請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/25906完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 符文美 | |
| dc.contributor.author | Ya-Hsuan Chiang | en |
| dc.contributor.author | 江雅暄 | zh_TW |
| dc.date.accessioned | 2021-06-08T06:56:53Z | - |
| dc.date.copyright | 2009-09-15 | |
| dc.date.issued | 2009 | |
| dc.date.submitted | 2009-07-21 | |
| dc.identifier.citation | References
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/25906 | - |
| dc.description.abstract | 精神分裂症是一種慢性衰退的精神異常疾病，並且許多報導指出此為遺傳性之異常心智混亂。根據2002年，由Stefansson等人對於冰島地區的精神分裂症家族所進行的大規模基因篩檢，Neuregulin 1(NRG1)首度被發現是精神分裂症致病基因之一。然而，NRG1參與在精神分裂症中的詳細機制仍不清楚。因此，在本論文中，我們使用NRG1異型合子基因突變小鼠 (NRG1 +/-) 以及其野生型對照組小鼠來探討神經生物層面之差異。本研究分為兩個部分：第一部分之研究目的在於評估NRG1對恐懼記憶之影響。第二部分則是根據過去所建立的假說-精神分裂症患者的神經突觸間血清素作用異常-在此探討血清素與NRG1之間的調控關係。
在實驗結果中我們使用被動型逃避學習作業與情境-條件恐懼制約作業兩種行為模式，研究發現NRG1 +/-小鼠的恐懼記憶表現較野生型小鼠差。另外，在免疫組織染色中觀察到NRG1 +/-小鼠腦部的杏仁核中核細胞帶有非常多的磷酸化ERK表現量。另外，我們的合作者在杏仁核中核的電生理實驗顯示，由PKC活化劑phorbol-12,13-diacetate (PDA)誘導長期增益現象(LTP)的效果在NRG1+/-小鼠是受到抑制的。在此，我們假設神經傳導物質之受體的不足或許是導致NRG1+/-小鼠的杏仁核相關恐懼記憶表現受損之因素。然而，透過西方點墨法之分析，我們發現NMDA受體與其磷酸化態受體以及AMPA受體的表現量在NRG1 +/-小鼠的杏仁核皆是較野生型小鼠來得高，反而是受體的下游傳遞物質PKCβΙ與PKCβⅡ表現量遠低於野生型小鼠，而PKCα則不受影響。曾有報告指出PKCβ與恐懼記憶有關，因此我們認為PKCβ的減少與NRG1 +/-小鼠的恐懼記憶缺失應該有所關聯。 在第二部分的實驗中，我們使用兩種常用的動物憂鬱行為模式：強迫性游泳測試以及吊尾測試來評估此兩群小鼠對於抗憂鬱症藥物desipramine之反應。結果發現NRG1 +/-小鼠對於藥物的反應相較於野生型小鼠來得敏感。並且藉由西方點墨法分析發現，在NRG1 +/-小鼠的多個腦部核區都出現血清素轉運蛋白的表現量增加的現象，表示其腦部的血清素再回收的速率較高，而導致血清素基礎活性受到抑制。另一方面，在體外探討血清素與NRG1之調控關係的實驗中，我們使用了人類星狀細胞瘤之細胞株A172與人類神經細胞瘤之細胞株SH-SY5Y，發現外給NRG1會抑制其血清素轉運蛋白的表現量，同樣結果也在大鼠皮質初代星狀細胞與神經細胞中被證實。而正腎上腺素轉運蛋白的表現量也同樣會受到外加的NRG1而抑制。相反地，若是在人類星狀細胞瘤之細胞株A172中外加血清素，則可以增加NRG1的受體ErbB4表現量增加，並且此結果是經由血清素受體1A亞型所調控。最後，為了模擬人體長期服用抗憂鬱藥物之療法，我們對此兩群小鼠多次注射desipramine之後，將小鼠犧牲以觀察腦部受體之變化。結果發現NRG1+/-小鼠在杏仁核以及額狀皮質的ErbB4表現量增加。我們的實驗顯示在NRG1和血清素之間存在著正向回饋的調控關係，表示血清素的功能不足可能牽涉於NRG1基因異常所誘發的精神分裂症狀之中。 綜合以上，藉由動物行為實驗與神經生物層面之分析，本論文探究了NRG1 +/-小鼠的表現型，包含恐懼記憶缺失以及抗憂鬱症藥物之敏感性增加，而與情緒認知關係密切的杏仁核似乎是一個相當關鍵的重要核區。同時，血清素、NRG1與ErbB4的失衡也可能是造成此心智異常的致病機制。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2021-06-08T06:56:53Z (GMT). No. of bitstreams: 1 ntu-98-R96443004-1.pdf: 2510057 bytes, checksum: a6bbb70d74a36b8cb3fdfded7da25c67 (MD5) Previous issue date: 2009 | en |
| dc.description.tableofcontents | 目錄
誌謝 I 摘要 II Abstract V Abbreviations 1 Chapter 1 Introduction 3 1-1 Schizophrenia 3 1-2 Neuregulin 1 (NRG1) 4 1-3 Association between NRG1 and schizophrenia 6 1-4 Emotion 9 1-4-1 Amygdala 10 1-4-2 Amygdala and fear memory 11 1-4-3 Associated proteins in learning and memory 13 1-5 Hypothesis of NMDA receptor dysfunction in schizophrenia 14 1-6 Hypothesis of serotonergic dysfunction in schizophrenia 16 1-7 Aim 20 Chapter 2 Materials and Methods 