催产素调节社会行为的上游机制以及催产素治疗自闭症样异常社会行为的作用

The normal and complete social behavior ability is the basic condition to ensure that the group members communicate and cooperate mutually, maintain the group life jointly. Abnormal social behavior is an important factor of threatening human health, and also is the characteristic of some psychiatric disorders (such as autism). Oxytocin is confirmed to promote social behavior, but whether oxytocin neurons are activated in social behavior and the neural mechanisms are still unknown. Amygdala is a crucial part of the neural loop for regulation of social behavior. Applicant previous study found that the medial amygdala was related to autistic-like abnormal social behavior and the activation of oxytocin neurons. In this study, the medial amygdala is taken as the critical research target and excitotoxin target point-injected is used to achieve the medial amygdala lesions. On this platform, tissue biochemical methods are used, combining a series of behavioral tests, to explore the associated function and mechanism between the medial amygdala and oxytocin in regulating social behavior, in order to explore the neural mechanism of social behavior. At the same time, this study will also use this platform to explore the recovery effects of exogenous oxytocin on autistic-like abnormal social behavior, in order to provide the positive and necessary data to research the new drug for the treatment of the autistic-like abnormal social behavior.

正常完整的社会行为能力是保证群体成员相互沟通与合作，共同维持群体生活的基本条件，社会行为异常是威胁人类健康的重要因素，也是一些精神类疾病（如自闭症）的显著特征。催产素被证实促进社会行为，但是在社会行为中是否催产素神经元被激活、通过怎样的神经机制被激活仍未知。脑杏仁体核是调节社会行为神经环路中的重要组成部分,申请者前期研究发现杏仁体内侧核与自闭症样异常社会行为以及催产素神经元的激活有关。本课题以杏仁体内侧核作为关键性的研究目标，利用兴奋性毒素微量靶点注射实现局限性杏仁体内侧核损伤，在此平台上运用组织生化等方法并结合行为学测试，探究杏仁体内侧核与催产素在调节社会行为中的关联作用与机制，为探索社会行为的神经调节机制寻找依据。同时本课题还将利用此平台探讨外源性催产素对异常社会行为的恢复作用，为研究或开发治疗自闭症样异常社会行为的新药提供积极必要的基础学数据。

有研究表明，催产素 (Oxytocin, OXT) 可作为一种抗焦虑的药物治疗自闭症 (Autism spectrum disorder, ASD)患者的社会行为，但其相关通路及作用机制的研究尚未明确。本研究采用N-甲基-D-天冬氨酸 (N-methyl-D-aspartate, NMDA) 杏仁体内侧核注射建立模型，结果证实催产素对该模型小鼠具有保护作用。我们的结果表明杏仁体内侧核损毁表现出明显的社会行为的缺失包括学习和记忆能力，而愤怒和焦虑情绪则有所增加。此外，我们的研究观察到催产素在NMDA受体损伤模型小鼠中表达降低，而提高NMDA受体损伤模型小鼠下丘脑内OXT水平可有效抑制ERK信号通路，其作用效果与ERK通路的抑制剂U0126相似。另外，催产素能够上调下游蛋白ProSAP1/SHANK2的表达，下调Creb及c-fos的表达，同时对神经元有一定的保护作用。我们的数据揭示了催产素在调节自闭症样小鼠的社会行为方面具有重要的作用。综上所述，本研究结果表明OXT可有效改善ASD症状，其作用与ERK通路的抑制相关。本研究为ASD的诊断、预防及治疗提供了新思路。