阻断恐惧再习得诱导的“巩固”与“再巩固”对长程恐惧记忆表达与复发的影响研究

Based on the labile nature of memory consolidation and reconsolidation, researches disrupted acquired memory successfully by amnestic agents and fear extinction. However, these amnestic agents and fear extinction are only effective for recent fear memory but not for remote fear memory. The reason for this separation may be that remote fear memory is not fully reactivated by retrieval. Researchers proposed that reconsolidation may only take place when memory reactivation involves an experience of prediction error. It was found that increasing shock expectancy by continuous context–shock pairings over several consecutive days could accelerates fear extinction. Therefore, based on the contextual fear conditioning of mice, we expect that by fear re-conditioning or re-learning before memory retrieval, remote fear memory could be fully reactivated and become sensitive to disruption during the process of reconsolidation. Meanwhile, we also expect that re-conditioning could be accompanied by a vulnerable memory state which is similar to the state of consolidation after initial conditioning. During these two liable periods, remote fear memory may be erased by protein synthesis inhibitor and fear memory extinction. Furthermore, we will explore the neural mechanism of re-conditioning contribute to erase remote fear memory. In the all, firstly, because of focusing on remote fear memory which possibly be crucial factor for the occurrence of stress-related mental disorder, our proposal may have a broader perspective in clinical practice. Secondly, our proposal also could provide research supports for further exploring the mechanism of fear memory storage and memory transform between recent and remote fear memory.

记忆两个不稳定的巩固与再巩固阶段为研究者抹除恐惧记忆开了两扇窗。但是，将能够抹除储存1-2天的短程恐惧记忆的方法用于长程恐惧记忆时均失去作用。这可能是因为单纯的提取无法真正激活长程恐惧记忆造成的。研究者认为，只有当记忆提取时产生预测误差才能使恐惧记忆变得更易于被清除。基于多次条件化匹配训练能够增强动物的预测误差，我们以小鼠场景条件化模型为基础，期望记忆提取前对动物进行恐惧再习得训练，能够使动物在记忆提取时真正进入不稳定的再巩固期；其次，我们还期望恐惧再习得后一个短暂的时间窗内，动物能直接处于一个脆弱不稳定的状态，即类似于记忆刚习得后的“巩固”阶段。在这两个时期内，可以利用蛋白合成抑制剂与消退训练实现抹除长程恐惧记忆的目的。同时，我们还将探索抹除长程恐惧记忆的中枢机制。我们的研究成果因关注长程恐惧记忆将具有更广的临床效度，也为我们进一步探索恐惧记忆痕迹在大脑中保存与转换的机制提供研究支撑。

应激创伤事件后所形成的恐惧记忆的有利于保证有机体的生存。但也可能会导致应激相关精神障碍的形成。幸运的是，研究者发现当恐惧记忆提取后会进入一个极不稳定的时间窗：恐惧记忆再巩固。在此时间窗内给予行为消退训练能够彻底清除已经形成的恐惧记忆。但是，这种提取-消退干预模式只将能够抹除储存1-2天的短程恐惧记忆，无法破坏长程恐惧记忆的表达。本研究首先发现对破坏短程恐惧记忆有效的单纯的提取-消退干预模式确实无法破坏长程恐惧记忆的复发（重建测试测得）。但这可能是应激强度依赖的。之后，我们对动物在恐惧记忆消退与不消退的基础上进行恐惧再习得训练，再次探索了提取-消退模式对短程与长程恐惧记忆的影响。发现恐惧再习得训练后，恐惧记忆表达过强，提取-消退模式对长程恐惧均无干预作用，反而增加了长程恐惧记忆的表达水平。为了不增加应激水平，我们又采用了先暴露激活再进行提取-消退干预的模式调控恐惧记忆，发现此模式能够破坏长程恐惧记忆的复发。蛋白合成抑制剂、尼莫地平等给药实验也证明了单纯的激活有利于对长程恐惧记忆的干预。我们还利用免疫组化、高尔基染色及其他分子生物学技术发现短程与长程恐惧记忆在相关脑区的蛋白表达及神经元形态学存在明显差异。我们的研究结果证明，记忆时程是临床干预恐惧记忆的一种重要需考虑因素，探索短程与长程恐惧记忆的分子机制将会更加有助于理解不同时程恐惧记忆的储存机制，为干预恐惧记忆提供良好的研究支撑。