Structural plasticity is critical for the functional diversity of neurons in the brain.Experimental autoimmune encephalomyelitis(EAE)is the most commonly used model for multiple sclerosis(MS),successfully mimicking it...Structural plasticity is critical for the functional diversity of neurons in the brain.Experimental autoimmune encephalomyelitis(EAE)is the most commonly used model for multiple sclerosis(MS),successfully mimicking its key pathological features(inflammation,demyelination,axonal loss,and gliosis)and clinical symptoms(motor and non-motordysfunctions).Recentstudieshave demonstrated the importance of synaptic plasticity in EAE pathogenesis.In the present study,we investigated the features of behavioral alteration and hippocampal structural plasticity in EAE-affected mice in the early phase(11 days post-immunization,DPI)and chronic phase(28DPI).EAE-affected mice exhibited hippocampus-related behavioral dysfunction in the open field test during both early and chronic phases.Dendritic complexity was largely affected in the cornu ammonis 1(CA1)and CA3 apical and dentate gyrus(DG)subregions of the hippocampus during the chronic phase,while this effect was only noted in the CA1 apical subregion in the early phase.Moreover,dendritic spine density was reduced in the hippocampal CA1 and CA3 apical/basal and DG subregions in the early phase of EAE,but only reduced in the DG subregion during the chronic phase.Furthermore,mRNA levels of proinflammatory cytokines(Il1β,Tnfα,and Ifnγ)and glial cell markers(Gfap and Cd68)were significantly increased,whereas the expression of activity-regulated cytoskeletonassociated protein(ARC)was reduced during the chronic phase.Similarly,exposure to the aforementioned cytokines in primary cultures of hippocampal neurons reduced dendritic complexity and ARC expression.Primary cultures of hippocampal neurons also showed significantly reduced extracellular signal-regulated kinase(ERK)phosphorylation upon treatment with proinflammatory cytokines.Collectively,these results suggest that autoimmune neuroinflammation alters structural plasticity in the hippocampus,possibly through the ERK-ARC pathway,indicating that this alteration may be associated with hippocampal dysfunctions in EAE.展开更多
目的探讨逍遥丸改善产前应激子代大鼠焦虑样行为的作用机制。方法采用随机数字表法选择28只SD子代大鼠,根据是否应激、灌胃不同药物,将大鼠分为对照组、产前应激组、产前应激+逍遥丸组和产前应激+氯化钠组,每组7只。然后通过旷场实验和...目的探讨逍遥丸改善产前应激子代大鼠焦虑样行为的作用机制。方法采用随机数字表法选择28只SD子代大鼠,根据是否应激、灌胃不同药物,将大鼠分为对照组、产前应激组、产前应激+逍遥丸组和产前应激+氯化钠组,每组7只。然后通过旷场实验和高架十字实验观察各组子代大鼠的焦虑样行为,随后提取海马组织,分别采用荧光定量聚合酶链反应(PCR)和Western blot法观察谷氨酸受体A1亚基(GluA1)信使RNA(mRNA)和蛋白表达的变化。结果在旷场实验中,与对照组相比,产前应激组潜伏期明显延长,中央区时间百分比和运动距离明显减少(P<0.01);与产前应激+氯化钠组相比,产前应激+逍遥丸组子代大鼠潜伏期明显缩短,中央区时间百分比和运动距离明显增加[(55±14)s比(108±10)s、(14.8±2.4)%比(6.6±1.8)%、(2673±296)cm比(1747±353)cm](P<0.01);但各组子代大鼠运动速度比较差异无统计学意义(P>0.05)。在高架十字迷宫实验中,与对照组相比,产前应激组子代大鼠开放臂运动距离和开放臂时间百分比明显减少(P<0.01);与产前应激+氯化钠组相比,产前应激+逍遥丸组开放臂运动距离和开放臂时间百分比明显增加[(157±20)cm比(21±3)cm、(0.74±0.14)%比(0.50±0.15)%](P<0.01);但各组子代大鼠运动速度比较差异无统计学意义(P>0.05)。荧光定量PCR和Western blot法结果显示,与对照组相比,产前应激组子代大鼠海马中GluA1 mRNA和蛋白表达显著降低(P<0.01);与产前应激+氯化钠组相比,产前应激+逍遥丸组子代大鼠海马中GluA1 mRNA和蛋白表达显著升高(0.950±0.199 vs 0.491±0.181,0.663±0.047 vs 0.464±0.074)(P<0.01)。结论逍遥丸可明显改善产前应激子代大鼠焦虑样行为,其作用机制可能与提高海马区GluA1的表达有关。展开更多
