应激下恐惧记忆障碍的神经环路

Fear memories are usually enduring and can even last across the life span, as the saying goes: “A burnt child dreads the fire.” Exposure to stress is thought of like adding fuel to the fire on the adverse impact of stress on fear processing in the brain. This can be highly detrimental to the fear processing in the brain, can lead to fear overgeneralization in some circumstances, as exemplified by cardinal symptoms of specific phobias and post-traumatic stress disorder (PTSD). Animal models have posited that fear memory overgeneralization is resulted from aberrations in the amygdala and its functional circuits which is so-called “fear center” of the brain. Very little, however, is known about how stress impacts on fear memory and consolidation in humans, and even less is known about the impact of stress on fear overgeneralization. Using a multi-disciplinary approach, including state-of-the-art functional magnetic resonance imaging (fMRI) in conjunction with stress induction, novel experimental paradigms, and cutting-edge multivariate analytic methods of brain representations and connectivity, our proposed studies aim to systematically investigate the cognitive and neural mechanisms underlying aberrant fear memory formation, consolidation and retrieval under stress, with a particular focus on fear overgeneralization occurring in perceptual, conceptual and contextual circumstances. Outcomes from the proposed studies will significantly advance our understanding of how stress leads to the overgeneralization of fear memories into different situations in terms of their perceptual, conceptual and contextual properties related to the actual fear stimuli. This will provide critical information for guide the development of more effective intervention and remediation programs by targeting on perceptual, conceptual and contextual components of fear overgeneralization in individuals with stress-related mental disorders.

恐惧记忆一旦形成，对人的心理行为产生长久影响，正如“一朝被蛇咬，十年怕井绳”。当面临突发强烈性应激事件的刺激时，恐惧记忆倾向于被过度泛化（overgeneralization）并引发消极情绪体验，严重者甚至导致难于逆转的精神障碍如恐惧症和创伤后应激障碍等，这种噩梦般的记忆让人痛不欲生。动物模型认为，恐惧记忆障碍跟杏仁核及相关神经环路的功能异常有关。然而，我们对人脑应激下如何导致恐惧记忆障碍知之甚少。为此，本研究旨在融合最新脑功能成像、应激诱发、生理生化检测、认知行为实验等多学科交叉技术，深入揭示应激下恐惧记忆形成、巩固和提取的认知神经机制，阐明应激下恐惧记忆在知觉、语义和情境层面上“过度泛化”的生理与心理行为特征及其神经环路基础。研究成果将有助于我们更加全面、深刻的了解大脑在应激条件下恐惧记忆障碍的认知神经机制，为有效干预和治疗相关精神障碍提供科学依据，具有重大的科学价值和临床意义。

本项目围绕“应激下恐惧记忆障碍的认知神经机制”这一核心科学问题来展开，研究团队通过四年努力和积累，采用最新无创脑功能成像包括fMRI和ERP、认知行为实验、心理应激与生理心理检测等多交叉技术和方法，开展了一系列基础性研究工作，顺利实施并成功完成了250例健康成年人多维度应激相关生理心理、情绪、认知行为和脑功能等关键数据，其中包括150例脑影像数据和应激生理心理检测（原计划80例）。从感知觉、语义和情景三个层面，解析了应激对恐惧记忆影响的认知神经机制，发展了基于脑的心理应激评估与情绪神经信息解码算法。..结合最新机器学习算法如K-均值、支持向量机和递归神经网络等，通过深入细致数据分析和挖掘，产出一系列具有影响力的高质量研究成果，包括Nature Commutations（1篇）、NeuroImage(3篇)、Psychoneuroendocrinology(1篇)等共10余项科研成果。具体来讲，研究团队首先研制了适合中国人心理应激诱发和恐惧记忆范式，以及能够功能性磁共振兼容的生理心理测评手段。接着，在国际上率先揭示了应激相关恐惧记忆信息在经睡眠固化后，更加难于被有效抑制或“驾驭”，不仅需要付诸更多前额叶执行功能资源的参与，而且还要通过不同的前额叶-海马和额顶叶两条通路来完成；这可能跟恐惧记忆表征信息经睡眠巩固后，更倾向于从海马转移到更广泛且分散的大脑皮层网络。然后，揭示了长期应激条件下人脑额顶执行控制系统和默认网络系统在功能激活和动态协同交互加工表现出异常模式，可能主要跟应激相关激素分泌并作用于前额叶神经网络有关。最后，采用K-均值和隐马尔科夫算法，揭示了恐惧情绪相关杏仁核不同亚区跟大脑皮层功能连接的整合和分离动态变化模式，以此预测个体日常心理应激与焦虑相关指标。 ..这些研究成果不仅对理解急性与慢性应激对人脑情绪与认知功能的影响及其深层神经生物机制具有重要科学价值，而且对研发应激所致情绪与认知障碍早期识别和早干预方案提供新的启示，为促进国民心理健康教育与咨询具有重要现实意义。