26 2-1 Reagents 26 2-2 Animals 27 2-3 Cell cultures 28 2-4 Western blotting 28 2-5 Primary Cortical neuronal cultures 29 2-6 Primary astrocyte cultures 29 2-7 Immunohistochemistry 30 2-8 Drug treatment 31 2-9 Behavioral studies 31 2-9-1 Passive avoidance 31 2-9-2 Freezing tests 32 2-9-3 Locomotor activity 33 2-9-4 Shock sensitivity 33 2-9-5 Forced swimming test 34 2-9-6 Tail suspension test 34 2-10 Data analysis 34 Chapter 3 Results 37 Part I: Inhibition of fear memory in NRG1 +/- mice 37 3-1. Inhibition of passive avoidance performance in NRG1 +/- mice. 37 3-2. Inhibition of freezing behavior following contextual- and cued-fear conditioning in NRG1 +/- mice. 37 3-3. Increase of ERK phosphorylation within the central nucleus of amygdala in NRG1 +/- mice. 39 3-4. Increase of NR2B, phospho-Y1472 NR2B and GluR1 in central amygdala in NRG1 +/- mice. 40 3-5. Comparison of the expression of NR2B, p-NR2B and GluR1 in various brain regions between WT and NRG1 +/- mice. 40 3-6. Expression of PKC isoforms in amygdala in WT and NRG1 +/- mice. 42 Part II : Hypersensitive to desipramine in NRG1 +/- mice 43 3-7. Increase of the sensitivity to desipramine in NRG1 +/- mice by using forced swimming test. 44 3-8. Increase of the sensitivity to desipramine in NRG1 +/- mice by using tail suspension test. 44 3-9. Increase of serotonin transporter (SERT) in various brain regions in NRG1 +/- mice. 45 3-10. Increase of norepinephrine transporter (NET) in amygdala in NRG1 +/- mice. 46 3-11. Decrease of serotonin transporter and norepinephrine transporter expression by NRG1β treatment in both astrocytes and neurons. 46 3-12. Increase of ErbB4 and NRG1 protein expression by serotonin in A172 cells. 47 3-13. Increase of ErbB4 expression by chronic desipramine treatment in NRG1 +/- mice. 49 Chapter 4 Discussion 51 Part I: Inhibition of fear memory in NRG1 +/- mice 52 Part II : Hypersensitive to desipramine in NRG1 +/- mice 56 Figures…………………...……………………………………………………………63 References 84 | |
| dc.language.iso | zh-TW | |
| dc.title | 致精神分裂症基因Neuregulin1功能之探討 | zh_TW |
| dc.title | Functional study of schizophrenia-related gene of Neuregulin 1 | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 97-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 尹相姝,楊春茂,嚴震東,簡伯武 | |
| dc.subject.keyword | 精神分裂症,NRG1,恐懼記憶,杏仁核,血清素, | zh_TW |
| dc.subject.keyword | schizophrenia,neuregulin-1,fear memory,amygdala,serotonin., | en |
| dc.relation.page | 98 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2009-07-21 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥理學研究所 | zh_TW |
| 顯示於系所單位： | 藥理學科所 | |
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