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题名	社会竞争失败病因学的树鼩抑郁症模型创建及其机制研究
作者	王静
学位类别	博士
答辩日期	2015-07
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 社会竞争 树鼩 学习记忆 突触可塑性
其他题名	Mechanisms of social defeat depression model in tree shrews
中文摘要	抑郁症是一种情绪、思维、学习记忆等脑高级功能紊乱的精神疾病。应激事件是抑郁症发病的重要危险因素之一。日趋激烈的社会竞争使抑郁症的发病率急剧上升。目前，抑郁症面临以下三个难题，包括抑郁症的发病机理尚不完全清楚，现有单胺类抗抑郁药物起效慢和缺乏快速起效的抗抑郁药物。针对抑郁症的三大难题，长期以来应用最广泛的啮齿类抑郁症动物模型并未取得突破性进展，部分原因归咎于啮齿类与人类巨大的种属差异。树鼩是灵长类的近亲，具有较高级的大脑功能，并且对应激十分敏感。虽已有对树鼩抑郁症模型的研究，但尚缺乏与人类抑郁症核心症状的对比以及抑郁症对树鼩突触可塑性的影响研究。同时，树鼩作为模式动物，已有的生理学指标并不完善，特别是与应激相关的指标。另外，对树鼩认知能力评价的动物模型较少，因而限制了对树鼩抑郁症发病机理与学习记忆关系的研究。上述种种问题都限制了树鼩作为新型模式动物应用于抑郁症发病机制的研究和快速起效抗抑郁药物的新药研发。 本研究通过创建社会竞争失败病因学的树鼩抑郁症模型、强迫游泳模型以及一次性被捕获条件反射的学习记忆模型和触摸屏成对选择认知模型，运用行为学、药理学和电生理手段研究树鼩抑郁症的发病机理和应激对学习记忆的影响，并探索树鼩在新药研究领域中的应用。在对社会竞争失败后树鼩的体重、快感缺失、活动性、自梳理行为、皮质醇水平和海马突触可塑性的研究中，发现树鼩具有与人类相似的抑郁症核心症状，社会竞争失败损伤海马突触可塑性。与一次性被捕获条件反射的学习记忆模型相结合，发现经典抗抑郁药物可以对抗一次性被捕获负性记忆，NMDA受体拮抗剂MK-801具有抗抑郁效果。上述结果说明社会竞争失败病因学的树鼩抑郁症模型具有很好的“三效验证”，进一步阐明了由应激诱导的抑郁症发病机理最终可以归结为突触可塑性的改变，并且谷氨酸系统分子通路可能是潜在的快速起效抗抑郁药物的作用靶点。通过创建树鼩触摸屏成对选择认知模型，发现与啮齿类相比树鼩具有较好的学习记忆能力。对树鼩给予持续光照慢性弱应激可损伤树鼩的学习能力，说明该模型可用于树鼩抑郁症与学习记忆共同分子通路的研究。运用经典的抗抑郁药效评价手段强迫游泳探索树鼩对新药研发的应用，发现树鼩对CXZ-123的药效反应与预期一致，即表现出快速抗抑郁效果。 综上所述，本研究完善了树鼩的基础生理指标，并运用社会竞争失败病因学的树鼩抑郁症模型对抑郁症发病机理进行了补充，同时创建了一次性被捕获条件反射的学习记忆模型和触摸屏成对选择认知模型，研究应激对树鼩学习记忆能力的影响。最后应用树鼩对快速抗抑郁新药进行药效评价。上述研究发现大脑谷氨酸系统和海马突触可塑性是新型抗抑郁药物研发的重要靶点。
英文摘要	Depression is a neuropsychiatric disorder associated with dysfunction of mood, thinking, learning and memory. Stress is one of the most important risk factors for the pathogenesis of depression. The increasingly prevalence rates of depression result from stronger social competition. At present, there are three problems of depression, including that the mechanism of depression is still unclear, the effect of monoamine-based antidepressants on depression has a long delay, and we are lack of rapid-onset of antidepressant drugs. However, rodent depression animal models do not successfully resolve the above problems. One possible reason is that there is a huge differences in species between rodents and humans. Tree shrews are the closest sister to primates, with higher brain functions, and very sensitive to stress. According to the researches of tree shrew depression model, there is a lack of study on the core symptoms of depression and mechanism of synaptic plasticity. At the same time, as an animal model, the existing physiological indexes of tree shrews are unsatisfactory, especially stress related indexes. In addition, little cognitive animal model of tree shrew limits the understanding of relationship between depression and learning and memory. These problems have restricted tree shrew as a new animal model in the study of pathogenesis of depression and development of rapid-onset antidepressants. In this research, we established social defeat depression model and force swimming model, as well as, a one-trial captive conditioning of learning and memory model and pairwise discrimination touchscreen cognitive model in tree shrews. By using behavior, pharmacology and electrophysiology methods, we investigated the etiology of depression, the effects of stress on learning and memory, and the application of tree shrew in the development of new antidepressants. In the study of social defeat depression model, we tested body weight, anhedonia, locomotion, self-grooming behavior, level of cortisol and hippocampal synaptic plasticity of subordinate tree shrew. The results showed that core symptoms of subordinate tree shrews are similar to depressed patients, and social defeat injured hippocampal synaptic plasticity. Monoamine-based antidepressants and NMDA antagonist MK-801 confronted one-trial captive conditioning of memory. These results clarified that social defeat depression tree shrew model had good validities and changes of synaptic plasticity were the final pathogenesis of depression. It suggested that glutamatergic system might be the potential target for rapid-onset of antidepressant drugs. Pairwise discrimination touchscreen cognitive test showed that tree shrew was much more clever than rodent. Chronic stress of continuous light on impaired learning ability of tree shrews, suggesting that pairwise discrimination touchscreen was a good model to investigate the common molecular pathways of depression and learning and memory. Finally, in the force swimming test, CXZ-123 showed fast antidepressant effects on tree shrew. In summary, this study improved the physiological indexes of tree shrew, and complemented the pathogenesis of depression. A one-trial captive conditioning of learning and memory model and pairwise discrimination touchscreen cognitive model in tree shrews were created to study the effect of stress on learning and memory. Tree shrew was also used to evaluate the efficacy of rapid-onset antidepressants. We conclude that glutamatergic system and hippocampus synaptic plasticity are the important targets of new antidepressants.
语种	中文
内容类型	学位论文
源URL	[http://159.226.149.26:8080/handle/152453/10144]
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	王静. 社会竞争失败病因学的树鼩抑郁症模型创建及其机制研究[D]. 北京. 中国科学院研究生院. 2015.

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