创伤性场景恐惧记忆遗忘机制的研究

Posttraumatic stress disorder (PTSD) is a mental disorder that may develop after a person is exposed to traumatic events, which is characterized by hypermnesia or cannot forgetting. However, little is about the forgetting of traumatic memory. Previous researches indicate the phenomena of unforgetting may be involved in serotonin and actin. We found Rac1 activity in hippocampus regulated the forgetting of contextual fear memory in rat，previous researches show 5-HT1A, 5-HT1B, 5-HT2A and serotonin transporter(SERT) are involved in to fear memory. Thus, we hypothesise 5-HT1A, 5-HT1B, 5-HT2A and SERT are involved in regulation of Rac1 activity in the hippocampus and the forgetting of contextual fear memory, Rac1 signal pathway may be the last pathway of PTSD. Here we will investigate ① the effects of contextual fear conditioning on the level of 5-HT1A, 5-HT1B, 5-HT2A, SERT and F-actin in the dorsal raphe nucleus(DRN) and hippocampus. ② the effect of promotion or inhibition of 5-HT1A, 5-HT1B, 5-HT2A and SERT in DRN or hippocampus on hippcampal Rac1 activity and contextual fear memory in rats.③ the level of serum Rac1 mRNA in PTSD patients. These data will be important for a better understanding of the forgetting mechanisms of traumatic memory and provide potential target to theatment of PTSD.

创伤后应激障碍（PTSD）以创伤性恐惧记忆的病理性增强、延迟或不能遗忘为核心症状。但关于创伤性恐惧记忆遗忘的机理几乎一无所知。研究表明记忆的"不能遗忘"现象可能与5-HT系统和Rac1下游分子actin有关。我们前期研究发现海马Rac1调控着大鼠场景恐惧记忆的遗忘，而5-HT系统与PTSD的生理病理密切相关。因此，我们推测5-HT系统可能调控海马Rac1的活性并参与创伤性场景恐惧记忆的遗忘。本课题将研究：①场景条件恐惧学习后大鼠背侧中缝核、海马等脑区5-HT1A、5-HT1B、5-HT2A受体、5-HT转运及 F-actin的表达；②干预条件恐惧学习所至5-HT1A、5-HT1B、5-HT2A、5-HT转运体及F-actin的变化，检测其变化与海马Rac1活性及动物场景恐惧记忆遗忘的关系。③PTSD病人外周血Rac1 mRNA的变化。实验结果将为PTSD的治疗提供新的途径。

创伤后应激障碍（PTSD）以创伤性恐惧记忆病理性增强、延迟或不能遗忘为核心症状。但关于创伤性恐惧记忆遗忘的机理几乎一无所知，Rac1是调控动物遗忘的关键分子，本项目研究了场景条件恐惧学习后大鼠中缝核、海马CA1区5-HT1A、5-HT2A受体及SERT的表达变化与动物海马Rac1活性及场景条件恐惧记忆遗忘的关系。项目研究发现①多次学习可导致强烈、持久的场景恐惧记忆；②场景恐惧学习后大鼠海马5-HT1A、5-HT2A受体、5-HT转运均表达增高；③场景条件恐惧学习后海马CA1区Rac1下游信号分子p-PAK1、p-cofilin的表达增高；④抑制海马5-HT2A受体诱发大鼠场景恐惧记忆减弱、激活海马5-HT2A受体导致大鼠场景恐惧记忆增强； ⑤海马5-HT2A受体与Rac1有相互作用：抑制海马5-HT2A受体激活大鼠海马Rac1、激活海马5-HT2A受体导致大鼠海马Rac1活性降低；⑥抑制5-HT2A受体导致场景条件刺激后大鼠海马CA1区c-fos表达减少;⑦褪黑素、阿戈美拉汀均可激活大鼠海马Rac1； ⑧大鼠、树鼩海马Rac1活性呈昼夜节律变化，急性逆转光照可导致大鼠、树鼩海马Rac1活性相位高峰、低谷发生移相。实验结果证实5-HT2A受体通过调节海马Rac1活性调节着大鼠场景恐惧记忆的遗忘，海马Rac1活性呈明显昼夜节律变化，受5-HT2a受体、光、皮质酮、褪黑素的调节。实验结果为PTSD的治疗提供了理论依据。