用电生理和FDG-PET成像技术研究背景恐惧记忆的神经环路
文献类型：学位论文
| 作者 | 谭继伟 |
| 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 | FDG-PET 海马 突触可塑性 背景恐惧记忆 强迫游泳 抗抑郁药 |
| 其他题名 | Identification of synaptic plasticity and neural circuit mechanisms of contextual fear memory by electrophysiological and FDG-PET imaging techniques |
| 学位专业 | 神经生物学 |
| 中文摘要 | 学习记忆是人类生存和发展的基础，它赋予人类更好地适应和改造环境的能力。正常的学习记忆是一种稳态过程，一旦稳态被打破，则可能造成适应不良，导致一系列精神疾病，如强烈而持久的负性记忆会导致创伤后应激障碍和抑郁症。创伤后应激障碍和抑郁症发病率高，后果严重，但治疗措施有限，因此揭示负性记忆的突触可塑性和神经环路机制有重要意义，有助于我们理解相关精神疾病的发病机制和新药研发。 背景恐惧记忆关联了环境线索和创伤事件，易被环境线索触发提取，并且具有清晰的形成，巩固，提取，消退等过程，因此常被用做创伤后应激障碍的动物模型。海马突触可塑性，特别是LTP被认为是背景恐惧记忆形成的细胞基础，但消退的海马突触可塑性机制和背景恐惧记忆各阶段脑动态活动还不清楚。强迫游泳是常用的习得性绝望抑郁症动物模型，其具有操作简单，药物预见性好等特点。但是强迫游泳的神经环路活动和抗抑郁药物的脑区作用机制仍不清楚。 小动物[18F]2-Fluoro-2-deoxy-D-glucose-PET (FDG-PET)成像是一种新型的功能成像技术，FDG作为葡萄糖类似物可以被神经元摄取并堆积在细胞。FDG摄取和PET扫描在时间上是分离的，我们可以在FDG摄取时进行行为或药理学操作， PET成像出的FDG分布就代表由行为或药物诱导的全脑神经活动。因此利用小动物FDG-PET成像技术可以揭示背景恐惧记忆的神经环路的动态变化，抑郁样行为的脑活动和抗抑郁药物作用机制。 我们利用电生理和行为学技术研究了胚胎期吗啡暴露对成年后背景恐惧记忆和突触可塑性的影响。胚胎期吗啡暴露的成年大鼠天然焦虑水平下降，而背景恐惧记忆虽有轻微降低但持久难以消退，同时海马突触可塑性对应激的反应消失，即应激既不能阻断LTP也不能易化LTD。海马LTD缺失可能是背景恐惧记忆不能消退的细胞机制。 我们利用小动物FDG-PET对大鼠背景恐惧记忆过程进行了动态脑活动观察，我们发现海马和纹状体全程参与背景恐惧记忆的形成，巩固，近期提取和远期提取；而杏仁核只参与了巩固和近期记忆提取。并且在提取阶段海马和杏仁核的活动方向相反。结合行为药理学的结果，在恐惧记忆的提取过程中，海马/压后皮质和杏仁核/纹状体等脑区可能交互抑制，以提取记忆并组织行为，使动物表现出恐惧行为（僵直）。 我们利用小动物FDG-PET结合强迫游泳大鼠抑郁症模型，发现强迫游泳可以抑制海马活动，而增强梨状皮层和岛叶皮层的活动。抗抑郁新药CXZ-123及阳性对照丙咪嗪和氯胺酮可以逆转强迫游泳的效应，激活海马，抑制梨状皮层和岛叶皮层。这表明海马可能是抑郁症发病的主要脑区和抗抑郁的最终靶点。 综上所述，我们利用小动物FDG-PET成像，行为药理学和电生理技术，初步发现了背景恐惧记忆消退的突触可塑性机制，背景恐惧记忆动态脑活动以及抑郁样行为和抗抑郁新药引起的脑活动变化。联合小动物FDG-PET成像技术，传统的行为药理学和电生理学等技术，可以快速推进情绪性精神疾病和相关新药研发的进展。 |
| 英文摘要 | Learning and memory is the basis for human survival and development, it endows people the abilities to adapt and remould the external environments. Learning and memory is a homeostasis process, and dysregulations and breaks with homeostasis may lead to mental illness. For example, excessive and long-lasting aversive memory causes posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). PTSD and MDD are characterized by high morbidity, serious consequences and poor treatments, thus revealing the synaptic plasticity and neural circuits underlying aversive memory will help us to understand the pathogenesis and develop new drugs for PTSD and MDD. Contextual fear memory associates the environmental cues and traumatic events, which is characterized by being easily retrieved by contextual cues and clear phases such as formation, consolidation, retrieval and extinction. Therefore, it usually serves as the animal model for PTSD. Hippocampal synaptic plasticity, especially LTP is believed to be the cellular substrate underlying contextual fear memory acquisition. However, the synaptic mechanism underlying contextual extinction and the dynamic neural circuit activity across contextual fear memory phases remain unclear. Forced swimming test (FST) is the learned despair model for MDD, with the features of easy to operate and high predictability for antidepressants. But the neural circuit activity underlying FST and the efficacy of antidepressants remain