五羟色胺、辣椒素受体在海马相关脑疾病中的分子机制研究
文献类型：学位论文
| 作者 | 贾云芳 |
| 学位类别 | 博士 |
| 答辩日期 | 2014-09 |
| 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 | 五羟色胺 辣椒素受体 海马 脑疾病 |
| 其他题名 | The molecular mechanisms of serotonin and TRPV1 in hippocampus related brain diseases |
| 中文摘要 | 单胺类神经递质五羟色胺（5-HT）被广泛认为参与情绪、学习记忆以及调控海马相关的脑疾病。中枢5-HT缺失小鼠的条件性恐惧记忆存在消退缺陷，说明5-HT调控牢固的有害记忆，如创伤后应激障碍和成瘾记忆。但仍不清楚5-HT如何调控牢固的成瘾记忆。另外，大脑内5-HT的水平下降被认为是焦虑和抑郁症发生的主要因素。而目前对于升高5-HT的水平缓解焦虑/抑郁症症状的作用机理还不清楚。为了回答这些问题，我们做了一系列工作： 本论文中，我们发现缺失中枢5-HT的小鼠对吗啡条件位置偏爱（MCPP）记忆异常保持，而这种异常保持可能是由于海马突触可塑性的长时程增强（LTP）的增强和长时程抑制（LTD）的损伤所导致。同时，中枢5-HT缺失小鼠的吗啡运动敏感化行为增强，而增强5-HT的功能可以抑制大鼠的海洛因自给药行为，这些也可能是吗啡记忆异常保持的一个可能性因素。这些结果表明5-HT可能通过调控海马突触可塑性参与成瘾，为将来研究成瘾的神经机制提供了一个新的靶点。 其次，我们继续使用这两种小鼠检测焦虑和抑郁样行为，发现焦虑水平降低，未有抑郁水平改变。而在缺失中枢5-HT同时患有糖尿病的小鼠模型中，焦虑水平升高，抑郁样行为降低，海马新生神经元增多。说明5-HT缺失不一定会导致焦虑和抑郁样行为的发生，糖尿病是焦虑的一个易感因子，而海马新生神经元增多可能是抑郁样水平降低的原因。 辣椒素受体（TRPV1）的激活易化海马LTP抑制LTD，增加锥体神经元兴奋性。而海马突触可塑性在成瘾记忆各阶段的表现均不同，暗示TRPV1可能调控成瘾记忆。另外，癫痫是由中枢神经系统的兴奋性和抑制性失衡导致的，TRPV1可以调控海马的兴奋性和抑制性系统，故TRPV1可能也参与癫痫发生。带着这些问题，我们进行了以下相关研究： 本论文中，我们利用药理学手段和转基因小鼠方法干扰TRPV1功能，发现系统给予TRPV1拮抗剂Capsazepine（CPZ）抑制MCPP的表达和点燃，抑制吗啡运动敏感化行为的形成。而TRPV1敲除小鼠不能提取MCPP消退记忆，且吗啡运动敏感化行为增强。这些结果表明TRPV1参与调节吗啡成瘾记忆的相关行为，这一发现为将来研究成瘾的神经生物学机制提供另一新靶点。 其次，我们继续使用相同的药理学手段和转基因小鼠的方式干扰TRPV1功能从而研究TRPV1的改变对戊四氮所诱导的癫痫发作的影响。我们发现系统给予TRPV1激动剂辣椒素（CAP）增加癫痫发作的严重性。但系统给予TRPV1拮抗剂CPZ或敲除TRPV1均降低癫痫发作的严重性。另外，海马注射CAP和CPZ或者在海马过表达TRPV1也降低了癫痫发作的严重性。这些结果表明系统给予TRPV1拮抗剂可能是一个新型的治疗癫痫病的潜在性药物靶点，而且我们首次证明了海马TRPV1在癫痫发作中的重要性。 本论文分别研究了5-HT对成瘾和焦虑/抑郁症的贡献，TRPV1对成瘾和癫痫的贡献，这些发现帮助我们进一步理解和深入探讨成瘾记忆的细胞生物学和分子生物学机制，也帮助理解焦虑/抑郁症的细胞作用机理，还为治疗癫痫病提供药物筛选的新靶点。 |
| 英文摘要 | The central serotonin (5-HT) system is known to be involved in emotion, learning and memory, as well as regulates hippocampus related brain diseases. Lack of central 5-HT shows extinction deficiency in contextual fear memory, indicating that 5-HT regulates stable harmful memory including posttraumatic stress disorder and addiction memory. However, it is still unclear how 5-HT regulates stable addiction memory. On the other hand, 5-HT deficiency in the brain is believed to be a major causative factor in anxiety and depression. The exact molecular mechanisms behind the antidepressant effects are not fully understood. In order to answer the questions, we performed a series of studies: In this investigation, we found that the central 5-HT-deficient mice could retrieval the morphine conditioned place preference (MCPP) memory, and the addicted central 5-HT-deficient mice displayed enhanced long-term potentiation (LTP) and impaired long-term depression (LTD) in the hippocampus. Besides, the central 5-HT-deficient mice showed enhanced behavioral sensitization induced by morphine, and enhance in 5-HT function inhibited self-administration behaviors induced by heroin, both of which may be the causative factors. Our findings demonstrate that 5-HT may play a critical role in drug addiction memory via hippocampal synaptic plasticity, which may