腹侧海马区miR-134在药物线索诱发的可卡因复吸行为中的作用及其机制研究

Ventral hippocampus (vHP) is thought to be involved in the process of context-(or cue-) and rewarding-associated learning and memory. Neuroadaptaion induced by cocaine exposure in vHP are believed to contribute to the development of cocaine relapse behavior. Recently, miR-134 is reported to take part in the processes of neuron mature, synaptic remolding and plasticity in hippocampus. In addition, miR-134 is found to be involved in regulating the development of hippocampus-related brain diseases. The current study is designed to explore the role of miR-134 on vHP in cocaine context (or cue)-induced relapse behavior. First, the expressions of miR-134 during several cocaine exposures (repeated cocaine exposure, cocaine withdrawal or extinction, and reinstatement) are examined in the subregions of vHP. Then, the effects of local knockdown or overexpresision of miR-134 in vHP on the reinstatement of cocaine-seeking behavior is explored using cocaine conditioned place preference (CPP) rat model and cocaine self-administration (SA) rat model. Last, the molecular and cellular mechanisms underlying the regulating role of miR-134 in cocaine relapse behavior is investigated from the following aspects: (1) Identification of target genes for miR-134 in vHP; (2) Regulating effects of miR-134 on synaptic pasticity in vHP; (3) Regulating effects of miR-134 on electrophysiological activity in vHP; (4) Regulating effects of miR-134 on the interaction between vHP and ventral tegment area (VTA), the other brain region targeted by cocaine abuse. The results of this study will help to better understand molecular and cellular mechanisms of drug abuse and may provide new targets for the development of therapeutic agents against drug addiction.

腹侧海马区(Ventral hippocampus,vHP)是学习和记忆药物相关线索（Context/Cue）信息的关键结构，该通路所发生的病理性神经适应性变化是可卡因戒断后产生复吸现象的关键原因之一。miR-134参与调控海马的神经元成熟和可塑性的构建，以及调节海马区相关脑病的病理发生过程。本项目拟采用可卡因相关线索诱发可卡因复吸的大鼠模型，观察vHP区miR-134在可卡因接触不同阶段(长期暴露，戒断或熄灭觅药，恢复觅药)的表达变化；利用局部沉默miR-134和过表达miR-134的技术，观察vHP区miR-134对可卡因复吸行为的影响；从靶基因筛选、海马突触微结构重建、海马区电生理活动、海马与其他成瘾脑区关联性四个方面，探索vHP区miR-134影响可卡因复吸行为的神经机制。本项目研究结果将有助于进一步理解可卡因复吸行为的分子生物机制，为预防复吸和戒毒治疗的新药开发提供了新的思路。

miR-134是脑组织特异性表达的microRNA，广泛表达在神经元突起、小胶质细胞和星形胶质细胞中，对神经系统的发育、成熟、结构和功能的可塑性起到重要的调控作用。在癫痫、抑郁、退行性神经系统疾病中，miR-134也发挥着重要的调控作用。盐酸可卡因是临床麻醉用药，也是常滥用的毒品之一。可卡因滥用的高复吸率是戒毒治疗的难点和重点。其中，戒断期的异常情绪往往是造成复吸的主要病理行为基础。我们研究发现：（1）在可卡因戒断期，miR-134水平呈腹侧海马区（Ventral Hippocampus，vHP）特异性升高；（2）敲低vHP区miR-134水平可以改善动物在可卡因戒断期的焦虑与抑郁行为；（3）miR-134通过调控vHP区的突触数目、树突棘密度、微环境参与可卡因戒断期异常行为的形成；（4）15个神经发育与可塑性密切相关的靶点因子与miR-134 对可卡因戒断的调控具有相关性；（5）SIRT1/miR-134/CREB/BDNF通路参与可卡因戒断行为的调控。这些结果为揭示戒断与复吸的表观遗传机制提供了依据，也为戒毒新药开发提供了新靶标。. 该项目相关研究成果发表SCI科研论文5篇，科学专著1部，在投SCI论文2篇；培养青年教师1名，硕士研究生2名，本科生2名。