unclear. [18F]2-Fluoro-2-deoxy-D-glucose-PET (FDG-PET) is a imaging technique with FDG as the tracer for glucose. Once FDG is uptaken, it can’t be released and will be accumulated in neurons. Because of temporal dissociation between FDG uptake and PET scanning, we can subject the animals to behavioral tasks or drugs, thus the distribution of FDG represents the neural circuit activity induced by behaviors or drugs. In the present study, we revealed the dynamic neural circuit activity underlying contextual fear memory, as well as the neural activity underlying FST and antidepressants. First, we tested the alterations of behavioral and synaptic plasticity induced by prenatal morphine exposure. We found that the prenatally morphine exposed rats showed reduced innate anxiety but impaired contextual fear extinction, meanwhile lacked the responses to acute stress of hippocampal synaptic plasticity, i.e. stress either did not block LTP or enable LTD. It is suggested that lack of LTD is the cellular substrate of impaired fear extinction in prenatally morphine exposed adult rats. We imaged the dynamic brain activity during contextual fear memory process by FDG-PET. We found that hippocampus and striatum were involved in contextual fear memory formation, consolidation, recent retrieval and remote retrieval, while the amygdala only involved in consolidation and recent retrieval. In addition, the activity direction was opposite between the hippocampus and amygdala during recent memory retrieval. Combining with behavioral pharmacological results, we speculate that the hippocampus/retrosplenial cortex and amygdala/striatum exhibit reciprocal inhibition to organize fear memory expression (freezing) during retrieval. To investigate the mechanism underlying MDD, we mapped the brain activity 24 hours after FST by FDG-PET. We found that FST decreased activity in the hippocampus, while increased activity in the piriform cortex and insular cortex. New antidepressant CXZ-123 and its positive controls including imipramine and ketamine reversed the effects of FST on brain activity, they activated the hippocampus and deactivated the piriform cortex and insular cortex. These results indicate that the hippocampus may be the main brain region involved in the pathogenesis of MDD, as well as the common target for antidepressants. In summary, in the present study, we found the synaptic plasticity mechanism of contextual fear extinction, dynamic brain activity during contextual fear memory process and brain activity for depressive-like behavior and efficacy of antidepressants. Thus FDG-microPET imaging combing with traditional pharmacological and electrophysiological techniques will advance the study progress for neuropsychiatric disorders and new drug development. |
| 语种 | 中文 |
| 源URL | [http://159.226.149.26:8080/handle/152453/10193]  |
| 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 | 谭继伟. 用电生理和FDG-PET成像技术研究背景恐惧记忆的神经环路[D]. 北京. 中国科学院研究生院. 2015. |
入库方式： OAI收割
来源：昆明动物研究所
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