空间学习对AD模型鼠海马突触可塑性及神经发生的影响

发布时间：2018-05-09 00:38

本文选题：空间学习 + 阿尔茨海默病　；参考：《华中科技大学》2012年博士论文

【摘要】：[背景] 临床研究显示,学习刺激治疗(cognitive stimulation therapy, CST)可改善阿尔茨海默病(Alzheimer's Disease, AD)患者的认知功能并延缓海马的萎缩,其分子机制仍不清楚。通过反复空间学习能降低AD转基因小鼠β-淀粉样蛋白(β-amyloid peptide, A(3)的沉积、tau蛋白过度磷酸化并提高学习记忆能力。AD模型脑内有明显突触的损伤、功能的降低以及海马神经发生减少,空间学习对以上AD相关病变有无改善作用目前仍无报道。 [目的] 本研究旨在对三种AD动物模型进行空间学习干预,探讨空间学习对AD模型鼠海马神经元树突形态、功能及神经发生的影响。 [方法] 对侧脑室注射Aβ1-42多肽AD模型、高同型半胱氨酸血症大鼠模型及Tg2576转基因鼠三种AD模型进行为期6d空间学习,学习结束后用免疫组化、银染及免疫印记等方法检测Aβ的沉积,并用高尔基染色技术统计分析海马CA1及DG区神经元树突的形态及树突棘的密度。通过记录内嗅区前穿质纤维(perforant path, PP)-齿状回(dentate gyrus, DG)通路长时程增强(long-term potentiation, LTP)来检测空间学习对AD模型鼠突触可塑性的影响。通过学习前7d及学习早期1-4d给予腹腔注射Brdu来标记新生神经元,再用免疫组化及免疫荧光计数研究新生神经元的存活和增殖。 [结果] 空间学习减少侧脑室注射Aβ1-42模型及Tg2576转基因鼠海马及皮层神经元内Aβ的聚积。同时,空间学习增加以上三种AD模型海马DG区颗粒细胞树突的复杂性、树突棘密度及突触蛋白的表达；并且提高Tg2576转基因鼠CA1区锥体神经元树突复杂性和树突棘密度。学习不仅对AD模型突触结构有改善作用,而且可提高Aβ1-42及高同型半胱氨酸血症模型大鼠海马PP-DG通路的突触功能。通过Brdu标记学习前7d的新生神经元,我们发现空间学习可增加Aβ1-42大鼠,但不能改善Tg2576转基因小鼠及高同型半胱氨酸血症大鼠模型海马齿状回的亚颗粒层(subgranular zone, SGZ)新生神经元的存活。我们也标记了学习早期1-4d的新生神经元,Aβ1-42及高同型半胱氨酸血症模型大鼠海马SGZ新生神经元的增殖显著增加,新生神经元的增殖在Tg2576转基因鼠模型中亦没有明显改变。此外,空间学习增加了三种AD模型鼠海马SGZ新生神经元树突的分支节点数。 [结论] 空间学习可能通过降低AD模型鼠脑内Ap的聚积、改善海马神经元突触形态、功能及增加SGZ新生神经元的存活,从而改善学习记忆能力。
[Abstract]:[background] Clinical studies have shown that cognitive stimulation therapy can improve cognitive function and delay hippocampal atrophy in patients with Alzheimer's disease (AD). The molecular mechanism of CSTs is still unclear. Repeated spatial learning could reduce the hyperphosphorylation of 尾 -amyloid peptide (A3) in 尾 -amyloid peptide (A3) and improve the ability of learning and memory. There were obvious synaptic damage, decrease of function and decrease of hippocampal nerve in AD transgenic mice. The effect of spatial learning on AD-related lesions has not been reported. [purpose] The purpose of this study was to study the effects of spatial learning on the morphology, function and neurogenesis of hippocampal neurons in three AD animal models. [methods] Contralateral ventricular injection of A 尾 1-42 polypeptide AD model, hyperhomocysteinemia rat model and Tg2576 transgenic rat AD model were conducted for 6 days. After the study, the deposition of A 尾 was detected by immunohistochemistry, silver staining and immunological imprinting. The morphology of dendrites and the density of dendritic spine in hippocampal CA1 and DG region were analyzed by Golgi staining technique. The effects of spatial learning on synaptic plasticity in AD model rats were investigated by recording long term potentiation (LTP) via long term potentiation (LTP) pathway. The newborn neurons were labeled by intraperitoneal injection of Brdu 7 days before learning and 1-4 days after learning. The survival and proliferation of new neurons were studied by immunohistochemistry and immunofluorescence counting. [results] Spatial learning reduced the accumulation of A 尾 in hippocampal and cortical neurons of rats with intracerebroventricular injection of A 尾 1-42 and Tg2576 transgenic mice. At the same time, spatial learning increased the dendritic complexity, dendritic spinous density and synaptophysin expression in the DG region of hippocampus of the three AD models, and increased the dendritic complexity and dendritic spinous density of CA1 pyramidal neurons in Tg2576 transgenic mice. Learning not only improved the synaptic structure of AD model, but also increased the synaptic function of hippocampal PP-DG pathway in A 尾 1-42 and hyperhomocysteinemia rats. We found that spatial learning increased the number of A 尾 1-42 rats by Brdu labeling in the first 7 days of learning. But it could not improve the survival of new neurons in the dentate gyrus subgranular layer of the dentate gyrus of Tg2576 transgenic mice and hyperhomocysteinemia rats. We also labeled the proliferation of hippocampal SGZ neonate neurons in the model of hyperhomocysteinemia, 1-4 d after learning, and the proliferation of newborn neurons was not significantly changed in Tg2576 transgenic rats. In addition, spatial learning increased the number of branches of dendrites of hippocampal SGZ neonate neurons in three AD model rats. [conclusion] Spatial learning may improve the ability of learning and memory by reducing the accumulation of AP in the brain of AD model, improving the synaptic morphology and function of hippocampal neurons and increasing the survival of newborn neurons of SGZ.
【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R749.16

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