Rac1介导AMPA受体转运对可卡因成瘾伏核区沉默突触形成的调控

神经可塑性变化是可卡因成瘾的标志性事件，突触重塑是可卡因诱导中脑边缘系统神经通路发生重塑的结构基础。研究显示，可卡因可诱导伏核（nucleus accumbens，NAc）区沉默突触形成，其介导了机体运动敏化行为。我们前期研究显示，Rac1介导可卡因诱导的纹状体细长型棘突（thin spine）和突触数量的增多，而thin spine主要参与构成沉默突触，提示Rac1可能参与介导可卡因诱导的沉默突触形成。本研究拟采用大鼠自身给药可卡因成瘾模型和细胞成瘾模型，利用基因手段干扰NAc区Rac1活性，采用电生理、免疫荧光、电镜技术检测Rac1对NAc区沉默突触的形成、AMPA受体分布及功能的调控，验证Rac1介导的沉默突触形成对成瘾行为的调控，并探究下游信号机制。旨在进一步深入阐明Rac1对可卡因成瘾神经可塑性的调控作用，为运用 Rac1作为分子开关控制沉默突触形成治疗可卡因成瘾提供理论基础。

Neural plasticity is a landmark event for cocaine addiction, and synaptic remodeling is the structural basis of cocaine-induced neural pathways plasticity of the limbic system in the brain. Recent studies have shown that silent synapses in the nucleus accumbens (NAc) are involved in regulating cocaine addiction, and the silent synapses contributes to cocaine-induced locomotor sensitization. Our previous studies have shown that, Rac1 mediates cocaine-induced increasing thin spine density and synapse number in striatum, and thin spine mainly constitute the postsynaptic structure of silent synapses, which suggested that Rac1 may be involved in cocaine-induced silent synapse formation. In the present study, we will use rat self-administration model of cocaine, intraperitoneal cocaine injection, or cellular addiction model, take viral vector-mediated genetic manipulations to specific interfere the Rac1 activity in NAc, then use the electrophysiology, immunofluorescence, and electron microscope techniques to detect the influence of Rac1 activity on the formation, structure and function of silent synapses in NAc, and detect the distribution and function of AMPA receptors during the formation of silent synapse mediated by Rac1 activity, furthermore, verify the relationship between silent synapse and addictive behavior, and investigate the downstream molecular mechanism. The present research will further clarify function of Rac1 in cocaine-induced neural plasticity, and provides a theoretical foundation for the use of Rac1 as a molecular switch to control silent synapses formation in the treatment of cocaine addiction.