前扣带回皮质-背内侧纹状体通路在Shank3孤独症小鼠社交行为障碍的作用机制研究

孤独谱系障碍（ASDs）是一类以社交障碍得名的神经发育性疾病，缺乏有效治疗方法，患者融入社会困难。我们新近证实前扣带回皮层（ACC）功能低下是Shank3敲除ASD小鼠社交障碍的关键机制，提示ACC在社交信息整合的重要作用。但社交行为需要多个阶段不同脑区的协同，而ASDs中ACC导致社交异常的详细环路机制尚不明确。我们预实验发现，ACC和背内侧纹状体（DMS）直接和间接通路形成单突触联系，并参与社交行为。DMS依赖直接通路和间接通路平衡调控多个社交相关认知过程，由此我们推测，ASDs中，ACC-DMS直接通路和间接通路失衡，影响社交决策及执行。本项目拟以Shank3敲除小鼠为模型，利用病毒标记、光遗传、钙成像、电生理等技术和Cre工具鼠，结合不同社交行为范式，解析ACC-DMS通路在社交调控的作用，研究其在ASDs社交障碍不同阶段的作用特征及内在突触分子机制，为ASDs诊疗策略提供新思路。

As a group of neurodevelopmental disorders, autism spectrum disorders (ASDs) are named after social communication/interaction deficits. Due to the lack of effective treatments for social communication/interaction deficits, ASDs patients have difficulty integrating into society and need life-long support services and long-term care, which increases the burden on families and society. Therefore, further research is needed to understand the mechanisms of the neural circuits’ alterations underlying social communication/interaction deficits in ASDs. Recently, we found that Shank3 knock-out (KO) mice — an ASDs mouse model caused by single gene mutation, showed a loss of dendritic spines and impairments in AMPAR-mediated excitatory synaptic transmission and plasticity in ACC (anterior cingulate cortex) pyramidal neurons. By applying optogenetics, chemogenetics and other approaches, we provide direct evidence that ACC has a significant role in the regulation of social behavior in mice. This indicates that ACC dysfunction may be involved in social impairments in ASDs. However, social behavior is complex and involves multiple stages and different brain regions. The circuit mechanisms for ACC to perform social regulation in ASDs are still unclear. Our preliminary data suggested that ACC sent glutamatergic projection to the principal neurons in the dorsal medial striatum (DMS) direct pathway and indirect pathway. DMS is the main input structure of basal ganglion. The balance between direct pathway and indirect pathway of DMS is important to locomotor regulation and learning. Interestingly, growing evidence suggests that both ACC and DMS are involved in complex cognitive processes, including goal-directed action, decision making, and behavioral flexibility. These processes are not only essential for the motor-related function but also social behavioral information process. Accordingly, we hypothesize that ACC may send integrated social information to DMS to regulate social decision-making and execution in normal state and this pathway may show imbalance deficits in ASDs. We will focus on dissecting the exact roles of ACC-DMS pathway in social behavior dysfunction with diversified social behavior paradigms. Specifically, we will observe or modulate ACC-DMS D1 and D2 MSNs (medium-sized spiny neurons) in Shank3 KO mice by using calcium imaging and optogentics method combined with transgenic mice such as D1-Cre and D2-Cre mice. Based on these in vivo data, we then are focusing on the excitatory synaptic function and structure of the ACC-DMS pathway by using D1-Tdtomato, D2-GFP mouse line, and virus labeling optogenetics. From that, we can demonstrate a working flow of the ACC-DMS pathway modulating social behavior and help to find a potential target for the diagnosis and therapies of social communication/ interaction deficit of ASDs.