Study On The Mechanism Of Depression-like Behavior In Mice Mediated By Exosomes From Depressed Patients

Object:Major depressive disdorder(MDD)is a neuropsychiatric disease characterized by depression,with high incidence and high suicide rate.According to statistics,the number of patients worldwide is about 322 million,of which 15%of people with depression die of suicide.Exosomes is a kind of vesicle secreted by many nerve cells.After it is secreted to the extracellular,it can act on the surrounding cells,or act on the distal cells through the circulatory system to change the receptor cells.Exosomal microRNAs(miRNAs)have been suggested to participate in the pathogenesis of neuropsychiatric diseases,its role and mechanism,and whether it can be used as a diagnostic method of the disease,especially in the role of MDD is unknown.This study reveals the important role and mechanism of exosomes in the occurrence and development of depression from the clinical,animal and cellular levels,and provides new ideas for clinical diagnosis and treatment.Method and results:1.We performed a genome-wide miRNA expression profiling of blood-derived exosomes from MDD patients and control subjects and revealed the top differentially expressed exosomal miRNA,i.e.hsa-miR-139-5p(up-regulated expression in MDD patients),had good sensitivity and specificity in distinguishing between MDD patients and controls.2.Then in vivo experiments,tail vein injection of blood exosomes isolated from MDD patients into normal mice caused their depressive-like behaviors as determined by the forced swimming,tail suspension,and novelty suppressed feeding tests,and through pathological sections and immunofluorescence staining,we found that neurogenesis in the hippocampus of mice treated with exosomes isolated from MDD patients with depression was significantly decreased;tail vein injection of blood exosomes isolated from healthy volunteers into unpredictable mild stress(CUMS)-treated mice alleviated their depressive-like behaviors and increased hippocampal neurogenesis.CUMS mice also showed significantly increased blood and brain levels of exosomal miR-139-5p.Furthermore,the depressive-like behaviors in CUMS-treated mice were rescued by intranasal injection of miR-139-5p antagomir,suggesting that increased exosomal miR-139-5p levels may mediate stress-induced depression-like behavior in mice.In addition,we stereotaxically injected miR-139-5p inhibitors into the hippocampal dentate gyrus of CUMS-treated mice,and found that miRNA-139-5p inhibitors increased neurogenesis in the hippocampus of mice,and the depression-like behavior of mice was alleviated.3.The role of miR-139-5p in neurogenesis was confirmed by in vitro experiments,indicating that miR-139-5p is a negative regulator of neural stem cell proliferation and neuronal differentiation.Abnormal high expression of miR-139-5p can significantly decrease the proliferation of neural stem cells and reduce the differentiation of neurons.Conclusion:The results show that exosomes isolated from MDD patients cause depression-like behavior in mice through miR-139-5p-regulated neurogenesis.Additionally,we found that injecting blood exosomes from healthy individuals into CUMS mice alleviated depressive-like behaviors and restored biochemical changes in the brain and peripheral blood,and promoted hippocampal neurogenesis,suggesting that exosomes play a crucial role in the progression of depression.Therefore,the experimental results provide further evidence for blood Exosome miRNAs as a potential biomarker of MDD,and confirm that exosome mediation is a new mechanism in the pathogenesis of MDD,which provides a new target for the diagnosis and treatment of MDD.