恐惧记忆泛化的海马环路和突触可塑性机理及PTSD易感性的研究
文献类型：学位论文
| 作者 | 熊贵静 |
| 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 | 恐惧记忆泛化 海马 突触可塑性 母婴隔离 恐惧消退 |
| 其他题名 | Hippocampal circuit and synaptic plasticity mechanisms underlie fear generalization and the etiology |
| 中文摘要 | 恐惧记忆是生物体遭受伤害性刺激时产生的一种强烈的负性情绪记忆。与伤害性刺激联合匹配后，特定中性刺激能够唤醒个体的恐惧反应，这一过程即为条件恐惧学习（Pavlovian fear conditioning）。环境中相似谱系的中性刺激也能引发恐惧反应，表现出恐惧泛化。过度的恐惧泛化将导致焦虑相关的精神疾病，如创伤后应激障碍综合症（Post-traumatic stress disorders; PTSD）。PTSD是与环境因素和基因因素密切相关的精神疾病，应激是其发病的重要诱因之一。大脑边缘系统的脑区包括海马、杏仁核和前额叶等是参与恐惧记忆的重要脑区。这些脑区的功能活动异常可能是介导恐惧泛化的重要机理及PTSD发病的重要病理。 海马参与背景条件化恐惧记忆的形成和表达。我们发现，动物对无关背景的恐惧反应随着原始恐惧记忆的巩固而逐渐增强，泛化的恐惧记忆很容易消退。通过药理手段在训练前、训练后或提取前损毁或抑制双侧海马将显著阻断原始恐惧记忆的表达，记忆泛化也随之减弱；然而损毁或抑制单侧海马仅仅显著抑制泛化记忆的表达。通过光遗传技术仅在记忆提取时精准抑制单侧海马同样仅仅显著阻断泛化记忆的提取。我们计划采用能够特异阻断一级神经连接的突触传递的病毒体系进一步阐明海马环路在泛化中的重要作用。行为干预如新颖环境暴露或应激通过影响海马的活动分别降低或增强恐惧记忆的泛化。 突触可塑性，长时程增强（Long-term potentiation, LTP）和长时程抑制（Long-term depression, LTD）被认为是学习与记忆的细胞机制。我们开发的短肽--Tat-A2能够特异阻断海马LTP的表达，系统注射Tat-A2靶向阻断LTP将阻断48小时点背景恐惧记忆的提取。工具药Tat-3Y已知能特异性阻断LTD的表达，系统或海马内注射Tat-3Y显著抑制恐惧记忆的泛化。 应激能够损伤海马和前额叶的结构和功能。大鼠（F1代）出生后经历2-14天每天3小时的母婴隔离应激（Maternal separation, MS）。成年F1代MS雌雄大鼠的运动能力、焦虑水平、水迷宫空间学习和记忆能力以及背景恐惧学习记忆能力正常；但表现出不同程度的背景恐惧记忆消退的损伤，其前额叶layer 2/3-layer 5和海马SC-CA1通路的LTP显著受损。慢性氟西汀处理能够消除F1代MS雄性大鼠恐惧记忆消退的损伤。F1代MS雄性大鼠繁育的雌雄子代（F2代），虽然在水迷宫空间学习记忆能力，背景条件化恐惧学习记忆和恐惧消退方面均表现正常；但表现出明显的低焦虑样行为。F1代氟西汀治疗逆转了F1代MS雄性大鼠前额叶和海马DNA甲基化结合蛋白MeCP2的表达变化，可能阻止了潜在的遗传效力，同样挽救了F2子代的行为改变。这些结果提示早期生活应激导致了恐惧记忆消退的损伤，是PTSD的重要风险因子；氟西汀治疗能够逆转早期生活应激造成的损伤及其潜在的遗传效力。 综上，我们首次报道了背景恐惧记忆的泛化过程依赖双侧海马的共同参与，阻断一侧海马的活动能够降低恐惧泛化；海马突触可塑性在背景恐惧记忆的精确提取过程中有重要作用。这些结果提示，恐惧记忆的泛化是原始恐惧记忆加工过程的产物，包含了复杂的脑活动变化过程。其次，我们发现氟西汀通过逆转前额叶和海马脑区的功能损伤消除了早期生活应激导致的亲本和子代的恐惧和焦虑行为的改变，这为治疗应激相关的精神疾病如PTSD提供了理论指导。 |
| 英文摘要 | Learned of fear can be elicited by neutral environmental stimuli that have been associated with aversive events, a process termed as Pavlovian fear conditioning. However, fear can also be retrieved in face to similar neutral stimuli leading to fear generalization, which may contribute to the etiology of anxiety disorders，including post-traumatic stress disorders (PTSD). PTSD is one of the psychiatric disorders that involve both genetic and environmental factors. Stress is one of the major risk factors in its etiology. The specific neural circuits within the limbic-cortical system, including hippocampus, amygdala and prefrontal cortex, mediate fear learning and memory. Dysregulation of these brain regions involved in the circuits may underlie the neural mechanisms of fear generalization and the etiology of PTSD. Hippocampus is critical for the encoding and retrieval of contextual fear memory. We found that fear response of animals to a different context became more and more strong with the passage of time after training, and the generalized fear is liable to extinction. Lesion or inhibition bilateral hippocampus before or after training can dramatically block the expression of contextual fear memory, and the same as the generalized fear memory. However, lesion or