齿状回发育异常参与孤独症社交辨识行为障碍的神经环路机制

孤独症是一种遗传度较高的神经发育障碍。社会交往受损是其主要核心症状之一。研究提示神经环路的精细结构和脑区间的信息传递在社交行为中发挥重要作用。既往报道孤独症患者存在社交辨识记忆障碍和齿状回(DG)发育异常表型，且本项目前期研究发现孤独症易感基因缺失导致的DG发育异常可能参与小鼠模型的社交辨识缺陷，但其内在因果关系及神经环路机制尚未完全明确。本项目拟通过活动特异性激活标记、光纤记录等方法明确参与社交辨识行为的DG相关神经环路和神经元类型；利用免疫荧光染色、电生理记录等方法系统评价神经环路的突触连接、结构和功能；进一步通过化学遗传和光遗传学操控特异神经环路的活动性，观察对小鼠社交辨识行为的影响。本项目预期结果将初步揭示DG发育异常导致的相关神经环路结构和功能缺陷在孤独症社交辨识障碍中的病理基础，并有助于理解社交辨识记忆的神经环路编码和信息传递机制，为寻找孤独症等社交缺陷疾病的治疗靶点提供线索。

Autism is a neurodevelopmental disorder with high heritability. Impairment of social interaction is one of the core symptoms of autism. Researches suggested that the fine structure of neural circuits and information transmission among brain areas play important roles in social behaviors. Previous studies reported impaired social recognition and abnormal development of dentate gyrus (DG) in autistic patients. In addition, our preliminary work showed that the abnormality of DG development might be involved in social recognition deficit of autistic susceptibility gene knockout mice models. However, the causal relationship and underlying neural circuitry mechanism remain unclear. In this study, the roles of DG related neural circuits in social recognition behavior will be investigated using activity-dependent labeling and optical fiber recording. The synaptic connection, structure and function in neural circuits will be systematically assessed using immunofluorescence staining and electrophysiological recording. The effects of neural circuits’ activation/inhibition on social recognition behavior will be explored using chemogenetics and optogenetics. This study will reveal pathological mechanism of social recognition deficit including the structural and functional defects of neural circuits due to the abnormal DG development in autism. In addition, it will be helpful to understand the neural circuitry mechanism and information transmission of social recognition memory, and provide clues for investigating the therapeutic targets of social defect disorders including autism.