| Part oneThe effects of anti-Lingo-1 antibody on the behavioral changes in depression rats with cognitive impairmentObjective Chronic Unpredictable Stress(CUS)depression model rats with cognitive impairment were studied.Morris water maze and other methods were used to study the effect of anti-Lingo-1 antibody on behaviors in depression rats with cognitive impairment in order to find the new treatment of the cognitive impairment in depressionMethods After 1 week of adaptive feeding of 4-6 week male SD rats,the rats were randomly divided into control group(10 rats)and model group(60 rats).The rat model of depression was established with 4 weeks chronic unpredictable stress(CUS).After 4 weeks,the depressed rats(23 rats)in model group were screened using sucrose preference test.The depressed rats were randomly divided into CUS group(12 rats)and Anti-Lingo-1 group(11 rats).The Anti-Lingo-1 group was treated with 8 mg/kg anti-Lingo-1 antibody weekly for 3 weeks.During the experiment,the control group rats were housed in normal conditions with five rats per cage,and the rats in the CUS group and the Anti-Lingo-1 group were still housed with one rat per cage.The body weight of the rats in each group was recorded at the same time frame per week.Sucrose preference test was done at the same time frame per week to evaluate the state of anhedonia.After 3 weeks of anti-Lingo-1 antibody treatment,Morris water maze test,open field test and novelty suppressed feeding test were used to evaluate the behavioral changes of the control group,the CUS group and the Anti-Lingo-1 group.Results 1.Body weight:After baseline adjustment,the body weight of the CUS group was significantly lower than that of the control group at the fourth week(P=0.000).After 3 weeks of anti-Lingo-1 antibody treatment,there was a significant difference in body weight among the control group,the CUS group and the Anti-Lingo-1 group(P=0.000),but there was no significant difference in body weight between the CUS group and the Anti-Lingo-1 group(P=0.130).2.Sucrose preference test:The sucrose preference in the CUS group was significantly lower than that of the control group at the fourth week(P=0.000).After 3 weeks of anti-Lingo-1 antibody treatment,there was a significant difference in the sucrose preference between the control group,the CUS group,and the Anti-Lingo-1 group(P=0.001).However,there was no significant difference in the sucrose preference between the CUS group and the Anti-Lingo-1 group(P=0,687).3.Morris water maze test:After 3 weeks of anti-Lingo-1 antibody treatment,there was no significant difference among the three groups in the first five days of latency time of hidden platform(P=0.966).On the sixth day of the Morris water maze test,the times across the platform in the control group,the CUS group,and the Anti-Lingo-1 group were significantly different(P=0.000).The times across the platform of the CUS group were significantly lower than those of the control group(P=0.004).Compared with the CUS group,the times across the platform in the Anti-Lingo-1 group were significantly increased(P=0.000).There was no significant difference in the time during platform quadrant among the control group,the CUS group and the Anti-Lingo-1 group(P>0.05).There was no significant difference in the distance percent during platform quadrant among the control group,CUS group and Anti-Lingo-1 group(P>0.05).4.Open field test:In the open field test results,there was a significant difference in the percentage of central distance among the control group,the CUS group and the Anti-Lingo-1 group in the open field box(P=0.008).Compared with the control group,the percentage of central distance of the CUS group showed a significant decrease(P=0.002).Compared with the CUS group,the percentage of central distance in the Anti-Lingo-1 group was not significantly different(P>0.05).5.Novelty suppressed feeding test:In the novelty suppressed feeding test results,the food consumption weight of the control group,the CUS group and Anti-Lingo-1 group were significantly different(P=0.000).Compared with the control group,the food consumption weight of the CUS group was significantly decreased(P=0.000).Compared with the CUS group,the food consumption weight of the Anti-Lingo-1 group was not significantly different(P>0.05).Conclusions Three-week anti-Lingo-1 antibody treatment did not improve depression-like behavior in CUS depression model rats,but it significantly improved spatial memory capacity in depression rats.Part twoStereology study of the effects of anti-Lingo-1 antibody on the volumes of hippocampus and white matter and hippocampal oligodendrocytes of depression rats with cognitive impairmentObjective Anti-Lingo-1 antibody therapy has been shown to improve spatial memory in depression,but the cellular mechanisms of the effect are unclear.This study was to investigate the effect of anti-Lingo-1 antibody on oligodendrocytes in hippocampus of CUS depression model rats,in order to provide the experimented evidence for the anti-Lingo-1 antibody-induced improvement of the spatial memory ability in depression.Methods After the behavioral