帕金森病脑网络与恒河猴关联模型的建立及疾病机制探索

发布时间：2018-04-05 20:41

本文选题：帕金森病　切入点：神经网络模型　出处：《浙江大学》2015年博士论文

【摘要】：帕金森病(Parkinson's disease)是中老年人最常见的神经退行性运动障碍。到目前为止,世界范围内尚没有有效治愈此病的方法,这给帕金森病患者的日常生活,及其所在家庭以及社会都造成了严重的负担。帕金森病的病因和发病机制目前尚未彻底阐明,中脑黑质区域内多巴胺能神经元不可逆地进行性丢失被认为是帕金森病主要的病理生理基础。目前帕金森病的一线治疗方法是长期药物治疗,对于药物治疗效果不理想的患者,二线治疗是深部脑刺激治疗,遗憾的是,两种治疗方法建立多年来,效果均一直难以令人满意。制约近年来帕金森病研究的可能原因,一是脑结构和功能的复杂性,超越了既往传统研究方法和理论所能把握的范围；二是目前的帕金森病动物模型仍然存在着诸多问题,不利于预测已有研究结果在人类患者上的应用效果。因此,发展或引入新的基本理论和更好的验证工具,可能为突破目前帕金森病研究的瓶颈提供新的动力。故而本研究拟在基本理论和动物模型两方面进行尝试,对其进行一些新的构建。在基本理论方面,随着对脑研究的不断推进,人们逐渐认识到大脑作为目前已知最为复杂的网络系统之一,具有极其复杂的结构和功能。越来越多的研究表明,很多大脑的高级功能,无论是运动、记忆或是情感,都承载于不同层次的神经环路和神经网络中,因此,寻找更合适分析这类问题的新分析方法,便成为一种新的探寻脑及其疾病的重要方向。鉴于此,本研究分析了现有的神经示踪数据库(也即构建脑解剖网络的基本结构数据)的基本现状,发现目前尚缺乏一种整合不同研究数据的方法,因而难于获得较大规模的可分析的脑解剖网络。为此,本研究首先提出一套能够整合不同来源的连接数据的算法,从而全面地利用了现有的连接数据,生成了首个可用于后续分析的恒河猴全脑宏观网络模型。在此过程中,本研究使用统计试验的方法证实了模型中的不确定性部分对最终结论的影响较小,模型适用性好。在此基础上,本研究依据现有对帕金森病病理生理机制的认识,在该网络模型中模拟了进展期帕金森病的脑网络结构；再次,基于正常与帕金森病的全脑网络模型,本研究运用图论等基本原理和复杂网络分析方法,初步描述并比较了理论模型中帕金森病发病前后脑网络各个脑区的改变,并利用降维方法给出了帕金森病全脑网络层面各脑区的变化模式。简单地说,结果显示各个脑区节点的网络中心性发生了不同的改变,如尾状核和壳核的输出角色明显降低；苍白球的中介角色明显增加；杏仁核的接收角色明显降低；其它脑区,如前额叶(包括运动前区)、丘脑、丘脑底核、海马、视皮层以及岛叶等也按各自的模式出现相对明显的中心性改变。建立了合适的网络分析方法后,我们能够方便地将帕金森病的脑网络转变为可供计算分析的数学模型。然而,仅将现实问题转化为数学模型是不够的,还需要将模型计算出的结果在与之对应的可靠的动物模型上进行验证。因此,开发与计算模型相匹配的动物模型也对未来的研究非常重要。在各种动物模型中,非人灵长类模型有着十分明显的优势,因而适合于作为可靠的验证工具。因此,在动物模型方面,本研究首先阐述了现有非人灵长类动物模型存在的问题,诸如帕金森病细胞损伤不完全,病理性的神经损伤和症状体征无法长期稳定,难以避免消化系统损伤及其它急慢性不良反应,症状和发病进程的个体差异很大,建模时和成模后基本生理状况很差,死亡率高等。各种问题背后实质上体现了造模过程的“特异性不足”,这也正是动物模型需要与计算模型相衔接的“接口”。为解决此问题,本研究分析并选用1-Methyl-4-phenylpyridinium iodide (MPP+)的生理盐水溶液作为损毁药物,特别设计了可同时满足给药方便、周边损伤小、特异性高的给药路径,通过改进的磁共振辅助的立体定位技术,将MPP+精确地送入恒河猴一侧黑质和纹状体内。实验通过对实验猴进行长期的研究人员回避的行为录像,定期进行的体重测量、呼吸计数和静脉血检验等相关指标的采集和分析,以及最终的病理切片和免疫组化,证实了通过本实验设计的方法,恒河猴一侧黑质-纹状体通路中的多巴胺能神经元可以获得精确和完整的损毁,而不影响临近的多巴胺能通路；其相关症状可以保持长期(至少28周)稳定,基本情况可以保持长期(至少28周)良好。其建模的快捷性、特异性、安全性优于现有模型,更适宜进行长期“无毒”的细胞移植研究和行为任务研究。本研究提供的神经网络模型和非人灵长类动物模型,具有同样的特异性和可操作性,可以在完整神经网络中特异性的对某一节点或通路进行精确干预,因而两者可以方便地联合使用,达到相互解释和预测的目的。在理论计算和实际验证层次上,同时提供高效特异的控制变量,将为未来的研究提供更多和更加科学的可能性。综上,本研究提供的新型帕金森病模型(体系),为未来帕金森病研究提供了新的基本理论和实验工具,并为两者的联合使用奠定了一定基础。
[Abstract]:Parkinson ' s disease is the most common neurodegenerative motor disorder in the aged and the elderly . So far , there has been no effective cure for Parkinson ' s disease . The etiology and pathogenesis of Parkinson ' s disease have not been fully elucidated .

