Chronic Mild Stress Leads To Aberrant Glucose Energy Metabolism In Depressed Macaca Fascicularis Models

BackgroundMajor depressive disorder(MDD)is a pathophysiologically unclear mental illness accompanied by complex etiology and clinical manifestations.Rodent depressive-like models have been widely used to mimic the morbid state of depression.However,research of emotional disorders can also benefit from the use of models in non-human primates,which share a wide range of genetic and social similarities with humans.MethodsTo investigate the pathophysiological mechanisms of depression,we established two models – naturally-occurring depression cynomolgus(NOD)and social plus visual isolation-induced depression cynomolgus(SVC),imitating chronic mild or acute intense stress,respectively.We used iTRAQ(isobaric tags for relative and absolute quantitation)-based quantitative proteomics and shotgun proteomics to identify differentially expressed proteins in cerebrospinal fluid(CSF)of the two monkey models and human MDD patients.DAVID and ingenuity pathway analysis(IPA)were used for further bioinformatic analyses.ResultsIn behavioral tests NOD monkeys achieved higher scores in depressive-like and anxiety-like behavioral measures,and spent more time on ingesting,thermoregulatory and locomoting actions compared with SVC monkeys.A total of 902 proteins were identified by iTRAQ,and 40 and 40 differentially expressed proteins were identified in the NOD-CON1 and SVC-CON2 group,respectively.Application of DAVID revealed dysregulation of energy metabolism in the NOD group,whereas lipid metabolism and inflammatory response pathways were significantly altered in the SVC group.Use of IPA and Cytoscape showed that the oxygen species metabolic process glycolysis I/gluconeogenesis I,accompanied by downregulation of tubulin beta 3 class III(TUBB3),RAC-alpha serine/threonine-protein kinase(AKT1)and glyceraldehyde-3-phosphate dehydrogenase(GAPDH),was the most significantly affected pathway in the NOD group.Furthermore,152 differentially expressed proteins in human MDD patients also showed disruption of glucose energy metabolism.Significant aberrant energy metabolism in various brain regions and the plasma and liver of chronic unpredictable mild stress(CUMS)rodent samples from a previous study was also observed.ConclusionsOur results primarily demonstrate the overall CSF protein profile of two cynomolgus monkey models of depression.We propose that chronic mild stress may effect to the disruption of glucose energy metabolism in NOD cynomolgus,and rodents.These findings may provide novel insight into the understanding of MDD pathophysiology and identify novel therapeutic targets.