伏隔核环状RNAcircPik3c2a靶向调控miR-206/BDNF参与药物奖赏性记忆再巩固过程的机制研究

Drug addiction is a serious public health and social problem. The persistence of drug rewarding memories is an important reason of relapse. Because of the reconsolidation process of drug rewarding memories is an essential stage of relapse prevention and treatment, the intervention of related proteins expression in this stage could inhibit drug addiction and relapse. Our previous study found that circPik3c2a (ceRNA) in the nucleus accumbens may play a role in the process of drug rewarding memories reconsolidation, but the molecular mechanism is not yet clear. In this project, we establish conditioned place preference model and self-administration model and apply multiple transcriptional techniques, bioinformatics, and gene regulation methods in order to: 1) clarify the network regulation mechanism of circPik3c2a-miR-206-BDNF; 2) explore the role of ceRNA regulatory network in the process of drug rewarding memories reconsolidation; 3) investigate the effect of ceRNA network on synaptic plasticity in the nucleus accumbens. In a word, the development of the current project not only provides new ideas for the pathogenesis of drug addiction and relapse, but also provides experimental evidence for developing drug addiction treatment targets and relapse intervention measures.

药物成瘾是严重的公共卫生和社会问题，药物奖赏性记忆的持续存在是导致成瘾者复吸的重要原因。药物奖赏性记忆再巩固过程是复吸防治的重要窗口，对此阶段相关蛋白表达变化进行干预可改变或消除原有药物奖赏性记忆。课题组前期研究发现伏隔核中环状RNAcircPik3c2a可能作为ceRNA参与药物奖赏性记忆的再巩固过程，但其机制尚未明确。本项目通过条件性位置偏爱和自身给药模型，运用转录组学、生物信息学技术及基因调控手段，旨在：1）明确circPik3c2a-miR-206-BDNF三者ceRNA网络调控机制；2）阐明伏隔核中该ceRNA网络在药物奖赏性记忆再巩固过程中的作用；3）探讨该ceRNA网络对伏隔核突触可塑性的影响。项目的开展不仅为药物成瘾及复吸的发病机制研究提供新思路，也为开发药物成瘾治疗靶点和复吸干预措施提供实验依据。

药物成瘾是严峻的公共卫生及社会问题。药物成瘾的本质是药物奖赏性记忆，其分子机制至今未明。破坏药物奖赏性记忆再巩固过程中相关蛋白的表达变化能抑制药物成瘾及复吸。本研究以药物奖赏性记忆再巩固过程为切入点，通过建立可卡因成瘾记忆再巩固模型，综合运用多种转录组学技术、生物信息学、行为学等方法，旨在：明确circTmeff1-miR-206-BDNF三者ceRNA网络调控机制；阐明伏隔核中circTmeff1-miR-206-BDNF调控网络在药物奖赏性记忆再巩固过程中的作用；探讨circTmeff1-miR-206-BDNF调控网络对伏隔核突触可塑性的影响。研究结果发现可卡因成瘾记忆再巩固过程中伏隔核circTmeff-1的表达升高，这种升高主要发生于伏隔核核部。可卡因成瘾记忆再巩固过程中circTmeff-1的表达具有时空特异性。非条件性刺激唤起记忆再巩固时间窗内敲减伏隔核核部circTmeff-1表达能够破坏再巩固过程，进而影响成瘾记忆的保留。此外，circTmeff-1作为miR-206的分子海绵，可以通过降低 miR-206对BDNF mRNA的抑制作用，从而影响BDNF蛋白合成，进而调控可卡因成瘾记忆的再巩固过程。本项目的开展不仅为药物成瘾及复吸的发病机制研究提供新思路，也为开发药物成瘾治疗靶点和复吸干预措施提供实验依据。