自闭症症状相关的 “皮层–基底神经节–丘脑–皮层”环路功能失常

Deficits in social interaction and restricted behavior are the core symptoms in autistic spectrum disorder (ASD) patients. Aberrant activation of dorsal lateral prefrontal cortex (dlPFC) is implicated in ASD. As a crucial part in basal ganglia, striatum plays a central role in core ASD phenomenology. However, it is unknown at the relationship between ASD symptoms and abnormal of the neural circuitry including dlPFC and striatum. The basal ganglia are comprised of GABAergic medium spiny neurons of the direct and indirect projections. Activation of the neurons expressing D1 dopamine receptor (D1DR, direct pathway) and D2 dopamine receptor (D2DR, indirect pathway) in striatum respectively disinhibit and inhibit the cortical activity through cortico-basal ganglia-thalamus-cortical loop. Our previous data showed that inactivation of D1DR expressing neurons in striatum led to behavioral inflexibility while inactivation of D2DR expressing neurons impaired social interaction. And then, upregulating the excitation of mPFC neurons also induced the impairment in social interaction. These previous findings suggest that direct and indirect pathway may respectively modulate the behavioral flexibility and social behaviors. Thus, we hypothesized that abnormal of cortico-basal ganglia-thalamus-cortical loop resulted from pathologic basal ganglia microcircuit may be underlying core ASD phenomenology. In this study, based on the valproic acid (VPA)-induced autistic mice model, we will use optogenetic, in vivo Ca2+ imaging and electrophysiological approaches, combined with plasmid construction and viral infection methods, 1) to selectively observe and modulate direct and indirect pathways functioning in ASD-like mice; 2) to clarify abnormal condition of mPFC-basal ganlia-thalamus-mPFC associated to social disability and behavioral inflexibility in ASD; 3) to provide preclinical support for rescuing the ASD behaviors by functional modulation in this brain loop.

社交能力缺失和行为灵活性下降是自闭症的两大核心症状。人类研究显示，前额叶皮层状态和任务依赖的活动性异常参与自闭症的发生；纹状体作为基底神经节的重要组成部分也是调控自闭症症状的关键脑区。然而，与前额叶皮层及纹状体相关联的脑环路的功能状态与自闭症之间的相关性研究是缺乏的。本实验室前期动物研究结果提示，基底神经节的直接通路和间接通路分别参与调控行为灵活性和社交行为。因此，我们推测，基底神经节内部微环路病变导致的“皮层–基底神经节–丘脑–皮层”环路功能失常是自闭症发生的神经基础。本研究将以丙戊酸诱导的小鼠自闭症模型为基础，应用电生理、光遗传学、以及活体动物钙成像等神经生物学方法，结合质粒构建、病毒转染等分子生物学技术，选择性地观察和调控基底神经节微环路，阐明与社会交往和行为策略转换障碍相关的“皮层–基底神经节–丘脑–皮层”环路的异常活动状态。对于该脑环路功能的调控可能成为矫正自闭行为的新方法。

行为灵活性缺失和社交障碍是自闭症的两大核心症状。然而，其背后的神经病理机制仍然未知。我们提出，以纹状体为核心的皮层-基底神经节-丘脑环路可能是行为灵活性的调节中枢，而海马可能在社交信息的处理中发挥重要作用。首先，我们利用特定区域神经损毁技术明确了背内侧纹状体的多巴胺1型受体表达（dopamine 1 receptor, D1R）和2型受体表达（dopamine 2 receptor, D2R）神经元在反转学习任务中发挥相反的调控作用；之后，采用光遗传学、免疫荧光组织化学和钙离子成像等实验方法，我们证明了背内侧纹状体的尾侧部的D1R受体表达神经元构成的神经环路在行为灵活性调节中具有重要作用，并且自闭症模型小鼠（Fmr1-knockout, Fmr1-KO）的行为灵活性缺失主要由于对于奖赏缺失信号的反馈失败所致；关于社交障碍的探索，我们发现海马的小清蛋白（parvalbumin, Pv）阳性中间神经元发挥着社交新旧个体“辨识器”样的作用，它的功能正常是动物进行社交信号处理的关键，自闭症动物存在着这类神经元的功能异常。整个项目按照计划执行并完成。相关研究结果已经发表5篇SCI论文，包括PNAS、Brain Structure and Function和Physiology and Behavior等杂志。依托此项目的执行，培养博士和硕士研究生4名，职称提聘2人。我们的研究结果能够为自闭症的干预提供明确的神经区域和环路靶点。