药物成瘾相关记忆的神经环路和分子基础

Drug addiction is a chronically relapsing neurobiological disorder. The drug related environmental cues, negative emotional cues and low dose of drugs can induce drug seeking and reinstatement. The long-term memory for drug reward and obsessive-compulsive craving are the complex key reasons for drug relapse, but the underlying neurocircuits and molecular mechanisms of addition memory storage and retrieval are unclear. Based on our previouse research findings, combined optogenetics and microinjection of AAV expressing Cre-loxp, the drug addiction mouse models are used in this project with Cre transgenetic mice to systemic investigate the individual roles of dopaminergic and glutamatergic neuronal projections in certain neurocircuits in environmental cue and negative emotional cue induced relapse and try to find out the possible addiction memory storage and retrieval dependent mechanisms. Meanwhile with the manipulation of the ensemble memory trace marked with addiction memory by optogenetics, we try to define the specific memory traces involved in memory storage and retrieval. The GRK and arrestin knockout mice are also introduced in our study to investigate their roles in addiction long-term memory storage. The expected results will be helpful for the understanding of the neurocircuits and molecular mechanisms of addiction memory, then provide the indications for the possible clinical interventions to reduce drug relapse.

药物成瘾是一种慢性、复发性脑疾病，药物相关环境线索、应激等负性情绪以及小剂量药物均可诱发复吸，成瘾相关记忆的长期存在和对药物的持续渴求是导致复吸的关键原因，但是成瘾相关记忆长期储存及提取的神经环路及分子机制还不清楚。本项目将在我们长期工作的良好基础上，运用Cre转基因小鼠，结合光遗传学技术和Cre-loxp病毒表达系统，研究成瘾相关脑区的多巴胺能和谷氨酸能神经投射在药物相关环境线索和应激诱发复吸中的作用，探讨成瘾记忆储存及提取的环路和途径。同时通过特异性地标记诱发药物复吸时被激活的神经元组合，通过光遗传学的方法操控这些神经元组合，研究其在成瘾记忆储存及提取中的作用及机制。我们将利用GRK和arrestin基因敲除小鼠，探讨GRK和arrestin在成瘾记忆长期储存中的可能作用和机制。本研究将增进对药物成瘾相关记忆的神经环路和分子基础的理解，为药物戒断后复吸的防治提供理论依据和干预新思路。

药物成瘾是一种慢性、复发性脑疾病，药物相关环境线索、应激等负性情绪以及小剂量药物均可诱发复吸，成瘾相关记忆的长期存在和对药物的持续渴求是导致复吸的关键原因，但是其具体的神经环路及分子调控机制还不清楚。本项目运用Cre转基因小鼠，成瘾行为学，结合光遗传学技术和Cre-loxp病毒表达系统，揭示了NAc GABA 能神经元抑制腹侧苍白球（VP）脑区细胞活性，且负性调控可卡因环境相关线索诱发的动机行为表达（Wang et al; Int J Neuropsychopharmacol, 2014）；发现了中央杏仁核（CeA）的PV中间神经元介导了吗啡撤退引起的负性情感及CeA 脑区CRH mRNA的上调（Wang et al., Int J Neuropsychopharmacol, 2016）。并通过即早基因c-fos， Arc的免疫组化标记，及海洛因处理前后的microarray结合成瘾数据库的生物信息学分析揭示了成瘾过程中的脑区活性和基因转录调控网络变化（Wang et al., Acta Physiologica Sinica, 2014）。并在原有的工作基础上发现了G蛋白偶联信号通路相关分子β-arrestin在成瘾记忆维持（Liu et al., Proc Natl Acad Sci U S A, 2015）及神经再生（Tao et al., Sci Rep, 2015）中的功能和新的调控机制，以及背外侧杏仁核（BLA）中细胞骨架调控蛋白Rac1（Gao et al., Front Mol Neurosci, 2015），和中脑边缘系统中的自然奖赏调控因子LepR（Shen et al., Translational Psychiatry, 2016）对负性和奖赏记忆形成及表达的调控及作用机制。期间在PNAS等刊物上共发表SCI论文8篇，我们的结果揭示了成瘾的神经生物学机制，并为干预成瘾性药物的复吸提供理论依据。