海马调控恐惧记忆消退的神经及分子机制

Neural circuit including the hippocampus, amygdala and medial prefrontal cortex (mPFC) is involved in the learning and memory processes of fear extiction. Although there are extensive studies to explore the neural circuit and mechanism underlying the roles of amygdala and mPFC in regulating fear extinction, little is known about the neural circuit and melecular mechanism by which hippocampus controls fear extinction. In fact, hippocampus serves as a gate to govern the processes of fear extinction through contextual control of fear memory. Recently, we revealed that nNOS-PSD-95 coupling is a target for neuronal injury (Nat Med 2010) and nNOS-CAPON interaction can serve as a target for anxiety behaviors (Nat Med 2014). Moreover, our preliminary experiments showed that nNOS-PSD-95 and nNOS-CAPON in the hippocampus had critical role in regulating fear extinction, we also explored possible mechanisms underlying the role. Here, we are planning to make a deep research for: (1) the roles of nNOS-PSD-95 and nNOS-CAPON couplings in the DG, CA3 and CA1 of dorsal and ventral hippocampus in regulating the extinction of recent and remote fear memories, (2) their roles in regulating functional and structural synaptic plasticity, and possible neural circuit, including hippocampal and hippocampus-mPFC-amygdala circuits, and (3) molecular mechanism underlying their roles in fear extinction. Findings from current project may reveal how hippocampus mediates fear extinction through contextual control, and may uncover neural mechanism of anxiety disorders with over-generalized fear, such as PTSD.

恐惧记忆消退的神经环路主要由杏仁核、内侧前额叶皮层（mPFC）、海马等脑区构成。尽管杏仁核和mPFC介导恐惧记忆消退的机制已有广泛研究，但海马的神经及分子机制所知甚少。实际上，海马是恐惧记忆消退的闸门。本课题组近来发现了介导神经损伤（nNOS-PSD-95）（Nat Med 2010) 和焦虑行为（nNOS-CAPON）(Nat Med 2014) 的两个重要靶点，预实验显示它们对恐惧记忆消退具有重要调控作用，并初步探讨了可能的分子机制。本项目将深入研究上述两个靶点：1）在背侧及腹侧海马的不同亚区对近期和远期恐惧记忆消退的调控作用，2）对海马突触功能和结构可塑性的调控作用，揭示可能的海马神经环路和海马-mPFC-杏仁核神经环路，3）调控恐惧记忆消退的分子机制。预期研究成果将阐明海马如何通过背景关联控制操纵恐惧记忆消退，也将从新的视角认识PTSD等以恐惧泛化为主要特征的焦虑症的神经机制。

海马、杏仁核和mPFC介导恐惧消退记忆和情绪调节。虽然杏仁核和mPFC神经环路在恐惧和焦虑调节中的作用已有广泛研究，但海马调控恐惧消退和焦虑的环路和分子机制所知甚少。为了揭示消退记忆和焦虑相关行为的神经环路和分子机制，我们研究了海马和mPFC的神经元一氧化氮合酶（nNOS）-突触后密度-95（PSD-95）和nNOS-羧基端配体蛋白（CAPON）耦联在调节消退记忆和焦虑相关行为中的作用，探索了在消退记忆和焦虑相关行为调控过程中，海马、mPFC、杏仁核和丘脑室旁核（PVT）之间的神经投射及信号通路。本项目研究主要发现：（1）背侧海马（dHPC）-下边缘皮层（IL）环路是恐惧消退提取的基础；（2）IL-PVT-中央杏仁核外侧部（CeL）投射是IL-杏仁核经典恐惧消退环路之外的新神经环路；（3）扣带回（ACC）-腹侧海马（vHPC）环路控制恐惧记忆泛化的表达；（4）基地外侧杏仁核（BLA）的nNOS+和nNOS-兴奋性神经元分别通过BLA-终纹床核（dBNST）和BLA-vPHC环路逆向调控情绪行为；（5）背侧海马CA3 (dCA3)的nNOS-PSD-95耦联通过下调脑源性神经营养因子（BDNF）-TrkB信号通路阻碍恐惧消退；（6）nNOS-CAPON耦联通过细胞外调节蛋白激酶2（ERK2）脱功能介导的神经可塑性缺陷阻碍消退记忆巩固和维持，阻断该耦联能防止消退的恐惧记忆和吗啡位置偏爱记忆回复；（7）海马nNOS-CAPON耦联介导慢性应激诱导的情绪障碍；（8）mPFC的nNOS神经元将来自PVT的疼痛信号转换为焦虑行为。伏隔核（NAc)壳部的nNOS神经元通过CDK5亚硝基化介导社交挫败应激的易感性及其抑郁行为。本项目的主要科学意义在于：阐释了伴有记忆泛化的焦虑障碍（如PTSD)的神经机制，发现了干预焦虑障碍的新靶点。本项目成果在Nat Commun、Nat Protoc、J Neurosci、Cereb Cortex 等刊物发表标注本项目基金号 (31530091)论文23篇，1篇投到Mol Psyhiatry的论文已2轮修稿，另有2篇论文再投。获得2件发明专利授权（含1件PCT专利）和1件实用新型专利授权，获国家自然科学将二等奖1项（2/5)、江苏省科学技术奖一等奖1项（1/9)。