应激导致大鼠习得性抑郁的海马突触可塑性机制研究
文献类型：学位论文
| 作者 | 井亮 |
| 学位类别 | 博士 |
| 答辩日期 | 2013-11 |
| 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 | 海马 突触可塑性 学习记忆 习得性抑郁 抑郁症 抗抑郁药 |
| 其他题名 | Hippocampal Synaptic Mechanisms in Stress Induced Learned Depression in Rat |
| 学位专业 | 细胞生物学 |
| 中文摘要 | 学习记忆是有机体从外界环境接受信息，对这些信息进行编码，加工，储存，并最终产生经验依赖的行为模式的变化的过程，是神经系统的核心功能之一。一方面学习记忆可以表现为知识的获取，技能的习得等正常功能；另一方面也可以表现为神经系统对异常外界环境病理性的适应，并导致精神疾病，例如抑郁症。抑郁症是与环境因素与基因因素均密切相关的精神疾病，不可控应激事件是其重要诱因之一。从学习记忆的角度来看，抑郁症可被视为机体在处理应激相关信息时产生的病理性适应行为。因此，神经系统的信息处理系统，尤其是学习记忆系统，可能是参与抑郁症病因病理的重要一环。海马是学习记忆产生的关键脑区，海马的神经可塑性，包括突触可塑性(长时程增强(LTP)和长时程抑制(LTD))，结构可塑性和神经元新生等，是学习记忆形成的细胞机制。同时，海马神经可塑性对应激事件极为敏感，动物研究表明应激可以损伤LTP的诱导，易化LTD的诱导，改变神经元的形态和抑制神经元新生。在抑郁症患者和抑郁症动物模型中，海马是结构和功能受损最严重的脑区之一。动物研究也表明海马的神经可塑性，特别是突触可塑性，参与了抗抑郁药物治疗机理。但到目前为止，海马突触可塑性在抑郁症中的具体作用尚不清楚。在本研究中，我们从海马突触可塑性的角度研究了抑郁症的病理病因。我们采用了常用的抑郁症动物模型—大鼠强迫游泳—来研究海马如何参与习得性抑郁样行为(习得性抑郁)的形成。我们发现，大鼠的习得性抑郁是一种不可逃避应激相关的学习记忆，通过降低或增加应激水平，其习得性抑郁相应的降低或增加，这种习得性抑郁依赖于应激激素皮质酮和糖皮质激素受体的激活。通过药物干扰海马学习记忆功能可以阻断习得性抑郁，阻断NMDA受体的功能也可以阻断习得性抑郁。与此同时，我们也发现了强迫游泳可以短暂的增强突触蛋白AMPA受体的磷酸化水平，说明强迫游泳可以增强AMPA受体功能，并易化突触长时程增强(LTP)的诱导。然后，我们用光基因的手段，发现海马的神经元活动可以调控习得性抑郁的表达。更直接的，我们用清醒动物电生理记录的方法发现强迫游泳可以直接在海马诱导出LTP。因此，大鼠的习得性抑郁是应激相关的习得性行为，并依赖于海马介导的学习记忆和NMDA受体介导的突触可塑性。最后，我们在对抗抑郁新药CXZ-123进行药理学研究时发现，CXZ-123可以调控突触功能，阻断应激带来的突触功能损伤。所以海马突触可塑性也是抗抑郁药物的潜在作用靶点。综上，本研究主要发现了：不可逃避应激导致的习得性抑郁依赖于海马的学习记忆功能，习得性抑郁的形成伴随着海马突触功能的改变；同时恢复应激带来的海马突触可塑性损伤是抗抑郁新药CXZ-123作用靶点之一。这些结果提示，海马的记忆系统介导的应激相关记忆可能是抑郁症的重要病因，重复不可控应激带来的海马突触功能的改变可能是抑郁症的病理之一，而恢复海马突触可塑性的正常功能是抗抑郁药物研发的重要靶点。 |
| 英文摘要 | Learning and memory is one of the most fundamental processes of nervous system, in which organics receive, encode and store information from environment, and finally make changes to their behavioral pattern. This process is normally functioned in the acquisition of skill or knowledge etc.. However, it can also be maladaptive to environment and lead to mental illness. Depressive disorder is one of the psychiatric disorders that involves both genetic and environmental factors. Uncontrollable stressful events are one of the major risk factors in its etiology. In the expect of learned behavior, depressive disorder can be considered as maladaptive to stressful events, thus the malfunctioned learning and memory process may be crucially involved in the etiology and pathology in depressive disorder.Hippocampus is the essential brain region in memory formation. Hippocampal neural plasticity, including synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD), structure plasticity, neurogenesis etc., is the cellular mechanism of learning and memory. It is also sensitive to stress events. Stress impaires induction of LTP, facilitate induction of LTD, induces hippocampal neural thrinkage, and impaires neurogenesis. Furthermore, hippocampus also play a role in the pathophysiology of depressive disorder, and is likely to be an important action site of many types of antidepressants. However, the role of hippocampal synptic plasticity in depressive disorder is not clear.In this research, we studied the role of hippocampal synaptic plasticity in the etiology and pathology of depressive disorder using rat forced swimming test (FST). FST, in which rat forms learned depressive-like behavior (learned-depression) after exposure to a single trial of forced swimming, is the most commonly used rodent depression model in evaluating antidepressant effect. We found that learned-depression is inescapable stress-related memory which required activation of glucocorticoid receptor by corticosterone. This learned depression can be blocked by intrahippocampal infusion of known amnesic drugs, or by intraperitoneal or intrahippocampal injection of NMDA receptor antagonists. We also found rapid phosphorylation of synaptic AMPA receptor subunit GluR1, and more directly, we detected that forced swimming process induced LTP in hippocampal CA1 area in freely moving rats. Furthermore, artificially activation of hippocampal neurons by Optogenetics tools can modulate depressive-like behavior in FST. Thus, the depressive-like behavior in FST is stress related learned behavior, which requires hippocampal memory function and NMDA receptor mediated synaptic plasticity. In addition, we found that hippocampal synaptic plasticity was an action site of newly developed antidepressant CXZ-123, which could prevent the synaptic functional damage caused by stress. Thus, the hippocampal synaptic plasticity can also be a target of antidepressant.In summary, this research found that the learned depression induced by inescapable stress is dependent on hippocampus and causes functional changes in hippocampal synapses. Restoring the hippocampal synaptic function after stressful events is one of the antidepressant target site of CXZ-123. These results suggest that: (1) the hippocampus dependent learned-depression may participate in the etiology of depression disorder; (2) hippocampal synaptic function altered by repeated stressful events may be one of the pathology of depressive disorder; (3) hippocampal synaptic plasticity is a potential target for developing new antidepressant. |
| 语种 | 中文 |
| 公开日期 | 2014-01-17 |
| 源URL | [http://159.226.149.42:8088/handle/152453/7781]  |
| 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 | 井亮. 应激导致大鼠习得性抑郁的海马突触可塑性机制研究[D]. 北京. 中国科学院研究生院. 2013. |
入库方式： OAI收割
来源：昆明动物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。