海马-前额叶通路对条件性恐惧记忆特异性与泛化的调控机制研究

Post-traumatic stress disorder (PTSD), one of the most common disorders after trauma, has been characterized essentially as a disturbance of the traumatic memory specificity and subsequent overgeneralization, impairing the capacity of the subject to identify the correct predictors of the threat and re-experiencing the fear response to irrelevant cues. Our previous studies have reported that the hippocampus is crucial for fear memory, chronic stress could induces hippocampal cell death by apoptosis, and decreased hippocampal volume and increased serum cortisol levels were found in PTSD patients. Since there are rich nerve fiber projections between hippocampal CA1 area and prefrontal PL and IL area, recently study has primarily confirmed that the prefrontal-nucleus reuniens-hippocampus circuit involved in the regulation of memory specificity and generalization, and infusion of glucocorticoids in the hippocampus after fear conditioning induces fear generalization, but the mechanism remains unclear. This project will focus on the “fear overgeneralization”, the essential character of PTSD, propose a new hypothesis that the HC-PFC pathway regulates the neuronal encoding of “specificity” and “generalization” neurons, and then induce the transition from cue-specific to generalized fear. Hoping to get solid evidence of hippocampal GCs’ key role, clarify mechanisms of HC-PFC pathway in regulating fear memory specificity and generalization.

创伤后应激障碍（PTSD）的本质特征是创伤性记忆的特异性受损并出现过度泛化，导致患者正确识别危险预测因素的能力降低，对无关线索出现恐惧反应。我们前期研究发现海马是恐 惧记忆形成的关键脑区，慢性应激可以导致海马细胞凋亡，PTSD患者存在海马体积缩小与血清皮质醇水平增高。海马CA1区与前额叶PL、IL区存在大量的神经突触联系，已有研究认为前额叶皮质-连结核-海马环路参与记忆特异性与泛化的调控，应激后海马高糖皮质激素（GCs）水平可以诱导恐惧记忆泛化的出现，但机制未明。本项目将紧紧围绕“恐惧记忆过度泛化”这一PTSD的本质特征，提出HC-PFC通路通过调控“特异性”与“泛化”相关神经元的信息编码，影响恐惧记忆从特异性向泛化转化的假设，分析海马对这一转化的启动作用。希望通过本项目获得海马高GCs发挥关键作用的明确证据，阐明HC-PFC通路对恐惧记忆特异性与泛化的调控机制。

创伤后应激障碍（PTSD）的本质特征是创伤性记忆的特异性受损并出现过度泛化，导致患者正确识别危险预测因素的能力降低，对无关线索出现恐惧反应。我们前期研究发现海马是恐惧记忆形成的关键脑区，慢性应激可以导致海马细胞凋亡，PTSD患者存在海马体积缩小与血清皮质醇水平增高。海马CA1区与前额叶PL、IL区存在大量的神经突触联系，已有研究认为前额叶皮质-连结核-海马环路参与记忆特异性与泛化的调控，应激后海马高糖皮质激素（GCs）水平可以诱导恐惧记忆泛化的出现，但机制未明。本项目紧紧围绕“恐惧记忆过度泛化”这一PTSD的本质特征，通过神经示踪、行为药理学、化学遗传学、光遗传学等技术，描绘HC-PFC通路，提出HC-PFC通路通过调控恐惧记忆的提取过程，影响恐惧记忆从特异性向泛化转化的假设。研究发现激活CA1-PL通路抑制恐惧记忆泛化，激活CA1-IL通路则增强恐惧记忆泛化。本研究着眼于恐惧记忆的关键特征：特异性向泛化的转变，并对机制进行初步探讨，促进了对PTSD 发生机制的了解，为PTSD 精神损伤和伤病关系等的客观评定提供科学依据。