恐惧记忆储存和消除的神经微环路机制

Dysfunction of emotional and memory circuits leads to a serial pathological memory-related disease, such as posttraumatic stress disorder (PTSD). In clinic, the exposure therapy, which is based on the theory of memory formation and extinction, has been used for the treatment of PTSD and phobia disorder. However, the effectiveness of the therapy is limited, and the pathological memory and the PTSD syndromes often spontaneously re-emerge after some passages of time. The key reason is that exposure-therapy inhibits the expression of original fear but does not erase the fear memory trace. Thus, it has been crucial scientific question that what is the key circuits of memory extinction, and how to enhance the process of memory extinction to erase fear memory with a non-pharmacological manner. Our previous studies have showed that unconditioned stimulus-induced memory retrieval-extinction procedure erases original fear memory, and prevents the return of fear response; additionally, we also found repeated exposure of conditioned stimulus during sleep leads to memory extinction. However, the neurobiological mechanisms underlying these findings remain unknown. In the present project, we will use multiple tools, including in vivo spike recording, visualized mapping of memory trace and tracing of memory circuits, to investigate neuronal encoding mechanisms of retrieval-extinction procedure; we will also combine the electroencephalogram, optogenetics and functional magnetic resonance imaging in rodent and/or human studies, to elucidate the distinct brain circuits of fear extinction during wakefulness and sleep status. Our aim is to integrate the procedures of memory retrieval-extinction and memory extinction in sleep to develop a new noninvasive and effective paradigm for the treatment of pathological memory-related disease.

情感和记忆环路的失调会引发一系列病理性记忆相关疾病，如创伤后应激障碍综合征（PTSD）等。目前在临床中，基于记忆消退理论的暴露疗法常用来治疗PTSD等精神疾病，但疗效有限，随着时间的推移病理性记忆会重现。其关键原因在于该疗法只是抑制了原有的记忆，并没有彻底消除病理性记忆。因此探索调控恐惧记忆消退的神经环路，发展新的可消除记忆的心理学范式是亟待解决的重大科学问题。我们前期研究发现非条件性线索唤起-消退心理学范式可以消除恐惧记忆，同时我们还发现在睡眠中可发生记忆的消退，但是其神经机制尚不清楚。因此，我们拟通过在体多通道记录、可视化记忆标记及微环路示踪等技术探索唤起-消退模式消除恐惧记忆的神经编码机制；同时应用睡眠脑电，光遗传和神经影像学等技术，结合动物和人体研究，探索睡眠与清醒状态下恐惧记忆消退神经微环路机制的异同，进而综合记忆唤起-消退和睡眠记忆消退范式的优势，发展有效的无创记忆消除范式。

创伤后应激障碍综合征（PTSD）和药物成瘾等被认为是认知和情感的失调引发的病理性情感记忆，消除这种强烈而持久的病理性记忆是疾病治疗的关键。然而目前在临床中，基于记忆消退理论的暴露疗法疗效有限，随着时间的推移病理性记忆会重现。因此探索调控病理性记忆消退的神经环路，发展新的可消除记忆的心理学范式是亟待解决的重大科学问题。本项目运用记忆再巩固与消退的原理，按照申请书中的研究目标开展了工作，取得了重要进展，主要包括：1）发现前额叶皮层的蛋白激酶 C 家族成员 PKMζ 以及背侧海马的磷酸腺苷活化蛋白激酶（Adenosine monophosphate-activated protein kinase, AMPK）在长时程恐惧记忆的维持中具有重要的作用，为PTSD等疾病提供了潜在的干预靶点；2）提出了消除病理性记忆的新范式—非条件性刺激唤起联合消退训练或者普萘洛尔干预病理性记忆的新范式，并在动物实验和吸烟者中均发现该范式可破坏尼古丁相关记忆，显著降低心理渴求；3）首次阐释了条件性刺激唤起和非条件性刺激唤起激活病理性记忆的神经元集群图谱，为病理性记忆操控范式提供了理论支持；4）发现睡眠剥夺对脑默认网络的功能连接有可分离作用，并提出睡眠状态下利用视觉相关线索的再暴露消除负性情绪记忆的新方法，为临床上消除病理性记忆提供新的思路。这些成果探索了病理性记忆唤起和消退的神经机制和干预策略，为治疗药物成瘾和PTSD等精神疾病提供了新型治疗途径。本项目执行期间在JAMA Psychiatry、Nat Commun、Biol Psychiatry、J Neurosci 等重要期刊发表论文13篇，其中IF>10的有4篇。项目负责人陆林教授2017年入选中国科学院院士，共出站博士后2名，毕业博士和硕士研究生18名。