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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 李立仁 | |
dc.contributor.author | Liang-Wen Juan | en |
dc.contributor.author | 阮亮文 | zh_TW |
dc.date.accessioned | 2021-06-16T23:33:00Z | - |
dc.date.available | 2013-09-18 | |
dc.date.copyright | 2012-09-18 | |
dc.date.issued | 2012 | |
dc.date.submitted | 2012-07-27 | |
dc.identifier.citation | Abazyan B, Nomura J, Kannan G, Ishizuka K, Tamashiro KL, Nucifora F, Pogorelov V, Ladenheim B, Yang C, Krasnova IN, Cadet JL, Pardo C, Mori S, Kamiya A, Vogel MW, Sawa A, Ross CA, Pletnikov MV (2010) Prenatal interaction of mutant DISC1 and immune activation produces adult psychopathology. Biological psychiatry 68:1172-1181.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/65255 | - |
dc.description.abstract | 精神分裂症(schizophrenia)是一種多致病因子的精神疾病。從一世紀前被命名至今,許多的研究已經確定了基因的因素與其相關病徵的關連性。Disrupted-in-Schizophrenia 1 (DISC1) 就是其中一種重要的易感性基因。DISC1基因的變異最先是在一個蘇格蘭家族被發現,此家族之許多成員都患有嚴重的精神疾病,然而DISC1變異與其致病的機轉至今仍不清楚。本實驗中,我們使用年齡8至12週之野生型 (wild type,WT),Disc1基因異型合子 (heterozygote,Het),同型合子(homozygote,Homo) 基因剔除(knockout)雄性小鼠,企圖了解基因缺損在大腦結構與行為上的影響。工作記憶(working memory)在人類是由背外側前額葉皮質(dorsolateral prefrontal cortex,DLPFC)所執行,並且此功能在精神分裂症患者有不良的情況。在小鼠的腦部中執行工作記憶的腦區則被認為是內側前額葉皮質(medial prefrontal cortex,mPFC)。故此,我們分析了三種基因型小鼠的大腦結構與mPFC的第二、三層錐狀神經元之樹突結構。我們發現,Disc1基因變異小鼠的側腦室有增大的情形。利用高基氏染色(Golgi-Cox impregnation),神經樹突結構得以被重構。相較於WT及Het knockout小鼠,Homo knockout小鼠mPFC神經元的樹突分支和複雜程度顯著地減少。並且,在Het knockout以及Homo knockout小鼠,樹突突起(dendritic spine)密度及樹突直徑也都有下降。這些結構上的改變暗示了在mPFC的錐狀神經元接受興奮性傳入的能力可能下降。另外,在mPFC中表現calretinin的細胞數量在Het knockout小鼠也有減少。我們接著利用了許多行為實驗,來觀察這些基因變異小鼠是否出現了類似精神分裂症的行為性狀。Het knockout小鼠的自發活動有稍微下降的情形。除此之外,這些變異小鼠的憂鬱和焦慮程度都沒有發生改變,空間學習以及短期記憶的功能也完整。這些Disc1基因變異小鼠最為顯著的變化是工作記憶的能力。在delayed non-match to place task中,與WT小鼠相比,Disc1基因變異小鼠,需要更久的實驗訓練過程以達到設定的標準。在實驗中,我們則觀察到隨著delayed time延長,Disc1基因變異小鼠之工作記憶能力也會有不良的情況。綜合以上,我們的數據顯示了Disc1基因變異小鼠的mPFC神經元結構以及由mPFC所主導的工作記憶功能都發生改變。這些結構的變化可能會造成大腦皮質神經傳導運作過程的不正常,而導致與精神分裂症相關的症狀出現。 | zh_TW |
dc.description.abstract | Schizophrenia is a multifactorial psychiatric disorder. One century after been so named, researches have confirmed the relation between genetic issues and schizophrenia-related mental illnesses. One of the leading candidate genes is Disrupted-in-Schizophrenia 1 (DISC1). Mutation of DISC1 gene was found in a Scottish family with major mental disorders, however, the mechanisms of DISC1 in pathogenesis of schizophrenia is still unclear. In the present study, in order to investigate the effects of Disc1 deficient on brain structural and function, 8-12 weeks old male wild type (WT), Disc1 heterozygote (Het) and homozygote (Homo) knockout mice were used. In human, working memory function is executed by dorsolateral prefrontal cortex (DLPFC) and is impaired in schizophrenia patients. Its functional equivalent area in mice is the medial prefrontal cortex (mPFC). So we examined the brain structure and dendritic structures of layer II/III pyramidal neurons in mPFC among these three genotypes of mice. The size of lateral ventricle was enlarged in Disc1 mutants. Using Golgi-Cox impregnation, the dendritic structures were therefore reconstructed. Compared to WT and Het knockout mice, the dendritic arborization and complexity of mPFC neurons were significantly reduced in Disc1 Homo knockout mice. The dendritic diameter and density of dendritic spine were also decreased in both Het and Homo group. These structural alterations indicated that the capability of receiving excitatory inputs might decrease in mPFC pyramidal neurons. Besides, calretinin expressing neurons in mPFC of Het knockout mice was also reduced. We then conducted several behavioral tests to investigate if there is schizophrenia like phenotypes in these mutant mice. Slightly reduced locomotor activity was found in Het mice. Besides the unchanged depression and anxiety level, mutant mice also showed intact spatial learning and short term memory. The dramatically altered phenotype in these Disc1 mutant mice was found to be working memory. In delayed non-match to place task, compared with WT littermates, it took longer training process for the mutant mice to master this task, and we also found there was a trend that the mutant mice showed impaired working memory when delayed time was expended. Our data revealed the altered neuronal structure in the mPFC and the impaired mPFC-mediated working memory function in Disc1 mutant mice. These structural changes might lead to impaired cortical transmission processes and schizophrenia-related behavioral deficits. