| BackgroundMajor depressive disorder (MDD) is a debilitating mental illness andthe disability rate of MDD ranked fourth among all diseases. Currentlythere are approximately90million MDD patients in China., The CentralGovernment has listed MDD as one of the three main prevention and curediseases of our country, thus to carry out researches on MDD is of greatsignificance.Metabonomics has great advantages in MDD study via systematicallycapturing the most critical signaling molecules in biological samples whichmight play important roles in pathophysiologic mechanism of MDD.However there are still some limitations for metabonomics study on MDD:1, While clinical studies are most relevant, their interpretation is hamperedby variability in subject characteristics (e.g. age at first onset, comorbidities,drug and alcohol use);2, Cerebrospinal fluid is of great importance in MDD study, but it is difficult to get CSF samples from MDD patients inreality;3, Animal models are able to conquer the aformentioned twoproblems. The most common depression models are rodent models,however they cannot truly reflect the human emotion and cognition due tothe enormous difference between the construction of cerebral cortex inhuman and rodents. Therefore, the best choice is to employ the non-humanprimate, which has the highest similarity with human, as the study carrierfor metabonomics study.Separation models and social-defeated models are the main streamnon-human primate depression models over the world, but they both havelimitations: firstly, separation models were generally employed in researchon children’s depression, which cannot reflect the depression in adulthood;furthermore, the model has been abandoned due to the ethical issue ofinfant monkeys; secondly, social-defeated models hardly simulate thecomplex social relationships, thus the animal model cannot reflect themajor depressive disorder with strong social attributes. In summary, toconstruct a non-human primate model of adult depression with mature andcomplex social relationships will not only be the guarantee for carrying outour research but also could provide the reliable study carrier for MDDresearch. Objective1, To construct a new social isolation-associated depression model ofmacaca fascicularis at two different levels.2, To provide new clues for revealing the possible pathogenesis ofdepression through CSF and serum metabolomic study with GC-MSapproaches.Methods1, Baseline behavioral observation and analysis were carried outbefore animal model establishment, then the experiment group were takenout from their original place. The experiment group were divided into twosubgroups, the first subgroup were placed in standard single cagesindividually (Standard single cage, SSC). This subgroup were sociallyisolated, while allowing visual, olfactory and auditory contact with otherSSC subjects; the second subgroup were placed in self-made cagesindividually (No visual contact, NVC), which were socially isolated withno visual contact, only allowing olfactory and auditory contact with otherNVC subjects. The isolation period was90days, after the isolation periodall study subjects were removed back to their original social group,behavioral observation and analysis were carried out again. The serum andCSF sample were collected before and after the isolation for follow-upstudy. 2, A metabolomic profiling of serum and CSF between depressedsubjects and control subjects were conducted through GC-MS approaches,afterwards differential metabolites were identified by multivariatestatistical methods.Results1, After90days isolation period, significant behavioral changes couldbe observed in SSC and NVC subjects(e.g. locomotive behavior, conflictbehavior, amicable behavior) compared to the pre-isolation behaviors. Acluster of four significantly changed behavioral items is able to distinguishSSC and NVC from Control subjects.(same-sex mounting, being groomed,embracing and huddling). Above all the huddling behavior (defined asdepressive-like behavior) significantly increased in SSC and NVC subjects,and the subgroup with additional visual isolation produced more profoundbehavioral changes than SSC subjects.2, OPLS-DA analysis revealed20differential metabolites in serumbetween depressed group (NVC+SSC) and control group. Thesemetabolites were involved in amino acid metabolism (L-Methionine,Glycine, L-Aspartic acid), energy metabolism (adenosine, inosine, maltose)and lipid metabolism (linoleic acid, arachidonic acid, stearic acid)pathways. Compared with control group respectively, five commonmetabolites (inosine, arachidonic acid, L-Aspartic acid, oleic acid, glycolic acid) increased in both SSC and NVC group. Arachidonic acid showedsimilar variation trend in two model groups, while the other fourmetabolites performed higher levels in NVC subjects than SSC subjects.3, OPLS-DA analysis revealed9differential metabolites in CSFbetween depressed group (NVC+SSC) and control group. Thesemetabolites were involved in amino acid metabolism (alanine, glutamicacid， L-Aspartic acid) and energy metabolism (erythritol, lactose, succinicacid，3-Hydroxybutanoic acid，glycerol and glucose) pathways. Glyceroland L-Aspartic acid showed significant changes in both serum and CSF.Conclusion1, In this study, an adult macaca fascicularis models of depression wassuccessfully constructed via social isolation methods. The depressive-likesymptom in cynomolgus monkeys became more obvious as the degree ofsocial isolation gets severer. The model conquered the defect that thetraditional non-human primate model cannot reflect the major depressivedisorder with strong social attributes.2, Metabonomics analysis of serum and CSF consistently revealed thatamino acid metabolism, energy metabolism and lipid metabolism pathwayswere closely associated with depression, this finding can provide insight into the mechanisms study of depression. |
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