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。

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.