pathogenesis and therapeutic mechanism of depression.We carry out metabolic networks analysis of the hippocampus and prefrontal cortex after action of antidepressant or stress by means of metabolomics methods.The association analysis was performed with the changes of the metabolic network of the microbe-intestine-liver-brain axis after stress.We hope to find the key molecular mechanism of venlafaxine in the treatment of depression,and look for the links among microbial metabolites-peripheral metabolites-central metabolites.Thus,provides reference for the discovery of new mechanisms for antidepressant drugs,and pave the way for the further development of the "microbiota-gut-liver-brain" axis pathogenesis for depression.METHODS1.Depression-related behavioral results were used to evaluate the effect of venlafaxine on rats.GC-MS metabolomics method combined with multivariate statistical analysis was used to analyze the brain region-specific metabolic network that venlafaxine exerted its antidepressant effect and screened phenotypic-related differential metabolites.2.The model of chronic social defeated stress in mice was established.In combination with LC-MS,GC-MS and NMR metabolomics methods,a comprehensive and systematic review of changes in gut contents,colon,liver,serum,hippocampus,and prefrontal cortex metabolic networks in depression models was conducted.Comparing the association of brain region-specific metabolic networks of hippocampus and prefrontal cortex with the microbiota-gut-liver axis in depression.In order to find the link among microbial metabolites-peripheral metabolites-central metabolites.RESULTS1.There were significant differences in depression-related behavioral studies between the venlafaxine group and the control group.And venlafaxine significantly changed both metabolic networks of the hippocampus and the prefrontal cortex.Furthermore,the altered metabolites had significant brain region specificities,and the altered metabolites in the hippocampus had significant correlations with the despair behaviors.2.The depressed group of the social defeated model showed typical depressive-like social avoidance behavior and anxiety behavior compared with the normal group.Metabolomics based on multiple detection revealed that stress can cause significant changes in the metabolome of the gut contents,colon,liver,serum,hippocampus,and prefrontal cortex.And the differential metabolites mainly focus on seven major class of metabolites: lipids and lipid-like molecules,organic acids and derivatives,organoheterocyclic compounds,nucleosides,nucleotides,and analogues,benzenoids,organic oxygen compounds,and organic nitrogen compounds.At the same time,the differential metabolites at various sites have distinct tissue specificity.The metabolic relationships between the hippocampus or the prefrontal cortex with the microbiota-gut-liver axis have significant specificity in common metabolites,pathways and functional networks,and bacterial specific metabolites.CONCLUSIONIn this study,the first comprehensive and systematic analysis of hippocampus and prefrontal cortex metabolic networks after action of antidepressant or stress was performed.And the association of the brain region-specific metabolic network in stress-induced microbiota-gut-liver-brain axis was studied.These provide a large amount of data support and reference for exploring the mechanism of antidepressant drugs and the “ microbiota-gut-liver-brain” axis theory of depression.This will provide new clues for the discovery of new antidepressant targets and further investigation of the relationship between gut microbiota and depression in the future.