RCS大鼠视网膜变性过程中α亚型神经节细胞形态学变化的研究
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摘要
视网膜色素变性(retinitis pigmentosa, RP)是一种由于感光细胞进行性缺失,导致视网膜内各层神经元发生继发变性的严重致盲性疾病,近年来人们已对该病的治疗进行了各种尝试,包括视网膜移植、基因治疗、视觉假体、药物干预等,取得了一定的进展,但由于视网膜色素变性的发病机制尚不明确,因此为了明确其发病机制,寻找有效的治疗手段,我们需要对该疾病进行深入的研究。
视网膜神经节细胞(retinal ganglion cells, RGCs)是视网膜内的第三级神经元,也是视网膜发育中第一个产生的神经元,其树突主要接受视网膜内的第二级神经元视锥双极细胞(retinal bipolar cells, RBCs)的信息传递,同时也可通过无长突细胞横向联系;其轴突延伸形成视神经,是视觉传输系统的重要组成部分。RGCs的树突是接受神经信号传入的主要部位,树突的形态发生对突触信号的输入、处理以及神经环路的形成起重要作用。
在对慢性高眼压、青光眼、年龄相关性黄斑变性和视网膜脱离等疾病的研究发现,RGCs数量在病变过程中逐渐减少,残留RGCs的树突分支随着病变的发展呈现递减的趋势。对多种视网膜变性动物模型的研究发现,随着感光细胞的死亡,RGCs虽然在数量上出现明显减少,但是存活的RGCs形态并未发生改变并且仍然能诱发出动作电位。既往的研究对视网膜变性过程中RGCs形态是否发生改变意见不一。本实验室既往的研究发现,RCS大鼠(Royal college of surgeon rat, RCS)视网膜变性过程中,RGCs数量在早期有明显减少,其中以胞体横径最大的α亚型减少最为显著,但是这些存活的α亚型RGCs在视网膜变性过程中形态是否发生改变未作进一步研究。综上所述,我们提出如下假设:RCS大鼠视网膜变性过程中,随着感光细胞的不断变性死亡,视锥双极细胞因失去信号输入,其位于内丛状层的与RGCs进行突触联系的轴突分支发生了形态学改变,导致RGCs中对损伤最为敏感的α亚型RGCs在突触形态上形态发生改变。
针对以上假设,本文的主要研究内容及研究结果如下:
1、通过对视网膜DiI染色方法进行改进,采用视网膜铺片DiI示踪标记RGCs的方法,从单细胞水平对α亚型神经节细胞树突一二级分支数目、一级分支直径及树突分支频率的变化进行研究,了解RCS大鼠视网膜变性过程中α亚型RGCs树突的形态学变化。结果发现:1)RCS大鼠视网膜变性过程中,P21dα亚型RGCs一级分支直径出现显著增粗,但是在病程的中晚期未见改变。α亚型RGCs一级分支直径为何在RCS大鼠变性早期出现显著增粗,这种改变有何意义尚不清楚,有待于进一步研究。2)RCS大鼠视网膜变性过程中,α亚型RGCs树突分支频率在早期P21、30d有显著增加,而在晚期P60、90d时RGCs的树突分支频率显著减少。树突分支频率是树突发生分叉的次数,反映了树突数量的变化,因此,我们推测在RCS大鼠视网膜变性早期,随着上级神经元数量的减少,为了接受上级神经元的信息传递并与周围神经元形成突触联系,α亚型RGCs代偿性更早地伸出更多的树突,与周围的神经元形成突触联系以维持其功能,在视网膜变性的中晚期,即P60、90d,随着视网膜各级神经元的进行性减少,RGCs上级神元大量缺失使神经信息传入减少,视网膜内残留的α亚型RGCs树突分支也出现大量萎缩丢失,分支数目显著减少。我们的研究既对α亚型RGCs的树突一二级粗大分支数目进行了测量,也对树突的终末分支频率进行了观察,结果表明,在视网膜变性过程中α亚型RGCs树突粗大分支数目没有明显改变,而其终末的细小分支则出现了明显的减少。提示了视网膜变性过程中RGCs树突形态变化主要在终末分支,这种形态学的改变可能与上级神经元视锥双极细胞的轴突数目减少导致的传入信息减少有关。
2、应用免疫组织化学方法,采用Recoverin特异标记2型及8型视锥双极细胞,观察RCS大鼠视网膜变性过程中视锥双极细胞轴突密度的变化。结果发现:RCS大鼠视网膜变性过程中,随着视网膜外核层的感光细胞进行性缺失,Recoverin阳性视锥双极细胞的轴突密度在P30d开始出现减少,P90d减少更为显著。结果提示:失去上一级信号传入后,视锥双极细胞的数目和轴突分支出现减少,这种改变可能对RGCs的信息传入产生影响。
综上所述,本课题得出如下结论:
1、采用视网膜铺片DiI荧光染色,可以较好的观察神经节细胞形态,对了解和分析正常及病变中神经节细胞形态特点及变化规律提供了一种简单易行的方法。
2、RCS大鼠视网膜变性过程中,α亚型RGCs树突一、二级分支数目无显著变化,而树突分支频率在变性过程中呈现先增高后降低的趋势。结果提示:RCS大鼠视网膜变性过程中,α亚型RGCs树突形态的改变可能主要是其树突终末分支的萎缩和丢失,而这种形态上的改变可能是由于传入信息减少所致,但是其在功能上发生了怎样的改变有待于进一步研究。
3、RCS大鼠视网膜变性过程中,2型和8型视锥双极细胞轴突密度呈现逐渐递减的趋势。结果提示:在视网膜变性过程中,2型和8型视锥双极细胞可能出现了细胞数量的减少,并且其轴突末梢分支也出现了萎缩和丢失,这种轴突形态上的改变可能对下级神经元RGCs的信息传入产生影响。
Retinitis pigmentosa (RP) is one of the most common etiological factors for hereditary blind by loss photoreceptor cells. Several therapeutic strategies for retina degeneration, such as retinal transplantation, gene therapy, visual prosthesis, drug application, were developed in recent years. However, no effective treatment methods to prevent progressive retinal degeneration or to restore visual function have been established. The exact pathophysiological mechanism of retinal degeneration is not fully elucided, which need further explore.
Retinal ganglion cells (RGCs) are the third levels of neurons in the retina and is the first development neurons in retina. The dendrites of RGCs communicated with cone bipolar cells as well as amacrine cells. The axons of RGCs are an important part of optic nerve.
