Chronic mild stress leads to aberrant glucose energy metabolism in depressed Macaca fascicularis models

Major depressive disorder (MDD) is a pathophysiologically uncharacterized mental illness with complex etiology and clinical manifestations. Rodent depression-like models have been widely used to mimic the morbid state of depression. However, research on 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.To 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 i-TRAQ (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. We also used DAVID and ingenuity pathway analysis (IPA) for further bioinformatic investigation.In behavioral tests, NOD monkeys achieved higher scores in depression-like and anxiety-like behavioral measures, and spent more time on ingesting, thermoregulatory, and locomotive actions than SVC monkeys. A total of 902 proteins were identified by i-TRAQ, and 40 differentially expressed proteins were identified in each of the NOD-CON1 and SVC-CON2 groups. 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 revealed disruption of glucose energy metabolism. Significantly aberrant energy metabolism in various brain regions and the plasma and liver of chronic unpredictable mild stress rodent samples were also observed in a previous study.Our results reveal for the first time the overall CSF protein profiles of two cynomolgus monkey models of depression. We propose that chronic mild stress may affect the disruption of glucose energy metabolism in NOD cynomolgus monkeys and rodents. These findings promote our understanding of the pathophysiology of MDD and may help to identify novel therapeutic targets.