Background: Depression is a serious public mental disease.It is a complex epidemiological psychiatric illness which is often associated with stressful events, and presents with depressed mood, loss of interest or pleasure and so on.It has been considered as a systemic disorder caused by impairment in different biochemical pathways[i].However its pathophysiological mechanism is not yet well understood.In addition, the current evaluate measurements for depression are short of objectivity Metabonomics is a systematic study of the endogenous, small-molecule metabolites involved in specific biological processes, providing an assessment of the physiological status of an organism.In this work, Metabonomics by GC-MS and multivariate statistical analysis were used to select potential biomarkers relating to the CUMS depression.The dynamic metabolic changes in rat serum were investigated to find potential disease biomarkers and to research pathology of depression induced by the CUMS depression model.Methods: A total of 16 male Sprague-Dawley (SD) rats were applied in this experiment.After 7 days habituation, all the rats were divided into the following two group, model group and control group (n=6).The model rats were housed individually and exposed to the chronic unpredictable mild stress (CUMS) in a random order every day.The changes in behavior and serum metabolic profiles were investigated during three-week CUMS exposure.The behavior projects conclude weight, open-field test, sucrose preference test, which time was scheduled at day O, 7, 14 and 21.Serum samples were collected at day 0, 6, 9, 12, 15 and 21, and the serum metabolic profiling was measured using GC-MS, followed by multivariate analysis.The GC-MS condition as follows: GC-MS analysis was performed using a Ploaris Q ion trap mass spectrometer (Thermo Fisher Scientific Inc., USA).Chromatography was performed on a DB-5MS capillary column (30m×250 μm i.d., 0.25 μm film thickness; 5% diphenyl cross-linked 95% dimethylpolysiloxane; Agilent J&W Scientific, Folson, CA, USA).Helium carrier gas was used at a constant flow rat of 1 ml.min-1.Volumes of 1.0 μl of derivatized samples were injected into the GC-MS instrument.To acquire a good separation, the column temperature was initially maintained at 60℃ for 3 min, and then raised to 140℃ at a rate of 7℃C/min for 4 min, to 180℃ at 5℃· min for another 6 min, to 280℃ at 5℃· min for another 2 min.After a solvent delay of 9 min, MS detection was implemented in electron ionization mode (electron energy of 70eV) and full scan mode (m/z 50-650).The potential biomarkers were screened from metabolites by principal component analysis and correlation analysis.The peak area of potential biomarkers was used to find the change of depression rats and describe the dynamic change.Results: Exposure to CUMS for three weeks caused depression-like behavior in rats, as indicated by significant decreases in weight gain, sucrose consumption, ambulation number and rearing numbers.Six potential biomarkers in serum including glycine (Gly), glutamic acid (Glu), fructose, citric acid, glucose and hexadecanoic acid are screening by metabonomics and multivariate statistical analysis.It was found that fructose, glucose and Gly was higher in model group, hexadecanoic acid, Glu and citric acid were lower in model group.According to the results of principal component analysis and correlation analysis, the correlation coefficient between the behavior scores and contents of potential biomarkers in serum are all more than 0.9.Conclusions The result suggested that the depressed progress may be associated with perturbation of glycometabolism, amino acid metabolism and energy metabolism.Gly, Glu, fructose, citric acid, glucose and hexadecanoic acid are might the quantitative diagnostic biomarker for depression.The representative and unique of biomarkers need be verified by pharmacological experiments, molecular pharmacology enzyme or gene.