基金supported by the National Research Foundation (NRF)of Korea Grant funded by the Korean Government (NRF-2022R1A2C100402212RS-2023-00219517)。
文摘Structural plasticity is critical for the functional diversity of neurons in the brain.Experimental autoimmune encephalomyelitis(EAE)is the most commonly used model for multiple sclerosis(MS),successfully mimicking its key pathological features(inflammation,demyelination,axonal loss,and gliosis)and clinical symptoms(motor and non-motordysfunctions).Recentstudieshave demonstrated the importance of synaptic plasticity in EAE pathogenesis.In the present study,we investigated the features of behavioral alteration and hippocampal structural plasticity in EAE-affected mice in the early phase(11 days post-immunization,DPI)and chronic phase(28DPI).EAE-affected mice exhibited hippocampus-related behavioral dysfunction in the open field test during both early and chronic phases.Dendritic complexity was largely affected in the cornu ammonis 1(CA1)and CA3 apical and dentate gyrus(DG)subregions of the hippocampus during the chronic phase,while this effect was only noted in the CA1 apical subregion in the early phase.Moreover,dendritic spine density was reduced in the hippocampal CA1 and CA3 apical/basal and DG subregions in the early phase of EAE,but only reduced in the DG subregion during the chronic phase.Furthermore,mRNA levels of proinflammatory cytokines(Il1β,Tnfα,and Ifnγ)and glial cell markers(Gfap and Cd68)were significantly increased,whereas the expression of activity-regulated cytoskeletonassociated protein(ARC)was reduced during the chronic phase.Similarly,exposure to the aforementioned cytokines in primary cultures of hippocampal neurons reduced dendritic complexity and ARC expression.Primary cultures of hippocampal neurons also showed significantly reduced extracellular signal-regulated kinase(ERK)phosphorylation upon treatment with proinflammatory cytokines.Collectively,these results suggest that autoimmune neuroinflammation alters structural plasticity in the hippocampus,possibly through the ERK-ARC pathway,indicating that this alteration may be associated with hippocampal dysfunctions in EAE.
文摘目的探讨逍遥丸改善产前应激子代大鼠焦虑样行为的作用机制。方法采用随机数字表法选择28只SD子代大鼠,根据是否应激、灌胃不同药物,将大鼠分为对照组、产前应激组、产前应激+逍遥丸组和产前应激+氯化钠组,每组7只。然后通过旷场实验和高架十字实验观察各组子代大鼠的焦虑样行为,随后提取海马组织,分别采用荧光定量聚合酶链反应(PCR)和Western blot法观察谷氨酸受体A1亚基(GluA1)信使RNA(mRNA)和蛋白表达的变化。结果在旷场实验中,与对照组相比,产前应激组潜伏期明显延长,中央区时间百分比和运动距离明显减少(P<0.01);与产前应激+氯化钠组相比,产前应激+逍遥丸组子代大鼠潜伏期明显缩短,中央区时间百分比和运动距离明显增加[(55±14)s比(108±10)s、(14.8±2.4)%比(6.6±1.8)%、(2673±296)cm比(1747±353)cm](P<0.01);但各组子代大鼠运动速度比较差异无统计学意义(P>0.05)。在高架十字迷宫实验中,与对照组相比,产前应激组子代大鼠开放臂运动距离和开放臂时间百分比明显减少(P<0.01);与产前应激+氯化钠组相比,产前应激+逍遥丸组开放臂运动距离和开放臂时间百分比明显增加[(157±20)cm比(21±3)cm、(0.74±0.14)%比(0.50±0.15)%](P<0.01);但各组子代大鼠运动速度比较差异无统计学意义(P>0.05)。荧光定量PCR和Western blot法结果显示,与对照组相比,产前应激组子代大鼠海马中GluA1 mRNA和蛋白表达显著降低(P<0.01);与产前应激+氯化钠组相比,产前应激+逍遥丸组子代大鼠海马中GluA1 mRNA和蛋白表达显著升高(0.950±0.199 vs 0.491±0.181,0.663±0.047 vs 0.464±0.074)(P<0.01)。结论逍遥丸可明显改善产前应激子代大鼠焦虑样行为,其作用机制可能与提高海马区GluA1的表达有关。
