Behavioral Abnormalities And Mechanisms Underlying Cuprizone Induced Demyelination

Objective: Multiple sclerosis(MS)is an autoimmune disease with central inflammatory demyelination as the main pathological.MS patients are not only physically disability,but also accompanied by schizophrenia-like clinical manifestations include depression,indifference,cognitive impairment.Cuprizone inducede mouse will specifically destroy central oligodendrocytes,which usually to research non-T lymphocyte-mediated myelination.Recent researchs shown the behavior change in cuprizone induced mouse,which is expected to as a schizophrenia animal model.It is not clear that how demyelination causes mental behavior abnormalities.In this research,we will explore the mechanism that leads to this by studying the cuprizone induced mouse behavioral changes,which was expected to provide more evidence to research new schizophrenia animal model and schizophrenia-like MS model.Methods: Male C57BL/6 mice were fed with chow containing 0.4% cuprizone to induce the white matter demyelination which corpus callosum was primary.In order to study the effect of demyelination on animal behavior,behavioral experiment will be conducted,Y-maze test(the ninth day),spontaneous locomotor activity test(the twelfth day),rota-rod test(the sixteenth day),novel object recognition test(the nineteenth day),climbing behavior test(the twentieth day).Western blotting was used to detect the levels of myelin basic protein and dopamine transporter.Myelin demyelination were evaluated by LFB staining,and myelin basic protein immunohistochemical staining.Levels of astrocytes(GFAP marked),microglia(Iba-1marked),oligodendrocyte precursor cells(NG2 marked)were detected by immunohistochemical staining.High-performance liquid chromatography(HPLC)was used to detect levels of neurotransmitters include dopamine(DA),dihydroxy-phenyl acetic acid(DOPAC),5-hydroxyindoleacetic acid(5-HIAA),homovanillic acid(HVA),norepinephrine(NE),5-hydroxytryptamine(5-hydroxytryptamine,5-HT).The effects of clozapine on Curpizone-induced behavioral abnormalities were observed by administration of clozapine 5mg/kg and 10mg/kg(body weitht)Results:1.Behavioral outcomes of CPZ-exposure mice:CPZ increased in the total explored distance,exploring velocity and arm entrances,decreased the rest time in Y-maze test;CPZ group showed more locomotor movements than the control group;no differences were found in latency to fall from the rotating drum in the rota-rod test;total explored time and familiar explored time increased,the CPZ mice also displayed decreased preference for the novel object during the recognition phase evaluated by the discrimination and recognition index;more climbing behavior was observed in CPZ group.2.CPZ mice were demyelinated in the third week,and cause high expression of microglia and astrocytes.3.CPZ increased the DA level of the prefrontal cortex,and reduced the levels of DA and DOPAC in the striatum.But the NE level of the striatum position was significantly increased.4.CPZ increased the level of DAT.5.High dose of clozapine improves the increase of total explored distance and exploring velocity in Y-maze test,furthermore improves the increase of locomotor movements and climbing behavior.Conclusion:1.CPZ-induced demyelination model had a significant change in behavior.2.The level of DA and DAT may be preferentially associated with their abnormal behaviors.3.High dose of clozapine improves the abnormal behaviors of CPZ-induced model.4.CPZ-induced animal models significantly for studying the neuropsychiatric symptoms of MS,and is expected as a complementary model of schizophrenia.