Cerebrospinal Fluid Metabolomics Of A Naturally-occurring Depression Model Of Macaques

Background: Major depressive disorder(MDD)is a serious mental illness worldwide,affecting nearly 300 million people,equivalent to 4.4% of the world population.According to a survey conducted by the Chinese Health Department,about 100 million people in China suffer from depression,accounting for 10% of women,and about 8% of men.Depression can be sustained or repeated,not only seriously affecting individuals,but also affecting their family harmony,children's growth and work environment.Depression is very likely to lead to suicide in patients.In China,hundreds of thousands of patients commit suicide every year because of depression.Depression is a multifactorial and influential neurological disease.The molecular mechanism of action so far is not clear.Because depression is a multifactorial neurological disorder,the underlying molecular mechanisms are still unknown.Although,in recent years,we have used rodent depression models to a certain extent,we have promoted a preliminary understanding of the diagnosis and treatment of depression in humans.However,the brain structure of rodents is quite different from humans and cannot effectively reflect the development of human depressive disorders.Therefore,using the cerebrospinal fluid of a non-human primate that is highly similar to the human brain as a research vehicle for metabolomics research will provide new ideas for the pathogenesis of depression and can provide new objective diagnostic markers.The material provides a theoretical basis and a large amount of evidence.Objective: In this study,a metabolomic analysis of the cerebrospinal fluid of naturally-occurring depression model of macaques and healthy control macaques by gas chromatography-mass spectrometry was performed for the first time.Potentially significant markers associated with the development of depression were sought,followed by analysis of significant markers to derive their more relevant metabolic pathways.We analyzed the possible metabolite content associated with depression from the differential metabolites of cerebrospinal fluid in natural depression model cynomolgus monkeys and healthy control cynomolgus monkeys,and then used statistical analysis to derive significant differences in molecules,according to metabolic molecules in the human body.The physiological functions exerted to explore the metabolic changes of the cerebrospinal fluid and the underlying pathophysiological mechanisms underlying the occurrence of depression in humans.Method: 1.Naturally-Occurring Depression Model of Macaques individual selection: Based on the previous and the foundation,combined with the actual observation of the cage groups to screen a group of individual sit alone,curled up to reduce the excitement of the outside world,social interaction was significantly less than other companions have Typical depression-like behaviors of macaques.2.GC-MS metabolomics analysis of naturally-occurring depression model of macaques and healthy control cynomolgus macaques cerebrospinal fluid,using multivariate statistics,including principal component analysis(PCA),partial least squares(PDS-DA)and Orthogonal partial least squaresdiscriminant analysis(OPLS-DA)were used to obtain the full spectrum of differential metabolites between the two groups,and then functional clustering and analysis of significant Metabolic pathway.Results: 1.Naturally-occurring depression model of macaques social interaction,exercise significantly reduced,but also manifested in the descendants and the friendly behavior of the group indifferent,individuals like to sit alone,no interest in food or external stimuli.2.Through multivariate statistical analysis,there was a significant metabolic difference in cerebrospinal fluid between the naturally-occurring depression model of macaques group and the normal individual control group.Compared with the control group,a total of 37 significant differences in metabolites were found,of which 35 metabolites were significantly reduced in naturally-occurring depression model of macaques group,and both metabolites were significantly increased.In addition,according to the results of bioinformatics analysis,these 37 significant differences in metabolites are mainly closely related to amino acid metabolism,energy metabolism,and lipid metabolic pathways.Conclusion: Thirty-seven metabolites were identified in the cerebrospinal fluid of naturally-occurring depression model of macaques.These metabolites were associated with biosynthesis of fatty acids,amino acid metabolism(mainly manifestations of aspartic acid metabolic disorders,threonine degradation,glycine,serine and threonine Metabolism as well as arginine and valine metabolism)).In our published paper,8 metabolites in the serum of naturally-occurring depression model of macaques overlap with differential metabolites in this cerebrospinal fluid,including some shortchain fatty acids and amino acids.These results indicate that peripheral metabolites can be transported through the plasma to the brain and vice versa.Therefore,this study utilizes nonhuman primate depression models and provides useful insights into the molecular mechanisms of depression.