阿片類物質(zhì)戒斷引起的負性情緒記憶是強迫性用藥和戒斷后復吸的重要原因。上海藥物所劉景根課題組在之前的工作中發(fā)現(xiàn)杏仁核突觸骨架重排（Actin重排）是嗎啡戒斷負性情緒記憶形成所必需的,。在此基礎(chǔ)上,，課題組深入地研究了杏仁核突觸骨架重排引起負性情緒記憶的分子機制。
研究工作發(fā)現(xiàn)杏仁核突觸骨架重排能夠使活性調(diào)節(jié)的突觸骨架相關(guān)蛋白（Arc）向突觸轉(zhuǎn)運,。突觸上Arc水平增加能夠促使突觸膜上AMPA受體內(nèi)吞,。用突觸骨架重排干擾劑抑制Arc蛋白向突觸轉(zhuǎn)運，或用慢病毒方法抑制杏仁核Arc蛋白表達,，能夠阻止AMPA受體內(nèi)吞和干擾負性情緒記憶的形成,。用小分子肽阻止突觸膜上AMPA受體內(nèi)吞可以抑制杏仁核LTD的產(chǎn)生和負性情緒記憶的產(chǎn)生。這些研究結(jié)果表明突觸骨架重排依賴的Arc蛋白向突觸轉(zhuǎn)運和由此產(chǎn)生的AMPA受體內(nèi)吞是嗎啡戒斷負性情緒記憶產(chǎn)生的關(guān)鍵分子事件,。該研究結(jié)果已于8月29日發(fā)表在神經(jīng)科學雜志（Journal of Neuroscience 32:12005-12017）上,。
該研究工作是與昆明動物所徐林研究員課題組共同完成的。劉瑤博士和周啟心博士是該工作的主要完成者,。研究工作得到國家自然科學基金重點項目和科技部“973”項目的資助,。（生物谷Bioon.com）
doi: 10.1523/JNEUROSCI.0871-12.2012
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Actin Polymerization-Dependent Increase in Synaptic Arc/Arg3.1 Expression in the Amygdala Is Crucial for the Expression of Aversive Memory Associated with Drug Withdrawal
Yao Liu, Qi-Xin Zhou, Yuan-Yuan Hou, Bin Lu, Chuan Yu, Jie Chen, Qing-Lan Ling, Jun Cao, Zhi-Qiang Chi, Lin Xu, and Jing-Gen Liu
Aversive memories associated with drug withdrawal may contribute to persistent drug seeking. Molecular mechanisms that are critical for aversive memory formation have yet to be elucidated. Recently, we showed in a rat conditioned place aversion (CPA) model that synaptic actin polymerization in the amygdala were required for aversive memory information. Here, we demonstrated that actin polymerization within the amygdala triggered transportation of activity-regulated cytoskeletal-associated protein (Arc/Arg3.1) into amygdalar synapses. Increased synaptic Arc/Arg3.1 expression contributed to aversive memory formation by regulating synaptic AMPA receptor (AMPAR) endocytosis, as in vivo knockdown of amygdalar Arc/Arg3.1 with Arc/Arg3.1-shRNA prevented both AMPAR endocytosis and CPA formation. We also demonstrated that conditioned morphine withdrawal led to induction of LTD in the amygdala through AMPAR endocytosis. We further demonstrated that Arc/Arg3.1-regulated AMPAR endocytosis was GluR2 dependent, as intra-amygdala injection of Tat-GluR23Y, a GluR2-derived peptide that has been shown to specifically block regulated, but not constitutive, AMPAR endocytosis, prevented AMPAR endocytosis, LTD induction, and aversive memory formation. Therefore, this study extends previous studies on the role of actin polymerization in synaptic plasticity and memory formation by revealing the critical molecular events involved in aversive memory formation as well as LTD induction, and by showing that Arc/Arg3.1 is a crucial mediator for actin polymerization functions, and, thus, underscores the unknown details of how actin polymerization mediates synaptic plasticity and memory.