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T23:33:00Z (GMT). No. of bitstreams: 1 ntu-101-R99446001-1.pdf: 4329393 bytes, checksum: 17ff10b7cca50273362f1f5cbabe395d (MD5) Previous issue date: 2012 | en |
dc.description.tableofcontents | CONTENTS
中文摘要....................................................i Abstract.................................................iii Contents...................................................v List of Figures.........................................viii List of Tables..........................................viii Abbreviations.............................................ix Introduction...............................................1 I. Schizophrenia and DISC1.................................1 II. Function of DISC1......................................2 III. Cognitive dysfunction.................................4 IV. Animal model: Disc1 mutated mice.......................5 V. Experimental design.....................................9 Materials and Methods.....................................10 I. Animals................................................10 II. Histology.............................................11 II-1. Perfusion.........................................11 II-2. Overall brain structure...........................11 II-3. Golgi-Cox impregnation............................12 II-4. Immunohistochemistry (IHC)........................14 III. Behavioral tests.....................................16 III-1. Open field.......................................16 III-2. Elevated plus maze (EPM).........................16 III-3. Forced swim test (FST)...........................17 III-4. Y-maze...........................................17 III-5. Novel object recognition test (NORT).............18 III-6. Morris water maze (MWM)..........................18 III-7. Delayed non-match to place task (DNMPT, T-maze)..19 IV. Statistical analysis..................................20 Results...................................................21 I. Morphological analysis.................................21 I-1. Enlarged in the volume of lateral ventricle in Disc1 mutant mice........................................21 I-2. Altered dendritic complexity in layer II/III pyramidal neurons in the medial prefrontal cortex of Disc1 Homo knockout mice...........................21 I-3. Spine density and dendritic diameter are both change in Disc1 Het and Homo knockout group...............21 I-4. Expression of calcium-binding proteins in the mPFC.22 II. Behavioral tests......................................22 II-1. Constant locomotor activity and emotional status in Disc1 mutant mice.................................22 II-2. Behavioral tests related to memory................23 II-3. Impaired working memory in Disc1 mutant mice......24 Discussion................................................26 Reference.................................................56 | |
dc.language.iso | zh-TW | |
dc.title | Disc1基因缺損小鼠之性狀特徵研究 | zh_TW |
dc.title | Phenotypic Characterization of Disc1 Deficient Mice | en |
dc.type | Thesis | |
dc.date.schoolyear | 100-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 胡海國,尹相姝,賴文崧 | |
dc.subject.keyword | Disrupted-in-Schizophrenia 1 (DISC1),精神分裂症,內側前額葉皮質,第二、三層錐狀神經元,樹突型態,工作記憶, | zh_TW |
dc.subject.keyword | Disrupted-in-Schizophrenia 1 (DISC1),schizophrenia,medial prefrontal cortex (mPFC),layer II/III pyramidal neurons,dendritic morphology,working memory, | en |
dc.relation.page | 62 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2012-07-27 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 解剖學暨生物細胞學研究所 | zh_TW |
顯示於系所單位: | 解剖學暨細胞生物學科所 |
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