tests being finished,five rats from each group were randomly selected and perfused transcardially with 4%paraformaldehyde.The brains were removed and split into two hemispheres through a midsagittal section.One cerebral hemisphere one rat was randomly selected and dehydrated in a gradient concentrations of sucrose water.Then,the hemispheres were embedded with OCT and coronally sectioned into 60-?m thickness sections on a cryostat microtome.The brain tissue was equally sampled according to the stereological sampling principle,and finally 6 sets of continuous equidistant sections were obtained.A set of equidistant sections were randomly selected and plated on a glass slide to dry for hematoxylin staining.Under the optical microscope,the cell structure was used to delineate the white matter and hippocampus.The white matter volume and hippocampal volume of each group rats were measured with the Cavalieri principle.A random set of consecutive equidistant sections containing the hippocampus were randomly selected.Oligodendrocytes(CNPase,was used to label mature stage oligodendrocytes)of each group rats were immunohistochemically stained,and CNPase cells in DG and CA1,CA3 regions of hippocampus were counted with the stereological methods.Another random set of consecutive equidistant slices containing the hippocampus is randomly selected.Immunofluorescence staining of hippocampal myelin(MBP:myelin marker)in each group was performed to observe the distribution of myelin in DG,CA1 and CA3 regions of hippocampus.Results 1.White matter volume:The volume of corpus callosum in the control group,the CUS group and the Anti-Lingo-1 group was significantly different(P=0.039).Compared with the control group,the volume of corpus callosum in the CUS group was significantly decreased(P=0.023).Compared with the CUS group,the volume of corpus callosum in the Anti-Lingo-1 group was significantly increased(P=0.030).There was no significant difference in the anterior commissure volume among the control group,the CUS group and the Anti-Lingo-1 group(P>0.05).The total volume of the corpus callosum and the anterior commissure was significantly different in the control group,the CUS group and the Anti-Lingo-1 group(P=0.045).Compared with the control group,the total volume of the corpus callosum and the anterior commissure was significantly decreased in the CUS group(P=0.025).Compared with the CUS group,the total volume of the corpus callosum and the anterior commissure was significantly increased in the Anti-Lingo-1 group(P=0.036).2.Hippocampal volume:There was no significant difference in the total hippocampus volume among the control group,the CUS group and the Anti-Lingo-1 group(P>0.05).There was no significant difference in the volume of hippocampal CA1 area among the control group,the CUS group and the Anti-Lingo-1 group(P>0.05).There was no significant difference in the volume of hippocampal CA3 area among the control group,the CUS group and the Anti-Lingo-1 group(P>0.05).There was no significant difference in the hippocampal DG area among the control group,the CUS group and the Anti-Lingo-1 group(P>0.05).3.Stereological results of the total number of CNPase+cells in the hippocampus:In the hippocampal DG region,the number of CNPase+of the CUS group was significantly decreased compared with the control group(P=0.026).The number of CNPase+cells of the Anti-Lingo-1 group was significantly increased compared with the CUS group(P=0.001).In the hippocampal CA3 region,the number of CNPase+cells of the CUS group was significantly lower than that of the control group(P=0.002).The number of CNPase+cells of the Anti-Lingo-1 group was significantly increased compared with the CUS group(P=0.002).In the hippocampal CA1 region,there was no significant difference in the number of CNPase+cells of the CUS group compared with the control group(P>0.05).Compared with the CUS group,there were no significant differences in CNPase+cells of the Anti-Lingo-1 group(P>0.05).4.Immunofluorescence staining of hippocampal MBP:In immunofluorescence staining,it showed that the expression of MBP in hippocampal DG,CA3 and CA1 regions of the CUS group was lower than that of the control group.The myelin arrangement was sparse and blurred in the CUS group compared to the control group.After treatment with Lingo-1 antibody,the expression of MBP in hippocampal DG,CA3 and CA1 regions of Anti-Lingo-1 group was higher than that of CUS group.The myelin sheath was dense and clear in the control group compared to the CUS group.Conclusions There was a decrease in the number of oligodendrocytes and a decline in myelination ability in the hippocampus of the CUS depression model rats.The 3-week anti-Lingo-1 antibody treatment might reduce the pathological changes of oligodendrocytes in the hippocampus of depression model rats through promoting the differentiation of oligodendrocytes and myelination.The positive effect of anti-Lingo-1 antibody on oligodendrocytes in hippocampus might be one of the important cellular mechanisms for the treatment of cognitive impairment in depression. |
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