大鼠老化时认知功能变化及其与白质损害关系
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摘要
目的:认知功能损害是脑老化的显著特点,其机制还不清楚,迄今亦无有效预防及治疗方法。近年来,基础及临床研究已经证实,脑白质损害是认知功能降低的重要原因之一,临床上也常见到脑白质改变能引起认知功能的下降。脑白质主要成分是胶质细胞、髓鞘和轴突。蛋白脂蛋白(Protein Lipid Protein,PLP)是髓鞘的重要成分之一,郎飞结(Ranvier node)的结旁区粘附分子Caspr(Contactin-associated protein)是维持髓鞘及轴突功能关键分子,两者变化会引起髓鞘和轴突结构和功能变化,进而影响白质功能。本研究从以下四个方面探讨了老龄大鼠学习记忆功能变化、白质结构和功能改变:(1)从行为学角度探讨老年大鼠认知功能变化;(2)老化时中枢神经传导功能的改变;(3)髓鞘蛋白PLP表达改变;(4)胶质/轴突界面粘附分子Caspr2变化及与轴突、髓鞘损害关系,目的是揭示老化对认知功能的影响及髓鞘和轴突的变化在其中的意义。
方法:将wistar大鼠分为两组:青年组(6-7月龄)和老年组(18-24月龄)。采用Morris水迷宫评定大鼠学习记忆功能;电生理方法记录大鼠穿通通路传导潜伏时,评定前脑区中枢神经传导功能;透射电镜观察大鼠的轴突、髓鞘等白质区结构的超微改变;应用免疫组化技术检测脑老化过程中PLP及粘附分子Caspr2表达变化,并用LEICAQWIN图像分析系统对PLP免疫染色的积分光密度值进行分析。
结果:
1.老年组大鼠较青年组大鼠隐匿平台逃避潜伏时显著延长(P<0.01);空间探索实验中:老年组大鼠游泳路径,在平台95%中心区域占总路径的百分数明显低于青年组(P<0.01),第1次穿越平台所在位置的时间明显长于青年组(P<0.05);可见平台逃避潜伏时,老年组较青年组明显延长(P<0.05)。
2.中枢传导功能:两组间存在显著差别,老年大鼠中枢传导潜伏时较青年组显著延长(P<0.01)。
3.白质区超微结构变化:老年大鼠轴突直径增加,轴突内含有巨大线粒体,线粒体结构模糊不清,脊崩解,轴突内也可见到囊泡和致密颗粒。轴突周围间隙扩大。髓鞘致密层分离,部分板层结构排列紊乱破坏、模糊、融合。胶质细胞胞浆内及细胞间隙电子密度增高,可见脂褐素沉积。
4.PLP免疫组化:两组于纹状体、胼胝体、前联合、皮层下区均可见阳性染色。但老年组各部位PLP表达量明显减少、其积分光密度值明显增大(P<0.01)。
5.Caspr2免疫荧光染色:青年组和老年组大鼠均可见到Caspr2的荧光染色。在纤维的顺行切面上表现为对称点状,呈绿色荧光,在横切面上表现为点状。老年组荧光染色强度显著低于青年组。
结论:
1.老年组大鼠空间参考学习、记忆能力较青年组大鼠明显减退,空间探索及记忆维持能力明显降低。
2.脑老化时穿通通路传导潜伏时延长,反映中枢神经传导功能降低,可能与老年大鼠学习、记忆功能减退有关。
3.脑老化时少突胶质细胞、髓鞘及轴突超微结构存在明显变化,是白质功能减退的重要原因。
4.髓鞘蛋白PLP表达减少,与髓鞘形态结构改变有关,这种变化可能与老化时神经传导功能降低和认知功能损害有一定联系。
5.脑老化时胶质/轴突间粘附分子Caspr2表达减少,导致髓鞘与轴突分离,进而影响白质结构及功能,在老化白质损害的机制中具有重要地位。
Objective:
The significant character of brain aging is the damage of recognitive function.Up to now,its mechanism is unknown.There are not effective methods of prevention and treatment.In the past several years,the basic and clinical researchs have already confirmed that white matter damage was an important cause of the decline of recognitive function.It was often seen that the white matter change resulted the decline of recognitive function in clinic.The essential component of white matter are gliacyte,myelin sheath and axon. Protein Lipid Protein(PLP)is an important component of myelin sheath.Adhesion molecule,Contactin-associated protein(Caspr),in paranode of Ranvier node,is the important molecule that maintains the function of myelin sheath and axon.Their Changes may result in structural and functional changes of myelin and axon.Furthermore,they affect white matter function.This thesis studied changes of learning and memory function, the structural and functional change of white matter in aged rats in four aspects.(1) In behavioral aspect,the changes of recognitive function was studied in aged rats;(2) the change of central conductive function during brain aging;(3) PLP expressive changes; (4)The expressive and functional change of Caspr2 between myelin and axon and its relationship with the damage of axon and myelin sheath.The purpose is to reveal the effect of aging on recognitive function and the significance of axon and myelin sheath changes.
