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题名	抑郁症与海马可塑性
作者	田孟
学位类别	博士
答辩日期	2009-06
授予单位	中国科学院研究生院
授予地点	北京
导师	徐林
关键词	抑郁症 海马 突触可塑性 长时程增强 长时程抑制
学位专业	动物学
中文摘要	本文主要做了2个方面的研究，第一部分主要是新型抗抑郁症药物的临床前研究，第二部分是抑郁症的海马突触可塑性机理的研究。 抑郁症是常见精神疾病，影响到全球20％的人口，是致残率、致死率最严重的十大疾病之一。临床抗抑郁症药物几乎都是增强中枢单胺类功能。但是，针对单胺类的药物只对50％左右的抑郁症患者有效，且具有2－4周的疗效延迟、毒副作用较大。越来越多的实验证据治疗抑郁症的靶点指向非单胺类神经系统。研发非单胺类抗抑郁症药物已成为必然的发展趋势。我们从传统中药中分离出小分子单体化合物CXZ-123(CXZ-1中的C、X、Z分别代表“陈（Chen）纪军”、“徐（Xu）林”和”周（Zhou）俊”名字的首字母缩写；1代表送来的第一种植物（名称暂时保密）)。并利用4种抑郁症动物模型，模拟3种不同发病因素，既行为绝望（强迫游泳和悬尾）、慢性不可预知温和应激和利血平耗竭单胺类，并以临床上常用的抗抑郁药氟西汀、丙咪嗪和文拉法辛作为阳性对照，对CXZ-123的抗抑郁症药效进行了系统的研究。另外，还利用高架十字迷宫和足部电击诱导的僵立行为对CXZ-123的抗焦虑效应进行了研究。发现，CXZ-123在以上多种抑郁症动物模型中具有显著的抗抑郁症效果，表现出显著的剂量－效应关系，且达到相同的疗效与氟西汀相比需要更低的剂量；明显的时间－效应关系，且起效时间比更短，单次给药后0.5小时起效，疗效达到24h以上；并且对老年大鼠CMS抑郁症模型具有显著的疗效；明显的改善大鼠的焦虑样行为。我们还发现，海马、前额叶和杏仁核等脑区参与介导了CXZ-123的抗抑郁效应。由于CXZ-123是纯植物提取物，毒性更小。由于CXZ-123对抗利血平耗竭单胺类没有明显剂量效应关系，推测，CXZ-123不是直接作用于单胺类系统。因此，CXZ-123可能成为一种非单胺类的新型抗抑郁症药物，具有潜在的临床药效特点，例如起效快、疗效好、对抗焦虑、毒副作用小等。 在第二部分，我们主要研究了海马长时程抑制对抑郁样行为的调控。利用强迫游泳模型，我们发现只有强迫游泳15min的大鼠才会表现出抑郁样行为，与此平行的是，低频刺激也只能在强迫游泳15min的大鼠海马诱导出LTD。临床抗抑郁症药物氟西汀可以阻断该抑郁样行为，同时阻断了强迫游泳易化的海马LTD现象。接着我们又利用NMDA受体拮抗剂AP5或含有NR2B亚单位的NMDA受体拮抗剂Ro25－6981选择性地阻断海马LTD的诱导，大鼠的抑郁样行为也同时被阻断，两者都具有明显的剂量效应关系。我们又利用突触后AMPA受体内吞的特异性抑制剂Tat－GluR23Y多肽，该多肽能选择性阻断海马LTD的表达而不影响LTD的上游信号通路。我们发现，Tat－GluR23Y多肽可以阻断剂量依赖性地阻断海马LTD，同时也阻断了大鼠的抑郁样行为，且具有明显的剂量效应关系。我们利用NMDA受体的激动剂和mGluR受体的激动剂DHPG在海马诱导出内源性LTD，发现，内源性海马LTD可以易化抑郁样行为的产生。同时，内源性海马LTD损伤了空间记忆的提取。以上结果表明，海马LTD是抑郁样行为的充分必要条件。同时，海马LTD又可以损伤空间学习记忆。提示我们，海马LTD的存在可能更易于提取绝望等负性记忆，而损伤正常空间的提取。相反，阻断海马LTD，绝望记忆的提取受阻，而正常的空间记忆又被提取出来。说明海马LTD对于不同记忆源之间提取的竞争起重要作用。
英文摘要	In this thesis, we conducted two parts of experiments. Part 1 is the preclinical research and development of new antidepressants. Part 2 we focus on the role of hippocampal long term depression (LTD) in organizing depression-like behavior in forced swim test models. Part 1：Depression is a common mental disorder, affecting 20% global population. The mortality ratios for depression and the cost of treating depression are high. The clinical antidepressants are mainly target the monoamine system. But, the ongoing antidepressants are effective in treating only 50% of depression patients, with a 2-4 weeks delay and side effects. More and more envidence suggests a depression mechanism independent on monoamine system. It is time to research and develop new antidepressants that not act at monoamine acid. We purified a component from traditional Chinese medicine and named CXZ-123. We used 4 animal models of depression which represent 3 different causing factors of depression, including behavioral despair, chronic unpredictive mild stress, reserpine induced depletion of monoamine. We also used the footshock induced freezing and elevated plusmaze to evaluate the anxiolytic effects of CXZ-123. We found that CXZ-123 produced robust antidepressant effects in different animal models of depression in a dose dependent manner. And lower doses were required to produce the same level of antidepressant effects compared with fluoxetine. CXZ-123 showed robust therapeutic effects with a short delay, as short as 30 min and a long last effect. CXZ-123 but not fluxotine is effective in treating old rat model of depression. CXZ-123 can also reduce the anxiety behavior. We also found that hippocampus, prefrontal cortex and amygdala underly the antidepressant effects of CXZ-123. CXZ-123 is a good candidate to be a new antidepressant independent of monoamine system, with fast and good therapeutic effect, anxiolytic effect and with little side effects. Part 2：We focused on the role of hippocampal long term depression in organizing depression like behavior. Retrieval of memory is the basis of a learned behavior, while this is highly sensitive to inescapable stress that impairs long-term potentiation (LTP) but facilitates long-term depression (LTD) in the hippocampus. It remains unknown whether hippocampal plasticity modulates retrieval of despair memory that may contribute to a despair-based depression-like behavior in Porsolt’s forced swim test. Here, we report that hippocampal CA1 LTD was facilitated and LTP was impaired only in rats with enhanced depression-like behavior. LTD and depression-like behavior are both decreased by the antidepressant fluoxetine or antagonists of NMDAR and NR2B-containing NMDAR or a specific inhibitor of LTD expression via AMPAR endocytosis. Remarkably, agonist of either NMDAR or mGluR I induced endogenous-like LTD in hippocampus while enhanced depression-like behavior and impaired spatial memory retrieval. Thus, hippocampal LTD alone may enhance retrieval of despair memory to confer depression-like behavior.
语种	中文
公开日期	2013-04-24
内容类型	学位论文
源URL	[http://159.226.149.42:8088/handle/152453/7404]
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	田孟. 抑郁症与海马可塑性[D]. 北京. 中国科学院研究生院. 2009.

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