AMPK信号通路在药物奖赏记忆中的作用及其表观遗传学机制

Drug addiction has become a serious economic and social problem. After repeated to drug exposures, persistent pathologic rewarding memories develop between repeated drug taking and drug-associated cues, which is the most important factor leading to relapse. Therefore, it is crucial to investigate the neurobiological mechanism of pathologic rewarding memories and seek out the effective intervention for pathologic rewarding memories, which is the key point for prevention and treatment of relapse. AMP-activated protein (AMPK) is a highly conserved serine/threonine protein kinase, which controls the protein synthesis through several downstream signaling pathways. While new protein synthesis is required in different stages of addiction memory such as consolidation, reconsolidation and extinction. Meanwhile, the persistence of drug seeking behavior is regulated by epigenetic mechanism. All these evidence suggests that epigenetic mechanism of AMPK may play an important role in different stages of pathologic rewarding memory. Using behavioral, molecular biological and epigenetic methods, our project investigates the role of AMPK in the consolidation, reconsolidation and extinction of cocaine associated rewarding memory. The epigenetic changes of AMPK are also detected in order to study the epigenetic mechanism underlying the role of AMPK in the consolidation, reconsolidation and extinction of cocaine associated rewarding memories.

药物成瘾已经成为一个严重的经济和社会问题。吸毒者在吸食成瘾性药物之后，对药物相关的线索和环境产生了一种持久存在的病理性奖赏记忆，这正是成瘾者发生复吸的根本原因。因此探索病理性奖赏记忆的神经机制，找到有效干预病理性奖赏记忆的手段，是防治药物成瘾复吸的关键。腺苷酸活化蛋白激酶AMPK是一种高度保守的丝氨酸/苏氨酸蛋白激酶，它能够通过影响其下游的多个信号通路控制蛋白质的合成，而成瘾记忆的不同阶段（如巩固、再巩固和消退）均需要新蛋白质的合成；同时觅药行为的长期维持需要表观遗传学修饰的调控过程。这提示AMPK的表观遗传学修饰可能在病理性奖赏记忆的不同阶段中发挥重要的作用。本课题拟采用行为学、分子生物学、表观遗传学等方法，观察AMPK在可卡因奖赏记忆的巩固、再巩固和消退过程中的作用；同时检测AMPK的DNA甲基化水平，初步研究AMPK影响病理性奖赏记忆巩固、再巩固和消退的表观遗传学机制。