eIF2α-ATF4信号通路在非条件性刺激诱导的病理性情感记忆再巩固中的作用及神经机制

Pathologic emotional memories related diseases, such as addiction and post-trauma stress disorder (PTSD), is a serious public health and social problem. The persistence of pathologic emotional memories induced by repeatedly exposure to abused drugs or trauma experience caused high rate of relapse to drug seeking or conditioned fear response. The key point in treatment of pathologic emotional memories related diseases is how to control relapse. Recently, it has been reported that disruption of the reconsolidation decreased the relapse rates. Either exposure to conditioned stimulus (CS) or unconditioned stimulus (UCS) induced the memory reconsolidation, but disruption of UCS-induced reconsolidation is more powerful to prevent relapse than disruption of CS-induced reconsolidation. Previous studies have found that Role of eIF2α-ATF4 signaling pathway has important role in regulating gene transcription, by which affects the synaptic plasticity and learning and memory. However, the role of eIF2α-ATF4 signaling pathway in UCS-induced reconsolidation of pathologic emotional memory is unkown. In the current project, behavioral, molecular pharmacologic and lenti-virus mediated genetic regulation methods will be integrated with conditioned place preference, self-administration and fear conditioning rats model to investigate the effects of UCS-exposure on eIF2α-ATF4 signaling pathway and transcription of downstream genes. Furthermore, the role of eIF2α-ATF4 signaling pathway in UCS-induced reconsolidation of pathologic emotional memories will be studied. Development of the current project will be helpful for uncovering mechanisms of pathologic emotional memories and for promoting the treatment of pathologic emotional memories related diseases.

病理性情感记忆相关疾病(如药物成瘾和PTSD)是严峻的公共卫生及社会问题。病理性情感记忆的持续存在是导致成瘾者复吸以及PTSD患者反复创伤性体验的根本原因。复发是病理性情感记忆相关疾病治疗的关键问题，破坏病理性情感记忆再巩固过程能抑制相关疾病的复发。条件性刺激(CS)或非条件性刺激(UCS)暴露都可以诱导记忆再巩固过程，破坏UCS诱导的再巩固产生的效果优于破坏CS诱导的再巩固，但UCS诱导的再巩固过程的机制尚无研究。eIF2α-ATF4信号通路调控基因转录过程，影响突触可塑性和学习记忆，但其在UCS诱导的再巩固中的作用尚不清楚。本项目拟运用行为学、分子药理学，基因调控手段，在大鼠条件性位置偏爱、自身给药和条件性恐惧模型中，研究eIF2α-ATF4信号通路在非条件性刺激诱导的病理性情感记忆再巩固中的变化规律及其神经机制。本项目在丰富对病理性情感记忆机制认识的同时，也为相关疾病治疗拓宽思路。

药物成瘾(drug addiction)和创伤后应激障碍(post-trauma stress disorder, PTSD)不但是严峻的公共卫生问题，同时也是危害社会发展的社会问题。这两种 疾病具有共同特征为持续存在，难以消退，易于复发，属于典型的病理性情感记 忆 。病理性情感记忆的持续存在是导致成瘾者复吸以及PTSD患者反复创伤性体验的根本原因。复发是病理性情感记忆相关疾病治疗的关键问题，破坏病理性情感记忆再巩固过程能抑制相关疾病的复发。条 件性刺激(CS)或非条件性刺激(UCS)暴露都可以诱导记忆再巩固过程，破坏UCS诱导的再巩固产 生的效果优于破坏CS诱导的再巩固，但UCS诱导的再巩固过程的机制尚无研究。eIF2α-ATF4信 号通路调控基因转录过程，影响突触可塑性和学习记忆，但其在UCS诱导的再巩固中的作用尚不清楚。本项目在大鼠条件性位置偏爱、自身给药和条件性恐惧模型中，研究eIF2α-ATF4信号通路在非条件性刺激诱导的病理性情感记忆再巩固中的变化规律及其神经机制。我们发现：（1）在UCS 暴露之后BLA脑区eIF2α磷酸化水平下降以及下游的ATF4 表达下降，并且在非条件性刺激暴露后2 小时恢复到正常水平，但是在CeA脑区中没有类似变化规律；（2）我们发现在BLA 脑区给予Sal003 抑制eIF2α的去磷酸化过程，能够抑制病理性情感记忆的表达，并且其抑制效果至少维持28天，而在CeA脑区给予Sal003没有作用；（3）发现先敲低ATF4表达，可以阻断Sal003 抑制eIF2α的去磷酸化过程导致的药物奖赏记忆再巩固的破坏作用，表明抑制eIF2α的去磷酸化对病理性情感记忆再巩固的破坏作用依赖于下游ATF4的表达。本项目在丰富对病理性情感记忆机制认识的同时，也为治疗病理性情感记忆相关疾病提供新的潜在药物开发靶点。