杏仁核和腹内侧前额皮层染色质组蛋白乙酰化修饰在吗啡戒断引起的负性情感消退学习中的作用研究

Aversive memories associated with drug withdrawal may contribute to persistent drug seeking. Understanding the molecular mechanisms underlying the extinction of aversive memories associated with drug withdrawal could lead to pharmacological approaches for enhancing extinction memory, which might facilitate the treatment of drug addiction. Our preliminary data showed that extinction training attenuated the expression of conditioned place aversion (CPA). Intra-vmPFC injections of the NMDA receptor partial agonist D-cycloserine and the histone deacetylase inhibitor TSA promoted CPA extinction. In contrast, intra-vmPFC injection of U0126 inhibits inhibited CPA extinction. Our preliminary data also demonstrated that extinction training induced induce histone H3 and H4 acetylations and increased BDNF and Arc expression. These initial data suggest that extinction of morphine withdrawal-induced conditioned place aversion is associated with chromatin modifications. Therefore, we will further study: 1) whether increases in histon acetylation in the vmPFC contributes to enhancement of BDNF and Arc protein expression; 2) what role ERK signaling plays in regulation of chromatin modification following extinction training; 3) whether enhancement of BDNF and Arc protein expression in the vmPFC is involved in the extinction of CPA; and 4) what interplay occurs among vmMPFC, amygdala and hippocampus during extinction training. This study will give insight in the mechanisms underlying the extinction of CPA, and thus facilitate the treatment of drug addiction.

阿片类药物戒断引起的负性情感记忆是吸毒者强迫性用药和戒断后复吸的重要原因。利用条件位置厌恶这一经典研究成瘾药物负性情感的动物模型，我们最近发现消退训练能够显著的降低吗啡负性情感。腹内侧前额皮层（vmPFC）注射NMDA受体部分激动剂和组蛋白去乙酰化酶抑制剂能够促进消退学习，而注射ERK激活抑制剂则弱消退学习。我们还发现消退训练增加vmPFC染色质组蛋白乙酰化水平和引起BDNF和Arc蛋白表达。这些初步结果表明吗啡负性情感记忆消退学习涉及到表观遗传机制。我们将深入研究vmPFC染色质组蛋白乙酰化修饰与BDNF和Arc蛋白表达的关系；研究ERK信号通路激活对染色质表观遗传修饰的调控作用; 研究BDNF和Arc蛋白表达在吗啡负性情感消退学习记忆中的作用；研究基底外侧杏仁核和vmPFC在消退学习记忆中的功能联系及神经环路。研究阿片负性情感消退学习记忆机制对治疗阿片成瘾和预防复吸有重要意义。

药物戒断引起的负性记忆是导致成瘾者不断渴求药物和引起复吸的关键因素。到目前为止，吗啡戒断负性情绪记忆消退的分子机制尚不清楚。利用大鼠急性条件位置厌恶（CPA）消退性学习为模型，我们发现腹内侧前额叶皮层（vmPFC）是大鼠CPA消退性学习的关键脑区，急性CPA的消退性学习伴随vmPFC脑区NMDA受体介导的ERK-CREB信号通路的激活，该通路通过调节组蛋白乙酰化促进BDNF表达，增加的BDNF激活Rac1-Pak1-Cofilin信号通路，从而介导突触骨架actin的重排，进而F-actin将Arc mRNA转运到突触部位，增加突触Arc蛋白表达，随后Arc蛋白介导GABAA受体3亚基的内吞，形成LTP，介导消退记忆的形成。此外，负性情绪记忆的消退学习还需要背侧海马和杏仁核功能的相互作用，CPA消退训练会伴随基底外侧杏仁核和背侧海马ERK/CREB信号通路激活，背侧海马的NMDA受体信号通路通过直接或间接方式调节基底外侧杏仁核ERK与CREB磷酸化进而调节消退记忆的形成。本研究对于阐述成瘾的神经生物学机制有重要意义，也为临床治疗成瘾与复吸提供了潜在靶点与理论认识。