【作者】 吴永明；

【导师】 舒斯云；

【作者基本信息】 中国人民解放军第一军医大学 ， 细胞生物学， 2003， 博士

【摘要】 学习记忆是大脑最基本也是最重要的高级神经功能之一，它的生物学基础称之为记忆痕迹。记忆痕迹在大脑内的定位一直以来都是神经科学、心理学和精神病学领域的研究热点之一。自从1957年Scoville报道了一例因双侧内侧颞叶切除而造成严重的近期记忆丧失的病例以来，内侧颞叶记忆系统、前额叶、杏仁核和Meynert基底核等脑区相继被证实参与了不同的学习记忆过程。纹状体边缘区是舒斯云等1988年在研究大鼠脑纹状体时发现的位于新纹状体尾内侧、靠近苍白球边缘的一个由梭形细胞构成的新亚区，富含多种神经肽类阳性纤维、终末和胞体。猫和猴脑内也存在类似的纹状体边缘区。双盲Y迷宫试验和即早基因c-fos表达法等均证实纹状体边缘区参与了大鼠的学习记忆过程。但人脑纹状体内是否也存在边缘区?如果存在，其结构和功能如何?边缘区在学习记忆环路中所处的地位又如何?为解决这些问题我们进行了如下研究。 为观察人脑纹状体内是否也存在边缘区及边缘区内是否也有大量神经递质表达，我们通过神经细胞形态染色及免疫组织化学方法证实了边缘区在人脑纹状体内的存在，并阐明了人脑纹状体边缘区内神经递质的分布特性；在证明人脑存在边缘区的基础上，利用功能磁共振成像(functional magnetic resonance imaging,fMRI)技术对正常人脑的边缘区是否具有学习记忆功能进行了研究，证实了人脑边缘区参与了听觉数字工作记忆过程；然后，在fMRI研究的基础上，我们进一步对临床病人的脑部MRI进行分析，发现其中20例边缘区损伤病例均有认知功能障碍，通过测定边缘区损伤患者的简易智能状态检查量表(Mini-Mental State Examination,MMSE)评分，结合磁共振影像学分析，从临床角度确证了人脑边缘区与学习记忆等认知功能的关系。最后，结合以前c-fos即早基因表达法、束路追踪法及行为学方法等研究的结果，从神经发育学、边缘区的血供、边缘区与其它学习记忆相关脑区之间的功能和结构联系及这些联系对学习记忆功能的影响等方面对边缘区在学习记忆环路中的地位做一探讨。第一部分人脑纹状体边缘区的结构研究 大鼠尾壳核内侧、猫、猴壳核内侧都有由梭形细胞构成的纹状体边缘区，富含SP、5.I]T、DA、L.ENK、NT、SOM和TH等多种神经肤阳性纤维和胞体。我们应用神经细胞形态染色(Nissl染色)和免疫组织化学方法研究了引产胎儿和病理解剖的脑部无病变的儿童及成人脑纹状体的细胞构筑及神经肤类递质分布。Nissl染色结果显示人脑纹状体壳核内侧缘靠近苍白球外节边缘，可见有一条明显的梭形细胞带。细胞的长轴呈背腹方向，与壳核内侧边界平行。免疫组织化学结果显示在上述边缘区部位可见大量SP、L.ENK、NT、SOM和TH免疫组织化学阳性纤维、终末和少量L.ENK及NT阳性胞体。以上结果首次证明人脑纹状体和大鼠、猫、猴脑纹状体相似，也存在纹状体边缘区，其位置、细胞形态、神经肤类递质分布情况与大鼠、猫、猴脑类似，边缘区在人脑最发达，明显厚于猴脑。因此，可以认为纹状体边缘区是哺乳动物共有的一个结构特殊的脑区。根据动物越高级，边缘区越发达这个现象，说明边缘区在种族进化中是一个发展中的结构，因此，我们推测边缘区在人脑中有重要功能。为此，我们选择了无创的D渡Rl技术对正常人体边缘【K的功能进行了研究。 第二部分人脑纹状体边缘区的功能研究 在动物实验中，通过损毁行为学试验、电生理方法和即早基因表达法等证实纹状体边缘区参与了动物的学习记忆过程。我们为检测人脑纹状体边缘区是否也参与了学习记忆过程，选取健康志愿者分别了进行听觉数字工作记忆和听觉非记忆任务作业，同时进行O涯Rl检查，检测脑区在不同任务下的激活情况。伍皿I结果显示受试者在进行听觉数字工作记忆时具有左侧优势的双侧前额叶皮层和左侧纹状体边缘区均有激活，出现高信号区，其它脑区激活不明显。而在进行听觉非记忆任务作业11寸，受试者的前额叶和边缘区均无明显激活。此结果表明左侧纹状体边缘区与前额叶一起参与了人脑的听觉数字工作记忆过程，说明人脑边缘区也具有学习记忆功能。为了确证边缘区和人脑学习记忆功能的关系，我们对临床有边缘区病变的病人的M[R1图像和认知状况进行分析，观察边缘区的损伤是否能造成临床上的智能障碍。 一4-第三部分人脑纹状体边缘区认知功能的临床观察 我们利用口涯Rl技术己证实人脑边缘区参与了听觉数字工作记忆过程，为从临床角度探讨脑边缘区损伤与认知功能下降的关系，我们对在我院住院病人的M[R1图像进行分析，发现其中有20例仅有包括边缘区的纹状体或仅有边缘区损伤的病例，全部病例均行常规M[R1检查，对梅一病例进行认知功能测定，并与M卫1表现对比分析。结果显示:(1)20例患者的M五左SE评分介于13一25分之间，平均19.7分，以记忆力及计算力下降为主;(2)单纯边缘区损伤组的认知障碍程度与边缘区合并一f纹状体其它部位损伤组无明显差异。此结果提示:人脑纹状体边缘区的病变可能是造成病人认知功更多还原