Basis on the before research on the chronic ocular hypertension, glaucoma and retinal detachment, the numbers of RGCs dendritic branch progressively decreased in the development of the disease. Numerous studies of retinal degeneration in animal model have found that the number of RGCs decreased significantly in the early stage lesions with the progressive loss of photoreceptor cells, whereas the survival of ganglion cell morphology has not changed. Previous results from our laboratory or others have shown that the number of ganglion cells decreased significantly in the early stage of RCS rats (Royal college of surgeon rat, RCS) retinal degeneration. However, the morphology of the survival of theαsubtypes of RGCs in the process of retinal degeneration is not fully clarifed. Taken together, we hypothesize that: the morphology of cone bipolar cells changed following the death of photoreceptor cells during the RCS ratsretinal degeneration. This morphology change may lead to the abnormal communication with RGCs, resulting in the morphology change of the most sensitiveαisoform of RGCs.
Our main results are showed as following:
1. The DiI staining method was used to study the morphological changes of the α-RGCs during the pathological process of RCS rat. The results showed that: In the pathological development of the retina of the RCS rats , the amount of first and second level of dendrite branching, the diameter of first level of dendrite branching, and the frequency of dendrite branching ofαsubgroup of retinal ganglion cells were determined. Dendritic branching frequency is the number of dendritic branching, reflecting the changes in the number of dendrites. There was significant difference of frequency of dendrite branching compare with RCS-rdy+ rats. There was also significant difference of the diameter of first level of dendrite branching between RCS and the RCS-rdy+ rats of different ages. But there was no significant difference of the amount of first and second level of dendrite branching between RCS-P+and RCS-rdy+ rats of different ages. Dendrites of RGCs is to receive incoming nerve signals the main parts of dendritic morphogenesis of synaptic signal input, processing and neural circuit formation play an important role. Whether this change in dendritic morphology occur the process of retinal degeneration due to neuronal survival in the microenvironment change need to be further studied.
2.The immunohistochemical method was used to study the axon density of cone bipolar cells during the pathological process of RCS rat. Results: Recoverin positive cone bipolar cell axon density began to decrease at P30d, P90d showed significantly reduced following the outer nuclear layer of retinal photoreceptor cells deletion during the RCS rat retinal degeneration process. The results suggest that, after losing on an incoming signal, the morphology of cone bipolar cells changes inevitably. Such reduction in axon density may be the next level of input neurons influence.