inhibition unilateral hippocampus merely impaired the expression of generalized fear memory. Utilizing optogenetics tools to precisely inhibit the activities of hippocampus during retrieval period, we also found that unilateral hippocampus inhibition merely blocked fear generalization. We attempt to establish a viral system, which can directly block the presynaptic neurotransmitter release, to further dissect the function of hippocampal circuit in fear generalization. In addition, novelty exploration and stress intervention can decrease or enhance the extent of fear generalization respectively. Synaptic plasticity including long-term potentiation (LTP) and long-term depression (LTD) is the cellular mechanism of learning and memory. We constructed a new peptide termed as Tat-A2. The result showed that Tat-A2 can specifically block the expression of hippocampal LTP and the retrieval of contextual fear memory 48 hours after training. Tat-3Y is known to specifically block the expression of LTD. We found that systematic or intra-hippocampus administration of Tat-3Y can dramatically inhibit the expression of generalized fear memory. The hippocampus and prefrontal cortex appear vulnerable to stress. Adult male and female rats (F1 generation) subjected to maternal separation (MS, 3 hours daily, postnatal day 2 to 14) exhibited significant impairment of contextual fear extinction and significant LTP inhibition within both infralimbic prefrontal cortex layer 2/3-layer 5 and hippocampal SC-CA1 pathways; despite they exhibited normal locomotion, innate anxiety, spatial acquisition and retention, fear acquisition and recall. Fluoxetine treatment can reverse the impairment of fear extinction caused by MS in F1 animals. The F2 generation generated from the F1 MS adult male rats displayed normal spatial acquisition and retention, fear acquisition and retention, and fear extinction, however, all of them exhibited a phenotype of low anxiety-like behaviors. Fluoxetine treatment in F1 male rats can reverse the dysfunction of MeCP2 protein in the prefrontal cortex and hippocampus, which may block the trans-generational effects of MS and also reverse the low anxiety-like behaviors in their F2 offspring. These results suggest that early life stress led to impaired fear extinction associated with PTSD, and fluoxetine may serve as a potential therapy for stress-related disorders across generations. In conclusion, our research firstly reports that the process of fear generalization dependents on the intact activities of bilateral hippocampus, and unilateral hippocampal inactivation would inhibit the phenomenon of fear generalization. Hippocampal synaptic plasticity plays an important role |
| 语种 | 中文 |
| 源URL | [http://159.226.149.26:8080/handle/152453/10184]  |
| 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 | 熊贵静. 恐惧记忆泛化的海马环路和突触可塑性机理及PTSD易感性的研究[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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