Methods:
The wistar rats were divided into two groups:young group(6-7 months) and aged group(18-24 months).Morris water maze was adopted to evaluate learning and memory function of rats.The conductive latency time of perforant pathway was recorded by Electrophysiological methods to evaluate central conductive function of forebrain regions in rats.Transmission electron microscope(TEM) was used to observe the ultramicrostructural changes of white matter in rats,such as myelin sheath and axon. Immunohistochemistry techniques was applied to detect expressive changes of PLP and adhesion molecule Caspr2 in brain aging.LEICA QWIN image analytical system was used to analyze integrated optical density(IOD) of PLP immunostaining.
Results:
1.The escape latency increased significantly in aged group rats than young group(P＜0.01).The mean percentage(%)of path in the 95%central zone were significantly lower in the aged group(P＜0.01),the first time passing hidden platform prolonged significantly in the aged group(P＜0.05).In the obvious platform experiment,escape latency significantly delayed in aged group than young group(P＜0.05).
2.The central conductive time increased significantly in aged group than young group(P＜0.01).
3.In the ultramicrostructural changes of white matter,axon diameter increased,which contained megamitochondrion.The structure of mitochondrion was vague,ridge was disaggregated.The dense granule was observed in aged groups.The gaps around enlarged. In myelin sheath,the compact layer separated and some layers structure of myelin were confused,destructed.It can be seen that electron density increased and lipofuscin deposited in cytoplasm of gliacyte.
4.In PLP Immunohistochemistry,it had been seen positive staining in striatum, callosum,anterior commissure,subcortex regions in two groups.But the PLP expressive capacity decreased obviously and IOD value(optical density value) increased obviously in aged group than young group(P＜0.01).
5.In Caspr2 immunofluorescence staining,positive fluorescent staining were seen in two groups.It showed points and strips in green fluorescence.Fluorescent staining intensity decreased obviously in aged group than young group.
Conclusions:
1.In aged group rats,not only the spatial reference learning and memory function but also the memory maintenance function significantly decreased than young group rats.
2.The conductive latency time of perforant pathway prolonged in brain aging,which showed that central conductive function decreased.It was probably relevant to the decline of learning and memory function in aged group rats.
3.There were significant changes of ultramicrostructure in oligodendrocyte,myelin sheath and axon,which may be an important reason of the decline of white matter function during brain aging.
4.The expression of PLP decreased,that is relevant to the morphological and structural changes of myelin sheath.This change probably have some relation with the decline of conductive function and the damage of recognitive function during brain aging.
5.Expression of Caspr2,an adhesion molecule between myelin and axon,decreased in brain aging.It resulted in separation between myelin sheath and axon.Furthermore,it affected structure and function of white matter.It has an important rank in the damage of white matter during brain aging.
方法:将wistar大鼠分为两组:青年组(6-7月龄)和老年组(18-24月龄)。采用Morris水迷宫评定大鼠学习记忆功能;电生理方法记录大鼠穿通通路传导潜伏时,评定前脑区中枢神经传导功能;透射电镜观察大鼠的轴突、髓鞘等白质区结构的超微改变;应用免疫组化技术检测脑老化过程中PLP及粘附分子Caspr2表达变化,并用LEICAQWIN图像分析系统对PLP免疫染色的积分光密度值进行分析。
结果:
1.老年组大鼠较青年组大鼠隐匿平台逃避潜伏时显著延长(P<0.01);空间探索实验中:老年组大鼠游泳路径,在平台95%中心区域占总路径的百分数明显低于青年组(P<0.01),第1次穿越平台所在位置的时间明显长于青年组(P<0.05);可见平台逃避潜伏时,老年组较青年组明显延长(P<0.05)。
2.中枢传导功能:两组间存在显著差别,老年大鼠中枢传导潜伏时较青年组显著延长(P<0.01)。
3.白质区超微结构变化:老年大鼠轴突直径增加,轴突内含有巨大线粒体,线粒体结构模糊不清,脊崩解,轴突内也可见到囊泡和致密颗粒。轴突周围间隙扩大。髓鞘致密层分离,部分板层结构排列紊乱破坏、模糊、融合。胶质细胞胞浆内及细胞间隙电子密度增高,可见脂褐素沉积。
4.PLP免疫组化:两组于纹状体、胼胝体、前联合、皮层下区均可见阳性染色。但老年组各部位PLP表达量明显减少、其积分光密度值明显增大(P<0.01)。
5.Caspr2免疫荧光染色:青年组和老年组大鼠均可见到Caspr2的荧光染色。在纤维的顺行切面上表现为对称点状,呈绿色荧光,在横切面上表现为点状。老年组荧光染色强度显著低于青年组。
结论:
1.老年组大鼠空间参考学习、记忆能力较青年组大鼠明显减退,空间探索及记忆维持能力明显降低。
2.脑老化时穿通通路传导潜伏时延长,反映中枢神经传导功能降低,可能与老年大鼠学习、记忆功能减退有关。
3.脑老化时少突胶质细胞、髓鞘及轴突超微结构存在明显变化,是白质功能减退的重要原因。
4.髓鞘蛋白PLP表达减少,与髓鞘形态结构改变有关,这种变化可能与老化时神经传导功能降低和认知功能损害有一定联系。
5.脑老化时胶质/轴突间粘附分子Caspr2表达减少,导致髓鞘与轴突分离,进而影响白质结构及功能,在老化白质损害的机制中具有重要地位。
Objective:
The significant character of brain aging is the damage of recognitive function.Up to now,its mechanism is unknown.There are not effective methods of prevention and treatment.In the past several years,the basic and clinical researchs have already confirmed that white matter damage was an important cause of the decline of recognitive function.It was often seen that the white matter change resulted the decline of recognitive function in clinic.The essential component of white matter are gliacyte,myelin sheath and axon. Protein Lipid Protein(PLP)is an important component of myelin sheath.Adhesion molecule,Contactin-associated protein(Caspr),in paranode of Ranvier node,is the important molecule that maintains the function of myelin sheath and axon.Their Changes may result in structural and functional changes of myelin and axon.Furthermore,they affect white matter function.This thesis studied changes of learning and memory function, the structural and functional change of white matter in aged rats in four aspects.(1) In behavioral aspect,the changes of recognitive function was studied in aged rats;(2) the change of central conductive function during brain aging;(3) PLP expressive changes; (4)The expressive and functional change of Caspr2 between myelin and axon and its relationship with the damage of axon and myelin sheath.The purpose is to reveal the effect of aging on recognitive function and the significance of axon and myelin sheath changes.
Methods:
The wistar rats were divided into two groups:young group(6-7 months) and aged group(18-24 months).Morris water maze was adopted to evaluate learning and memory function of rats.The conductive latency time of perforant pathway was recorded by Electrophysiological methods to evaluate central conductive function of forebrain regions in rats.Transmission electron microscope(TEM) was used to observe the ultramicrostructural changes of white matter in rats,such as myelin sheath and axon. Immunohistochemistry techniques was applied to detect expressive changes of PLP and adhesion molecule Caspr2 in brain aging.LEICA QWIN image analytical system was used to analyze integrated optical density(IOD) of PLP immunostaining.
Results:
1.The escape latency increased significantly in aged group rats than young group(P＜0.01).The mean percentage(%)of path in the 95%central zone were significantly lower in the aged group(P＜0.01),the first time passing hidden platform prolonged significantly in the aged group(P＜0.05).In the obvious platform experiment,escape latency significantly delayed in aged group than young group(P＜0.05).
2.The central conductive time increased significantly in aged group than young group(P＜0.01).
3.In the ultramicrostructural changes of white matter,axon diameter increased,which contained megamitochondrion.The structure of mitochondrion was vague,ridge was disaggregated.The dense granule was observed in aged groups.The gaps around enlarged. In myelin sheath,the compact layer separated and some layers structure of myelin were confused,destructed.It can be seen that electron density increased and lipofuscin deposited in cytoplasm of gliacyte.
4.In PLP Immunohistochemistry,it had been seen positive staining in striatum, callosum,anterior commissure,subcortex regions in two groups.But the PLP expressive capacity decreased obviously and IOD value(optical density value) increased obviously in aged group than young group(P＜0.01).
5.In Caspr2 immunofluorescence staining,positive fluorescent staining were seen in two groups.It showed points and strips in green fluorescence.Fluorescent staining intensity decreased obviously in aged group than young group.
Conclusions:
1.In aged group rats,not only the spatial reference learning and memory function but also the memory maintenance function significantly decreased than young group rats.
2.The conductive latency time of perforant pathway prolonged in brain aging,which showed that central conductive function decreased.It was probably relevant to the decline of learning and memory function in aged group rats.
3.There were significant changes of ultramicrostructure in oligodendrocyte,myelin sheath and axon,which may be an important reason of the decline of white matter function during brain aging.
4.The expression of PLP decreased,that is relevant to the morphological and structural changes of myelin sheath.This change probably have some relation with the decline of conductive function and the damage of recognitive function during brain aging.
5.Expression of Caspr2,an adhesion molecule between myelin and axon,decreased in brain aging.It resulted in separation between myelin sheath and axon.Furthermore,it affected structure and function of white matter.It has an important rank in the damage of white matter during brain aging.
引文
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