Our main conclusion is showed as following:
In the pathological development of retinitis pigmentosa, frequency of dendrite branching ofαsubgroup of retinal ganglion cells increased significantly in the early stage, while the frequency of dendrite branching decreased during middle and late stage. Our research suggests that the process ofαsubgroup of retinal ganglion cells in the retinal degeneration of dendrites of the information transmission function may have changed.
视网膜神经节细胞(retinal ganglion cells, RGCs)是视网膜内的第三级神经元,也是视网膜发育中第一个产生的神经元,其树突主要接受视网膜内的第二级神经元视锥双极细胞(retinal bipolar cells, RBCs)的信息传递,同时也可通过无长突细胞横向联系;其轴突延伸形成视神经,是视觉传输系统的重要组成部分。RGCs的树突是接受神经信号传入的主要部位,树突的形态发生对突触信号的输入、处理以及神经环路的形成起重要作用。
在对慢性高眼压、青光眼、年龄相关性黄斑变性和视网膜脱离等疾病的研究发现,RGCs数量在病变过程中逐渐减少,残留RGCs的树突分支随着病变的发展呈现递减的趋势。对多种视网膜变性动物模型的研究发现,随着感光细胞的死亡,RGCs虽然在数量上出现明显减少,但是存活的RGCs形态并未发生改变并且仍然能诱发出动作电位。既往的研究对视网膜变性过程中RGCs形态是否发生改变意见不一。本实验室既往的研究发现,RCS大鼠(Royal college of surgeon rat, RCS)视网膜变性过程中,RGCs数量在早期有明显减少,其中以胞体横径最大的α亚型减少最为显著,但是这些存活的α亚型RGCs在视网膜变性过程中形态是否发生改变未作进一步研究。综上所述,我们提出如下假设:RCS大鼠视网膜变性过程中,随着感光细胞的不断变性死亡,视锥双极细胞因失去信号输入,其位于内丛状层的与RGCs进行突触联系的轴突分支发生了形态学改变,导致RGCs中对损伤最为敏感的α亚型RGCs在突触形态上形态发生改变。
针对以上假设,本文的主要研究内容及研究结果如下:
1、通过对视网膜DiI染色方法进行改进,采用视网膜铺片DiI示踪标记RGCs的方法,从单细胞水平对α亚型神经节细胞树突一二级分支数目、一级分支直径及树突分支频率的变化进行研究,了解RCS大鼠视网膜变性过程中α亚型RGCs树突的形态学变化。结果发现:1)RCS大鼠视网膜变性过程中,P21dα亚型RGCs一级分支直径出现显著增粗,但是在病程的中晚期未见改变。α亚型RGCs一级分支直径为何在RCS大鼠变性早期出现显著增粗,这种改变有何意义尚不清楚,有待于进一步研究。2)RCS大鼠视网膜变性过程中,α亚型RGCs树突分支频率在早期P21、30d有显著增加,而在晚期P60、90d时RGCs的树突分支频率显著减少。树突分支频率是树突发生分叉的次数,反映了树突数量的变化,因此,我们推测在RCS大鼠视网膜变性早期,随着上级神经元数量的减少,为了接受上级神经元的信息传递并与周围神经元形成突触联系,α亚型RGCs代偿性更早地伸出更多的树突,与周围的神经元形成突触联系以维持其功能,在视网膜变性的中晚期,即P60、90d,随着视网膜各级神经元的进行性减少,RGCs上级神元大量缺失使神经信息传入减少,视网膜内残留的α亚型RGCs树突分支也出现大量萎缩丢失,分支数目显著减少。我们的研究既对α亚型RGCs的树突一二级粗大分支数目进行了测量,也对树突的终末分支频率进行了观察,结果表明,在视网膜变性过程中α亚型RGCs树突粗大分支数目没有明显改变,而其终末的细小分支则出现了明显的减少。提示了视网膜变性过程中RGCs树突形态变化主要在终末分支,这种形态学的改变可能与上级神经元视锥双极细胞的轴突数目减少导致的传入信息减少有关。
2、应用免疫组织化学方法,采用Recoverin特异标记2型及8型视锥双极细胞,观察RCS大鼠视网膜变性过程中视锥双极细胞轴突密度的变化。结果发现:RCS大鼠视网膜变性过程中,随着视网膜外核层的感光细胞进行性缺失,Recoverin阳性视锥双极细胞的轴突密度在P30d开始出现减少,P90d减少更为显著。结果提示:失去上一级信号传入后,视锥双极细胞的数目和轴突分支出现减少,这种改变可能对RGCs的信息传入产生影响。
综上所述,本课题得出如下结论:
1、采用视网膜铺片DiI荧光染色,可以较好的观察神经节细胞形态,对了解和分析正常及病变中神经节细胞形态特点及变化规律提供了一种简单易行的方法。
2、RCS大鼠视网膜变性过程中,α亚型RGCs树突一、二级分支数目无显著变化,而树突分支频率在变性过程中呈现先增高后降低的趋势。结果提示:RCS大鼠视网膜变性过程中,α亚型RGCs树突形态的改变可能主要是其树突终末分支的萎缩和丢失,而这种形态上的改变可能是由于传入信息减少所致,但是其在功能上发生了怎样的改变有待于进一步研究。
3、RCS大鼠视网膜变性过程中,2型和8型视锥双极细胞轴突密度呈现逐渐递减的趋势。结果提示:在视网膜变性过程中,2型和8型视锥双极细胞可能出现了细胞数量的减少,并且其轴突末梢分支也出现了萎缩和丢失,这种轴突形态上的改变可能对下级神经元RGCs的信息传入产生影响。
Retinitis pigmentosa (RP) is one of the most common etiological factors for hereditary blind by loss photoreceptor cells. Several therapeutic strategies for retina degeneration, such as retinal transplantation, gene therapy, visual prosthesis, drug application, were developed in recent years. However, no effective treatment methods to prevent progressive retinal degeneration or to restore visual function have been established. The exact pathophysiological mechanism of retinal degeneration is not fully elucided, which need further explore.
Retinal ganglion cells (RGCs) are the third levels of neurons in the retina and is the first development neurons in retina. The dendrites of RGCs communicated with cone bipolar cells as well as amacrine cells. The axons of RGCs are an important part of optic nerve.