【Abstract】 Learning and memory function are one of the most important, and fundamental mental processes of the brain. The engram is the representation of a memory in the brain. The localization of the engram in the brain is intensively studied in the fields of neuroscience, psychology and psychiatry. After Scoville and Milner reported a persistent impairment of recent memory caused by bilateral medial temporal lobe resection in man in 1957, the hippocampus and other brain areas, e.g. the medial temporal lobe memory system, prefrontal cortex (PFC), amygdala, and basal nucleus of Meynert (NBM), were successively thought to be involved in learning and memory. The marginal division of the striatum (MrD) is a newly identified structure at the caudal most edge of the neostriatum, near the rostral border of the globus pallidus, in the brain of the rat, discovered by Shu et al in 1988. The MrD is distinguished from the rest of the striatum by consisting of spindle-shaped neurons, special connections, and intensely expressed neurotransmitters in the fibers, terminals, and neuronal somata. The MrD was also identified in the brains of cat and monkey. It was proved to be involved in learning and memory function of rat brain by a double blinded Y-maze behavioral test and c-fos expression experiment. However, whether there is a MrD in human striatum is still undiscovered. And if there is a MrD in human brain, does it have the function of learning and memory? What is the role of the MrD in neuronal memory circuits?In these studies, firstly, the existence and the immunohistochemistry properties of the MrD in human brain were proved and demonstrated with Nissl stain and immunohistochemical methods. Secondly, the involvement of the human MrD in learning and memory was investigated with a functional magnetic resonance imaging (fMRI) experiment. It is proved that the MrD was involved in auditory digital working memory in human. Then clinical cases with MrD lesions were investigated, combining MRI and cognitive function analyses with Mini-Mental State Examination (MMSE), to explore in clinic whether the MrD is involved in the cognitive function of humanbrain. The learning and memory function of the MrD was then verified by clinic investigations. Finally, the role of the MrD in neuronal memory circuits was discussed according to the nervous auxology of the MrD, blood supply of the MrD, the functional and structural connections between the MrD and other memory-related structures, and the influence of these connections on learning and memory function.Part I Study on the structure of human MrDThe MrD in the rat, cat and monkey brains consist of fusiform neurons and is densely packed by SP, L-ENK, NT, SOM and TH positive somata and fibers. To demonstrate the existence of the MrD in the human striatum, the cytoarchitecture and distribution of neurotransmitter in the human striatum were studied using Nissl stain and immunohistochemistry. In the Nissl stained section, there is a distinct fusiform cell zone between the putamen and globus pallidus of the human striatum. The long axes of these neurons were running dorsoventrally, parallelly to the medial border of the putamen. Numerous SP, L-ENK, NT, SOM and TH positive fibers and terminals and some L-ENK, NT positive cells were found in this area. The results proved the existence of the MrD in the striatum of human brain, as well as in the rat, cat and monkey brains. The shape of the neurons and the distribution of the neuropeptides in human MrD are also similar to the rat, cat and monkey MrD. It is indicated that the MrD is a common structure in mammalian brains. The MrD is much thicker in higher mammalians, which suggested that the MrD is a developing structure in the evolution. We inferred that the MrD might have important function in human brain. Then the function of human MrD was investigated in healthy volunteers using fMRI technique.Part II Study on the function of human MrDThe MrD was identified to be involved to learning and memory function of the rat brain by behavio更多还原