The possible causes of Parkinson ' s disease research in recent years are the complexity of brain structure and function , which goes beyond the scope of traditional research methods and theories .
Second , there are many problems still exist in the animal model of Parkinson ' s disease , which is not conducive to the prediction of the application effect of the existing research results on human patients . Therefore , it is possible to develop or introduce new basic theories and better verification tools , which may provide new impetus for the breakthrough of the bottleneck of Parkinson ' s disease research .

In the basic theory , with the continuous improvement of brain research , people gradually realize that the brain is one of the most complex network systems , and has extremely complex structure and function . More and more research shows that many advanced functions of the brain , whether moving , memory or emotion , are carried on neural circuits and neural networks at different levels . Therefore , finding a new analytical method for more suitable analysis of these problems becomes an important direction for finding the brain and its disease .

In the light of this , the present study has analyzed the basic present situation of the existing nerve tracing database ( i.e . , the basic structure data of constructing the brain anatomy network ) , and it is found that there is not a method for integrating the data of different sources .
Thirdly , based on the whole brain network model of normal and Parkinson ' s disease , this paper describes and compares the changes of the brain regions of the brain network before and after the onset of Parkinson ' s disease in the theoretical model by using the theory of graph theory and the complex network analysis method .
There was a significant increase in the mediating role of the pallidus ;
The receiving characters of the almond kernel are obviously reduced ;
Other brain regions , such as the frontal lobe ( including the exercise zone ) , the thalamus , the nucleus of the thalamus , the hippocampus , the visual cortex , and the islands , also exhibit a relatively significant central change in their respective patterns .

However , it is not enough to transform the brain network of Parkinson ' s disease into a mathematical model which can be used for calculation analysis . However , it is not enough to convert the real problem into a mathematical model , and it is necessary to validate the results obtained by the model on a reliable animal model corresponding to it . Therefore , it is very important to develop an animal model that matches the computational model . In various animal models , the non - human primate model has obvious advantages and is suitable for a reliable verification tool .

In order to solve this problem , it is very difficult to avoid digestive system injury and other acute and chronic adverse reactions , and it is difficult to avoid digestive system injury and other acute and chronic adverse reactions , and it is difficult to avoid digestive system injury and other acute and chronic adverse reactions .
The related symptoms can be maintained for a long period of time ( at least 28 weeks ) , and the basic condition can be maintained for a long time ( at least 28 weeks ) .

The neural network model and the non - human primate animal model provided by the study have the same specificity and operability , can perform precise intervention on a certain node or channel in a complete neural network , so that both can be conveniently combined and used , thus achieving the purpose of mutual explanation and prediction .

【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R742.5;R-332

【共引文献】