酸敏感离子通道调节病理性程序性学习的机制研究

Habitual-seeking behavior is a key step in the development of chronic drug addiction from repeated drug abuse. It is essentially a pathologically procedural learning process which is mechanically dependent on the dorsal striatum-associated neural circuits. However, the synaptic plasticity occurred on these neural circuits for habitual learning in addition to the molecular and cellular mechanisms driving the addiction behavior remain largely not clear. Being a major member in the research team lead by Prof. Tian-Le Xu at Shanghai Jiao Tong University for up to 10 years, the applicant has participated into a serial of advanced studies on the roles of acid-sensing ion channel (ASIC) in pathological and physiological neuronal signaling processes. Recently, the applicant and colleagues identified the involvement of ASIC in the regulation of aversive memory extinction and characterized the underlying synaptic plasticity mechanisms in cortical circuits (Nat Commun, 2016; Sci Adv, 2018). Moreover, she and colleagues revealed an ASIC-dependent signaling cascade in dorsal striatal glutamatergic synaptic remodeling and procedural motor learning (Sci Signal, 2018). Notably, as the preliminary observation, the research team identified that ASIC null mice displayed a substantially reduced susceptibility to the addictive drugs such as morphine and cocaine, and consistently that the dorsal striatal ERK signaling activation to cocaine treatment were significantly impaired in ASIC null animal. Based on these progresses, here the applicant proposes to further advance the mechanistic studies of ASIC regulation of pathological procedural learning, aiming to behaviorally clarify the circuit-specific roles of ASIC in habitual-seeking under the chronic alcoholism model, meanwhile, to electrophysiologically characterize the ASIC-dependent synaptic adaption mechanisms in dorsal striatum-centered neural circuits. Hopefully, we well identify a novel role of ASIC in habitual-seeking behavior and provide novel insights for guiding the translational medicine research on addiction control.

习惯化觅药行为是重复药物滥用发展为慢性药物成瘾的关键步骤，其本质是病理性程序性学习过程，机制上依赖背侧纹状体相关神经环路，然而行为成瘾习惯化学习的神经环路可塑性及赖以驱动的分子细胞机理仍不清楚。申请人依托课题组以酸敏感离子通道（ASIC）为攻关目标，参与ASIC调节记忆消退神经环路可塑性的机制研究（Nat Commun, 2016; Sci Adv, 2018），还参与揭示ASIC调节纹状体谷氨酸能突触重塑和程序性运动学习的机制（Sci Signal, 2018）。基于课题组关于ASIC影响可卡因等成瘾药物敏感性及纹状体ERK信号途径激活的预实验发现，本项目以纹状体突触可塑性调控机制为切入点，深入ASIC调节病理性程序性学习的机制研究，鉴定ASIC在慢性药物成瘾中的作用，分析神经输入和输出投射特异的纹状体环路适应性改变，探索靶向ASIC干预成瘾行为的新途径。

精神活性药物的滥用给个体和社会带来巨大的危害，机制上依赖于习惯化觅药行为的病理性调控，然而这种病理性程序性学习及精神活性药物引起高运动性的神经环路可塑性及赖以驱动的分子细胞机理仍不清楚。高运动性是精神活性药物使用后的外在表型，机制上主要依赖于背侧纹状体相关神经环路。本项目依托课题组关于酸敏感离子通道（acid-sensing ion channel, ASIC）调控神经环路可塑性的若干前期研究，进一步以纹状体突触可塑性调控机制为切入点，借助基因工程修饰小鼠，结合电生理学、行为学、形态学、光遗传学、生物化学与分子细胞生物学等多学科技术手段，深入研究了ASIC调节病理性程序性学习的细胞和分子机制，鉴定了ASIC参与吗啡等精神活性药物强迫觅药行为的细胞特异性机制，阐明了纹状体兴奋性突触稳态重塑机制贡献于程序性学习和运动调节的新规律，还拓展研究了病理性情绪记忆反复提取的神经环路可塑性机制，发现了情绪记忆总是重复出现的关键神经机制，为相关神经精神疾病的治疗提供了理论借鉴。本项目在《National Science Review》、《Nature Communications》、《Molecular Psychiatry》等国际期刊发表论文4篇，协助课题组培养博士研究生毕业3人，协助课题组以联合培养的方式为国内兄弟单位培养研究生毕业2人；培养项目组成员获各类资助项目、奖励或人才计划5项目；项目组成员参与国内国际学术会议交流5次，顺利完成项目任务。