中脑腹侧被盖区-海马通路多巴胺系统对“恐惧-消退”竞争平衡的双向调控机制研究

Post-traumatic stress disorder (PTSD) is one of the typical mental injuries. Great difficulty in fear extinction results in the chronicity of PTSD. Fear memory will be retrieval once patient is out of treatment. So far, the mechanism of context-dependent extinction is not far from clear. We put forward the hypothesis that “there is a competition between fear memory and extinction memory” based on the coexistence of these two memories and the complex concept of “context”. It is known that hippocampus plays a key role in integrating multiple informations, from which output context information can determine the direction of this competition. According to our studies, hippocampus and its dopamine (DA) system originating for ventral tegmental area (VTA) involved in fear conditioning and extinction. Therefore, we assume that by the regulation of DA system in VTA, the hippocampal microcircuit could enter and regulate the context information bidirectionaly. In vivo and in vitro animal experiments will be used to further study the mechanism of context-dependent extinction and the competition between fear memory and extinction memory in order to provide a scientific basis of objective assessment of mental injury.

创伤后应激障碍（PTSD）是典型的精神刺激所致精神损伤之一。PTSD患者表现为脱离治疗环境恐惧记忆重现。“消退记忆场景依赖性”机制远未阐明。消退后，生物体不仅面临场景变化，还涉及恐惧记忆（CS-US）与消退记忆（CS-no US）的竞争平衡。海马是负责汇聚、整合信息的重要脑区，整合后的场景信息是形成CS-US和CS-no US记忆必要条件。腹侧被盖区（VTA）DA能神经元通过紧张性和位相性释放，调控海马抑制性微环路，对其突触可塑性有双向调控作用。因此，我们提出“VTA-海马的DA通路对‘恐惧-消退’竞争平衡有双向调控作用”的科学假设。旨在获得“恐惧-消退”竞争中海马突触可塑性及VTA的DA能神经元兴奋特征，阐明VTA的DA能神经元释放对海马抑制性微环路的双向调控，影响海马对场景信息的编码与整合，实现对两种记忆形成的双向调控，达到“恐惧-消退”竞争平衡的的机制，为精神损伤客观评提供科学依据。

创伤后应激障碍（PTSD）是典型的精神刺激所致精神损伤之一。PTSD患者表现为脱离治疗环境恐惧记忆重现。“消退记忆场景依赖性”机制远未阐明。续新是其中一种恐惧记忆重现的模式。消退后，生物体不仅面临场景变化，还涉及恐惧记忆（CS-US）与消退记忆（CS-no US）的竞争平衡。我们提出“VTA-海马的DA通路对‘恐惧-消退’竞争平衡有双向调控作用”的科学假设,旨在获得“恐惧-消退”竞争中VTA的DA能神经元兴奋特征，阐明VTA的DA能神经元活动对消息记忆的双向调控，进一步找到VTA的DA能系统的调控下游脑区，阐明“恐惧-消退”竞争平衡的的机制，为精神损伤客观评提供科学依据。本研究从组织学和电生理学初步揭示了VTA脑区及其DA能神经元在两种模式：恐惧续新（ABA）和消退（ABB）有不同的活动方式，表现为在ABA模式下活性更强。进一步证实VTA多巴胺能投射的脑区海马DG区内的cAMP-PKA信号通路在ABA模式下也发挥作用。同时，杏仁体、vCA3、dCA1、dCA3与vCA1脑区的兴奋性神经元在ABB和ABA中被激活的程度不同。利用化学遗传学的方法，激活VTA-海马的神经通路，发现促进ABA的发生，表明该神经通路是参与续新过程的。本研究揭示了VTA区多巴胺能系统及其下游脑区在“恐惧-消退”中的作用。