provide a new target and view to investigate drug addiction related behaviors. Next, we found that the reduced anxiety level but no alteration in depression-like behaviors in these central 5-HT-deficient mice, while increased anxiety-like but lowered depression-like behaviors in mice with both central 5-HT deficiency and diabetes, to which the enhanced hippocampal neurogenesis may contribute. These results suggest that central 5-HT deficiency may not be sufficient to induce depression-like behaviors, and the diabetes is a risk factor in developing anxiety. It was reported that activation of transient receptor potential vanilloid 1 (TRPV1) facilitated long-term potentiation (LTP) and inhibited long-term depression (LTD) in hippocampus, and also enhanced the excitability of pyramidal neurons. The altered hippocampal synaptic plasticity during addiction process implied that TRPV1 may play an important role in addiction. Epilepsy is characterized by the imbalance between excitation and inhibition of central nervous system (CNS), and TRPV1 regulates the balance of excitation and inhibition in CNS such as hippocampus, which implies its important role in epilepsy. We performed a series of researches to answer these questions as follows: In this investigation, we used both pharmacological manipulations and transgenic mice to disturb the function of TRPV1 and found that systemic administration of TRPV1 antagonist capsazepine (CPZ) suppressed the expression and challenge of MCPP, and also inhibited morphine induced behavioral sensitization. Furthermore, TRPV1 knock out mice could not retrieval MCPP extinction memory, and showed enhanced behavioral sensitization induced by morphine. These results suggest that interference of TRPV1 alters addiction related behaviors; TRPV1 may be involved in regulating addiction. Our findings provide a novel molecular target to study the neural mechanisms of addiction. Next, we used the same manners to disturb the function of TRPV1 and then studied the effects of these alterations on the susceptibility of pentylenetetrazol (PTZ)-induced seizures. Our results showed that systemic administration of TRPV1 agonist capsaicin (CAP) increased the severity of seizure. In contrast, systemic administration of TRPV1 antagonist CPZ and TRPV1 knockout mice exhibited reduced seizure severity. Furthermore, hippocampal administration of CAP or CPZ and hippocampal TRPV1 overexpression mice showed decreased susceptibility of PTZ-induced seizures. Our findings suggest that the systemic administration of TRPV1 antagonist may be a novel therapeutic target for epilepsy, and alteration of hippocampal |
| 语种 | 中文 |
| 源URL | [http://159.226.149.26:8080/handle/152453/10142]  |
| 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 | 贾云芳. 五羟色胺、辣椒素受体在海马相关脑疾病中的分子机制研究[D]. 北京. 中国科学院研究生院. 2014. |
入库方式： OAI收割
来源：昆明动物研究所
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