Basis on the before research on the chronic ocular hypertension, glaucoma and retinal detachment, the numbers of RGCs dendritic branch progressively decreased in the development of the disease. Numerous studies of retinal degeneration in animal model have found that the number of RGCs decreased significantly in the early stage lesions with the progressive loss of photoreceptor cells, whereas the survival of ganglion cell morphology has not changed. Previous results from our laboratory or others have shown that the number of ganglion cells decreased significantly in the early stage of RCS rats (Royal college of surgeon rat, RCS) retinal degeneration. However, the morphology of the survival of theαsubtypes of RGCs in the process of retinal degeneration is not fully clarifed. Taken together, we hypothesize that: the morphology of cone bipolar cells changed following the death of photoreceptor cells during the RCS ratsretinal degeneration. This morphology change may lead to the abnormal communication with RGCs, resulting in the morphology change of the most sensitiveαisoform of RGCs.
Our main results are showed as following:
1. The DiI staining method was used to study the morphological changes of the α-RGCs during the pathological process of RCS rat. The results showed that: In the pathological development of the retina of the RCS rats , the amount of first and second level of dendrite branching, the diameter of first level of dendrite branching, and the frequency of dendrite branching ofαsubgroup of retinal ganglion cells were determined. Dendritic branching frequency is the number of dendritic branching, reflecting the changes in the number of dendrites. There was significant difference of frequency of dendrite branching compare with RCS-rdy+ rats. There was also significant difference of the diameter of first level of dendrite branching between RCS and the RCS-rdy+ rats of different ages. But there was no significant difference of the amount of first and second level of dendrite branching between RCS-P+and RCS-rdy+ rats of different ages. Dendrites of RGCs is to receive incoming nerve signals the main parts of dendritic morphogenesis of synaptic signal input, processing and neural circuit formation play an important role. Whether this change in dendritic morphology occur the process of retinal degeneration due to neuronal survival in the microenvironment change need to be further studied.
2.The immunohistochemical method was used to study the axon density of cone bipolar cells during the pathological process of RCS rat. Results: Recoverin positive cone bipolar cell axon density began to decrease at P30d, P90d showed significantly reduced following the outer nuclear layer of retinal photoreceptor cells deletion during the RCS rat retinal degeneration process. The results suggest that, after losing on an incoming signal, the morphology of cone bipolar cells changes inevitably. Such reduction in axon density may be the next level of input neurons influence.
Our main conclusion is showed as following:
In the pathological development of retinitis pigmentosa, frequency of dendrite branching ofαsubgroup of retinal ganglion cells increased significantly in the early stage, while the frequency of dendrite branching decreased during middle and late stage. Our research suggests that the process ofαsubgroup of retinal ganglion cells in the retinal degeneration of dendrites of the information transmission function may have changed.
引文
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