大鼠腹内侧前额皮层部位BDNF调控的GABAA受体转运参与负性情绪的消退学习

Increasing evidence shows that negative reinforcement may play a crucial role in loss of control over drug taking and relapse after abstinence. Extinction therapy has been proposed as a method to reduce the motivational impact of drug-associated cues to prevent relapse.Our previous study has shown that extinction of aversive memory of morphine withdrawal requires epigenetic regulation of BDNF gene transcription in the vmPFC through activation of the ERK-CREB signaling pathway perhaps in a NMDA receptor-dependent manner. In this study, We will investigate the role of Pak1-PP2A signaling pathway during extinction of aversion memory.We try to elucitate the role of this pathway in GABAA receptor endocytosis which has been demonstrated that it contributes significantly to the extinction of aversion memory. Our results will provide the first evidence that activation of Pak1-PP2A pathway in the vmPFC is an important mechanism that is involved in the extinction of aversive memories associated with morphine withdrawal. Our results will define a series of molecular mechanisms whereby extinction training leads to GABAA receptor endocytosis. Our findings may facilitate the development of treatments for drug craving and relapse.

药物戒断诱发的负性情感是复吸的主要因素。研究如何阻止与负性情绪相关线索诱导成瘾者复吸成为成瘾领域研究的主要目标。研究者前期工作发现消退学习可显著降低急性CPA大鼠的厌恶成绩，提示消退性学习可能是用于降低成瘾复吸行为的有效方法。进一步工作表明CPA大鼠消退学习过程中需要腹内侧前额皮层中BDNF蛋白的参与，并且对于其上游信号通路已经阐述清楚。基于以上结果，申请者拟在本项目重点研究BDNF下游信号通路Pak1-PP2A在消退学习记忆过程中的功能改变。为了进一步阐明Pak1-PP2A通路调控的下游信号分子，我们将进一步检测Pak1-PP2A通路调控突触膜GABAA受体β3亚基内吞与循环的分子机制。本项目从突触可塑和受体转运的角度探索药物戒断负性情感消退学习的分子机制，不仅有助于深入研究消退学习的内在机制，而且对临床上治疗药物成瘾和干预戒断后的复吸具有重要意义。

药物戒断所引起的负性记忆是导致患者不断渴求药物和引起复吸的关键所在。与成瘾药物相关的环境线索在药物复吸的过程中扮演着十分重要的作用，研究如何阻断环境线索诱导复吸是成瘾领域重要研究目标。我们的前期研究发现大鼠腹内侧前额叶皮层（vmPFC）脑区BDNF表达增加在药物戒断负性情绪记忆的消退中发挥了重要作用，但vmPFC内BDNF调控负性情绪记忆消退的分子机制仍不清楚。在本项目中，我们发现条件位置厌恶（CPA）消退训练后vmPFC脑区增加的BDNF可通过激活Rac1-Pak1-Cofilin信号通路引起突触骨架actin重排，继而将Arc蛋白转运至突触部位，增加突触Arc蛋白表达，介导GABAA受体3亚基内吞，引起vmPFC脑区LTP的形成。此外，我们还发现吗啡戒断负性记忆的消退学习需要背侧海马（DH）与基底外侧杏仁核（BLA）功能的相互作用，背侧海马NMDA受体通过抑制基底外侧杏仁核ERK和CREB磷酸化调节消退记忆的形成。本项目从突触可塑性角度和受体转运角度探索了药物戒断负性情绪消退的分子机制。研究成果不仅有助于深入阐述消退学习的内在机制，对临床上治疗药物成瘾和干预戒断后复吸有重要意义。

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