mPFC-NAc谷氨酸能神经投射在酒精性认知障碍中的作用机制研究

长期酗酒导致的认知障碍是酒精成瘾临床治疗维持性差、复发率高的重要原因。mPFC是介导酒精成瘾认知障碍的关键脑区，然而目前仍不清楚mPFC调控酒精成瘾认知损害的具体机制。课题组前期研究发现，慢性酒精暴露会导致mPFC→NAc谷氨酸能神经环路结构和功能异常，但该环路在酒精成瘾小鼠认知障碍中的具体作用尚不明确，其神经可塑性调控机制亦不清楚。我们提出科学假设：酒精成瘾使mPFC→NAc神经环路谷氨酸能信号产生适应性变化，神经元可塑性改变，继而导致注意力下降、冲动性增加等认知障碍，最终复发饮酒行为。本项目采用5-项选择连续反应时间任务评估酒精成瘾小鼠各方面认知功能障碍；电生理明确mPFC激活的神经元类型，阐明mPFC→NAc神经环路的突触可塑性机制；通过光遗传和深部脑刺激干预该环路功能，评估注意力、冲动性及工作记忆等认知改善情况，为长期酗酒引起认知障碍提供新理论依据，为治疗酒精成瘾复发提供潜在靶点。

Cognitive impairment caused by long-term alcohol abuse is an important reason for poor maintenance and high relapse rate of clinical treatment for alcohol addiction. mPFC is a key brain area that mediates cognitive impairment of alcohol addiction. However, the specific mechanism by which mPFC regulates cognitive impairment of alcohol addiction is still unclear. Our previous research found that chronic alcohol exposure could lead to abnormal structure and function of mPFC→NAc glutamatergic neural circuit, but the specific role of which in the cognitive impairment of alcohol addiction is not yet clear, as same as the neuroplasticity regulated mechanism. We propose a hypothesis: alcohol addiction causes adaptive changes in the glutamate signal of the mPFC→NAc neural circuit, which in turn leads to cognitive impairments such as decreased attention and increased impulsivity, and eventually relapses into drinking behavior. In this study, we will assess various aspects of cognitive dysfunction in alcohol-addicted mice by using the 5-item continuous response time task; detect the type of neurons activated in mPFC, and clarify the mechanism of synaptic plasticity of the mPFC→NAc neural circuit by electrophysiology; intervene in this circuit function through optogenetics and deep brain stimulation to assess cognitive improvement such as attention, impulsivity and working memory. This study will provide new theoretical basis for cognitive impairment caused by long-term alcohol abuse, and potential targets for the treatment of alcohol addiction relapse.