背侧海马区到内侧前额叶皮层环路在增强恐惧记忆及创伤后应激障碍中的作用

Dorsal hippocampus (dHC) is critical for the consolidation of episodic memories, whereas medial prefrontal cortex (mPFC) is important for controlling emotions. Emerging evidences from electrophysiological and human brain imaging studies suggest that the communication between these two brain regions plays an important role in memory processing. However, little is known about the underlying neural circuit and molecular mechanisms. Our previous work has revealed novel functional projections from the dHC to mPFC in retrieval-mediated memory modulation. On the basis of our previous work，the proposed project is aiming at understanding the mechanisms of how dHC to mPFC direct projections regulate fear memory strengthening, combining multi-level analyses including neural circuit manipulation, molecular techniques and behavioral studies. Furthermore, we will explore the regulation and function of this circuit in a form of non-adaptive fear memory strengthening, post-traumatic stress disorder (PTSD). Collectively, this project will significantly advance the understanding of dHC-mPFC circuit, and of the regulatory mechanisms of emotional memories. From a clinical perspective, findings from the proposed studies will provide novel targets for effective and selective regulation of emotional memories, as well as novel strategies for treating PTSD.

背侧海马区（dHC）掌管情景记忆的巩固，内侧前额叶皮层（mPFC）掌管情绪调控。基于电生理以及人类脑成像的研究成果，学界认为这两个脑区的相互通讯在记忆调控中发挥重要作用，但目前对相关的神经环路及分子机制知之甚少。我们前期的研究发现，少数dHC神经元可以直接投射到mPFC，此环路的激活在记忆提取的过程中可调控恐惧型情景记忆的强度。在这些工作的基础上，本项目将综合应用神经环路调控、分子生物学和行为学等不同层面的研究手段，探索dHC到mPFC环路在恐惧记忆增强中的作用机制，并进一步研究此环路在非可适应性的恐惧记忆增强，如创伤后应激障碍（PTSD）中的变化和作用。这些研究不仅会推进神经科学领域对dHC-mPFC环路的认识，而且对全面了解情绪记忆的调节机制具有重要意义；并可以为临床上有效、有选择性地调控记忆提供新靶点，为治疗PTSD提供新策略。

记忆是脑的基础认知功能。恐惧记忆的过度强化和过度泛化是创伤性应激障碍的核心症状。过去几十年神经科学的研究，认为海马区掌控情景恐惧记忆的巩固，内侧前额叶皮层（mPFC）掌控情绪调控。这两个脑区的协同作用在恐惧记忆调控中发挥重要作用，但目前神经科学界对两者协同作用的神经环路和分子机制仍然知之甚少。本项目利用小鼠场景恐惧记忆训练模型和可变应激模型研究发现：1）在恐惧记忆形成过程中，轴突生长因子Plexin-A1在mPFC抑制性神经元中表达量特异性下降，通过改变抑制性神经递质 GABA合成酶GAD67在突触的分布，改变mPFC兴奋/抑制平衡及下游脑区活性，进而调控后续记忆的精准性。2）同一场景的重复训练增强恐惧记忆的强度，而不同场景的重复训练促进恐惧泛化；在恐惧记忆测试过程中，海马区和mPFC通过终纹床核整合场景信息，差异性调控情景恐惧记忆的强度和泛化。3）恐惧记忆巩固早期，神经肽VGF在海马区和mPFC的翻译均快速上调，通过促进突触致密核心囊泡关键蛋白的合成，形成正反馈，增强记忆。4）可变反复应激差异性损伤雌鼠而非雄鼠脑膜淋巴管，导致mPFC脂质排泄受损，进而损伤mPFC星形胶质细胞。这一系列发现不仅推进神经精神疾病领域对恐惧相关记忆机制的认识，而且为临床上干预创伤性应激障碍、抑郁、焦虑等相关精神疾病提供新思路和实验依据。