| 题名 | 吗啡暴露对海马MeCP2基因表达的影响 |
| 作者 | 许新丽 |
| 学位类别 | 硕士 |
| 答辩日期 | 2013-05 |
| 授予单位 | 中国科学院研究生院 |
| 授予地点 | 北京 |
| 导师 | 徐林,曹军 |
| 关键词 | 海马MeCP2基因表达 急性和慢性吗啡 吗啡戒断 |
| 其他题名 | Morphine treatments affect the expression of MeCP2 gene in the mouse hippocampus |
| 学位专业 | 神经生物学 |
| 中文摘要 | 毒品成瘾是一种慢性的、具有强迫性症状的脑疾病。其核心症状表现为不可控制地毒品寻求和复吸。最近的证据表明，海马在环境线索导致的毒品寻求和复吸中起着至关重要的作用。表观遗传机制在记忆、应激记忆和毒品成瘾中都发挥重要作用。其中，甲基化CpG结合蛋白2（Methyl-CpG-binding protein 2,MeCP2）在大脑内高表达，尤其是海马。MeCP2能特异地识别甲基化的DNA，主要的功能是通过与甲基化的DNA相互作用调控基因转录。MeCP2既可以调节活动依赖的基因表达，也可以调节突触结构和功能以及学习和记忆。目前，急、慢性吗啡暴露如何影响MeCP2基因表达不清楚。我们在急性吗啡暴露后、慢性吗啡暴露过程中以及吗啡戒断时，利用荧光定量PCR技术检测MeCP2基因表达水平。我们发现，急性吗啡暴露1小时后，海马MeCP2基因表达显著上调，这种表达的上调依赖于μ型阿片受体，阻断μ型阿片受体的作用，可以阻断急性吗啡诱导的海马MeCP2基因表达上调。在12天的慢性吗啡暴露过程中，随着吗啡注射天数的增加，海马MeCP2基因表达逐渐增加，到第2天达到最大值，之后表达水平又逐渐下调，总体表达趋势呈倒“V”型，提示海马MeCP2可能参与吗啡成瘾过程。在吗啡成瘾之后戒断1小时，海马MeCP2基因表达显著下调，随着戒断时程的延长，表达又逐渐上调，最终达到与急性吗啡处理之后1小时相当的水平。其次，应激参与了急性吗啡对海马MeCP2基因表达的调控，糖皮质激素受体的拮抗剂RU38486能阻断急性吗啡诱导的MeCP2、受体蛋白亚基NR2A、NR2B、GluR1、GluR2以及可塑性相关分子KCC2、NSF、FosB基因表达的上调。再次，伴随着吗啡耐受的建立，海马MeCP2基因表达呈现显著的动态变化，提示可能参与吗啡耐受的调节。上述初步结果为将来研究MeCP2对成瘾形成、应激或环境线索触发的毒品寻求行为的干预效应及其海马突触可塑性机制研究打下基础，可为临床干预提供新思路。 |
| 英文摘要 | Drug addiction is characterized by persistent and compulsive drug craving and re-lapses. Recent evidence indicates that the hippocampus plays crucial roles in the processes of drug craving and relapses triggered by drug-associated cues or stress. Epigenetic mechanisms play important roles in memory, stress and drug addiction. Methyl-CpG binding protein 2 (MeCP2) is highly expressed in the brain, especially the hippocampus. MeCP2 specifically recognize methylated DNA and the main function is to regulate gene transcription via the interaction with methylated DNA. MeCP2 can regulate activity-dependent gene expression. It also modulates synaptic structure and function, as well as learning and memory. So far, how Acute and chronic morphine treatments affect MeCP2 gene expression is not clear. In this study, we use qPCR (real-time quantitative PCR) technology to detect hippo-campal MeCP2 gene expression levels in different addictive stages. Firstly, this re-search focuses on hippocampal MeCP2 gene expression following acute morphine treatment, during the process of chronic morphine treatments and morphine with-drawal. We find that 1 hour after the acute morphine administration, MeCP2 gene expression in the mouse hippocampus is significantly up-regulated. However, MeCP2 mRNA levels are down-regulated by μ-opioid receptor agonist, naloxone. Accompanied by chronic morphine exposure, MeCP2 mRNA level shows an inverted "V" shape, suggesting that hippocampal MeCP2 is involved in morphine addcition. More importantly, withdrawal for 1 hour after chronic morphine treatment, the expression of MeCP2 gene in hippocampus is reduced sharply, which is just contrast to acute morphine group at the that time. Whereas, MeCP2 mRNA level is characterized by a persistent enhancement during morphine withdrawal. Secondly, stress is involved in regulating the expression of hippocampal MeCP2 gene after the administration of acute morphine, since RU38486, glucocorticoid receptor antagonist, can block the acute morphine-inducing the up-regulation of MeCP2, NR2A, NR2B, GluR1, GluR2 ,KCC2 and NSF. Finally, along with the establishment of morphine tolerance, hippocampal MeCP2 expression shows significant dynamic changes, which indicates that hippocampal MeCP2 may be involved in regulating morphine tolerance. These preliminary results lay the foundation for future research on intervention effect of MeCP2 on addiction, stress or environmental cues trigger drug seeking behavior and its mechanism of hippocampal synaptic plasticity. |
| 语种 | 中文 |
| 公开日期 | 2013-06-21 |
| 内容类型 | 学位论文 |
| 源URL | [http://159.226.149.42:8088/handle/152453/7509]  |
| 专题 | 昆明动物研究所_学习记忆的分子神经机制 |
| 推荐引用方式 GB/T 7714 | 许新丽. 吗啡暴露对海马MeCP2基因表达的影响[D]. 北京. 中国科学院研究生院. 2013. |
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