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可卡因戒断期前额叶皮质转录组谱图的动态变化
其他题名Dynamic Expression Changes of the Transcriptome in PFC after Repeated Exposure to Cocaine in Mice
徐艳华
学位类型硕士
导师赵媚
2015-05
学位授予单位中国科学院研究生院
学位授予地点北京
学位专业心理学
摘要可卡因的反复使用可以导致脑适应性的可塑性改变和机体行为的长期改变。虽然有大量的文献对可卡因等神经兴奋类药物引起的神经可塑性变化进行描述性报道,然而对其分子机制的了解并不十分清楚。已有的研究表明,可卡因重复使用影响到相关脑区的多个分子、涉及到多条信号通路和转录过程等调控机制。但这些结论主要从对伏隔核的可卡因成瘾研究中获得。虽然人和动物的研究均表明,前额叶皮质在可卡因成瘾过程中扮演了重要作用,但是对其展开的分子研究较少。我们的研究采用了转录组测序技术RNA-Seq,在可卡因慢性处理后戒断时间点2 小时、24 小时和7 天,对前额叶皮质转录组mRNA 的表达水平和剪切方式进行测序,分析和比较。通过Cufflinks 算法对测序结果分析,我们在不同戒断时间点得到了不同数目的差异表达基因:463 个(2 小时)、14 个(24 小时)、535 个(7 天)。对这些差异表达基因的动态变化进行时间序列相关性分析,进一步将他们分成了动态变化显著相关的五个簇。而通过GO 基因本体论和KEGG信号通路方法,对各个时间点和各个相关簇的差异表达基因进行高级分析,我们发现了几条显著富集的信号通路,且他们在可卡因戒断期间呈动态变化。例如:节律信号通路和MAPK 信号通路相关基因在戒断后2-24 小时,表达显著上调;到7 天时,仅有MAPK 中的ERK 信号通路维持了改变。这提示:节律信号通路和MAPK 信号通路可能均介导了可卡因的急性效应;而ERK 信号通路可能同时介导了长期的可塑性改变和成瘾行为。除此之外,我们还发现可卡因重复使用戒断后,前额叶皮质神经元内的能量代谢和蛋白代谢通路基因的表达呈逐渐降低趋势,并在7 天戒断时间点达到显著降低。这从系统分子水平首次表明了神经元的代谢通路参与了可卡因的成瘾过程。然而,我们并没有在前额叶皮质中找到戒断期间的明显替代剪切事件。这与已有的在伏隔核中的相关研究结果不同: 反复可卡因注射后24 小时,伏隔核中产生了几倍于其所引起的差异表达基因量的替代剪切事件。这提示我们,可卡因经由调控剪切方式的改变而影响相关脑区内的分子变化的方式,存在脑区的特异性。
其他摘要Repeated exposure to psychostimulants such as cocaine, leads to long term alterations to both the brain and the behavior. Although, there are plenty of researches devoted to depict such plasticity changes of the brain, molecular mechanisms underlying such structural alterations are not very clear. Studies focused on nucleus accumbens (NAc) have discovered many genes and signal pathways are involved in these plastic changes. Even though studies from both human and rodents have shown that PFC have an important role in mediating the long term effects of cocaine. There are very few molecular studies dedicated to it. In search of such molecular mechanisms, we used the sequencing method RNA-Seq, at three time points after chronic cocaine injections, to check the dynamic changes of mRNAs in PFC on the transcriptome level. Different numbers of differentially expressed genes (DGEs) were discovered at three withdrawal time points: 463 (2H), 14 (24H), 535 (7D). DEGs from all three time points were then pooled together to analyze the correlation of their dynamic expression changes along the time line, as a result of which, five time-serielly correlated clusters were obtained. Further analysis of DEGs from individual time points and clusters revealed several dynamically changed pathways. To be specific, both the circadian and MAPK signaling pathways were up-regulated from 2H-24H, with ERK pathway from MAPK still altered at time point 7D, implying a role in mediating the acute effects of cocaine by both circadian and MAPK signaling pathways and ERK pathway’s involvement in the long term brain and behavior changes. Other than that, we also found a decline tendency in the metabolism (both energy and protein) pathways, which reached a significant low level at withdrawal time day 7, supporting a role of metabolism pathways in the long term cocaine effects. This is also the first report of such a role at the systematic molecular level. At last, to our surprise, no alternative splicing event were discovered in any of the three time points, in contrast to the previous study reporting chronic cocaine exposure has led to many alternative splicing events in the nucleus accumbens, suggesting the regional specificity of splicing regulation by cocaine.
学科领域行为遗传学
语种中文
文献类型学位论文
条目标识符http://ir.psych.ac.cn/handle/311026/19736
专题健康与遗传心理学研究室
作者单位中国科学院心理研究所
推荐引用方式
GB/T 7714
徐艳华. 可卡因戒断期前额叶皮质转录组谱图的动态变化[D]. 北京. 中国科学院研究生院,2015.
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