基底外侧杏仁核-前边缘皮层投射在药物成瘾记忆系统巩固中的作用及机制研究

Drug addiction is a chronic relapsing brain disorder. The strong and long-lasting drug craving is originated from pathological memory based on changes in synaptic plasticity, which existed chronically after withdrawal. Consolidation process is required for long-term maintenance after memory formation, and memory consolidation consists of synaptic-level consolidation and systems consolidation. Recent memory stabilizes and turns into remote memory during systems consolidation. Previous studies demonstrated that during systems consolidation of normal memory, the prefrontal engram cells, with support from hippocampal memory engram cells, became functionally mature with time, while hippocampal engram cells gradually became silent with time. However, the neural mechanisms of systems consolidation of drug memory remains unclear. The results of preliminary experiment suggest that basolateral amygdala (BLA) and prelimbic cortex (PrL) may play important roles in recent and remote memories. Using cocaine self-administration model and chemical genetic, electrophysiological and immunofluorescent techniques, the present project aims to investigate the roles and synaptic plasticity changes of BLA and PrL in recent and remote drug memory, and to reveal the roles of BLA-PrL projection in systems consolidation of drug memory by specifically labeling and regulating engram cells in BLA and PrL and their projection. This project will provide new ideas and theoretical basis for mechanism investigations of drug addiction and treatment of relapse.

药物成瘾是一种慢性复发性脑疾病，成瘾者强烈而持久的心理渴求的本质是以突触可塑性改变为基础的病理性记忆，在戒断后仍然长期存在。记忆在形成后需经过巩固过程才能够长期维持，记忆的巩固分为突触水平的巩固和系统巩固，在系统巩固过程中近期记忆转化为稳定的远期记忆。既往研究发现正常记忆的系统巩固过程中发生从海马到新皮层的神经重塑，然而病理性成瘾记忆系统巩固的神经机制目前尚不清楚。预实验结果表明基底外侧杏仁核和前边缘皮层可能分别在近期成瘾记忆和远期成瘾记忆中发挥重要作用。本项目拟采用可卡因自身给药模型，利用化学遗传、电生理、免疫荧光等技术，探索基底外侧杏仁核和前边缘皮层在近期和远期成瘾记忆中的作用及突触可塑性变化，通过特异性标记和干预基底外侧杏仁核和前边缘皮层的记忆印记细胞及其投射，揭示其在从近期记忆到远期记忆转化的系统巩固过程中的作用及机制，以期为药物成瘾的发病机制研究和防复吸治疗提供新思路和理论依据。

药物成瘾是一种慢性复发性脑疾病，给个体、家庭和社会带来严重危害，然而其发病机制不清、治疗手段有限。成瘾者强烈而持久的心理渴求的本质是以突触可塑性改变为基础的病理性记忆，在戒断后仍然长期存在。记忆在形成后需经过巩固过程才能够长期维持，记忆的巩固分为突触水平的巩固和系统巩固，在系统巩固过程中近期记忆转化为稳定的远期记忆。既往研究发现正常记忆的系统巩固过程中发生从海马到新皮层的神经重塑，然而病理性成瘾记忆系统巩固的神经机制目前尚不清楚。本项目采用可卡因自身给药模型，利用化学遗传、免疫荧光、逆行示踪等技术，发现戒断后大鼠脑网络发生时间依赖性的重组，基底外侧杏仁核（basolateral amygdala, BLA）和前边缘皮层（prelimbic cortex, PrL）分别调控戒断早期和晚期的可卡因觅药行为，BLA-PrL谷氨酸能投射对晚期觅药行为和成瘾记忆系统巩固至关重要。本项目还围绕成瘾领域的关键问题，建立了新的药物成瘾复吸动物模型，揭示了尼古丁成瘾的神经影像学新机制，发现了深部脑刺激治疗复吸的新靶点，阐明了网络成瘾的全球流行趋势及新冠疫情对网络成瘾的影响和危险因素。以上研究成果为成瘾发病机制和干预方法研究提供了理论依据和新思路。项目执行期间在Clinical Psychology Review、Frontiers in Pharmacology、Addiction Biology、American Journal on Addictions等期刊发表论文8篇，其中SCI论文6篇，IF>10分1篇，IF>5分3篇。项目负责人孟适秋入选了中国科协青年人才托举工程和北京市科协青年人才托举工程，将继续致力于为我国成瘾医学及相关学科的发展作出积极贡献。