Systematic Biology Research On Social Defeat Stress Modeland Humanized Depression Model

PART 1: SOCIAL DEFEAT STRESS CAUSES DEPRESSION-LIKE BEHAVIOR WITH METABOLITE CHANGES IN THE PREFRONTAL CORTEX OF RATSMajor depressive disorder is a serious mental disorder with high morbidity and mortality.The role of social stress in the development of depression remains unclear.Here,we used the social defeat stress paradigm to induce depression-like behavior in rats,then evaluated the behavior of the rats and measured metabolic changes in the prefrontal cortex using gas chromatography-mass spectrometry.Within the first week after the social defeat procedure,the sucrose preference test(SPT),open field test(OFT),elevated plus maze(EPM)and forced swim test(FST)were conducted to examine the depressive-like and anxiety-like behaviors.For our metabolite analysis,multivariate statistics were applied to observe the distribution of all samples and to differentiate the socially defeated group from the control group.Ingenuity pathway analysis was used to find the potential relationships among the differential metabolites.In the OFT and EPM,there were no significant differences between the two experimental groups.In the SPT and FST,socially defeated rats showed less sucrose intake and longer immobility time compared with control rats.Metabolic profiling identified 25 significant variables with good predictability.Ingenuity pathways analysis revealed that “Hereditary Disorder,Neurological Disease,Lipid Metabolism” was the most significantly altered network.Stress-induced alterations of low molecular weight metabolites were observed in the prefrontal cortex of rats.Particularly,lipid metabolism,amino acid metabolism,and energy metabolism were significantly perturbed.The results of this study suggest that repeated social defeat can lead to metabolic changes and depression-like behavior in rats.PART2: PROTEOMIC PROFILING REVEALS MICROBIOTA-DRIVEN SENSING MECHANISMS OF THE GUT-BRAIN AXIS IN DEPRESSIONMajor depressive disorder(MDD)is a serious mental illness.Compelling evidence from both animal and human studies indicates that the gut microbiome is actively involved in onset of depression via the gut–brain axis.However,the underlying molecular basis remains largely unknown.Gut microbiota can markedly alter the host's metabolic signature,although changes at the protein level are rarely reported.To examine the protein changes modulated by gut microbiota,germ-free mice were transplanted with gut microbiota from MDD patients to induce depression-like behaviors.A quantitative proteomics approach was then used to examine changes in protein expression in the prefrontal cortex(PFC),liver,cecum and serum,which are important components of the gut–brain axis.Behavioral tests verified generation of depression-like behavior following transplantation of gut microbiota.More than 5,000 proteins were identified in all four tissues.The proportion of various functional proteins in the cecum was similar with the liver,but different to the PFC and serum.We identified 159,187,148 and 55 differentially expressed proteins in the PFC,liver,cecum,and serum,respectively.Gut microbiota recipient mice also showed distinct patterns of differentially expressed proteins compared with traditional rodent models of depression.Pathway enrichment analysis revealed that the NRF2-mediated oxidative stress response was activated in the PFC,cecum,and serum.Notably,cascade reactions between the PFC and peripheral tissues may contribute to the influence of gut microbiota on behaviors.Our data suggest the gut microbiota can strongly regulate protein expression on multiple components of the gut–brain axis in a fecal microbiota transplantation model of depression,and that these protein changes are different from traditional chronic stress models.Further,gut microbiota mainly influence the oxidative stress response and cascade reactions in the development of depression,which may be a potential sensing mechanism of the gut–brain axis.