Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University.
Department of Cellular and Molecular Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University.
Biol Pharm Bull. 2022;45(8):1124-1132. doi: 10.1248/bpb.b22-00200.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms, including impairments in social behavior and repetitive interests. Recent studies have revealed that individuals with ASD also display decreased empathy, ultimately leading to difficulties in social relationships; however, another report indicated that individuals with ASD have enhanced emotional empathy. Nonetheless, the neurobiological mechanisms underlying altered empathy in individuals with ASD remain unclear. In this study, we assessed empathy-like behaviors in valproic acid (VPA)-treated mice-a mouse model of ASD with observational fear learning. We then investigated the brain regions and signaling systems responsible for the altered empathy-like behaviors in VPA-treated mice. As a result, mice prenatally exposed to VPA displayed increased empathy-like behaviors, which were not attributed to altered sensitivity to auditory stimuli or enhanced memory for pain-related contexts. Immunohistochemical analysis revealed that the number of c-Fos positive oxytocinergic neurons in the paraventricular nucleus of the hypothalamus (PVN) was significantly higher in VPA-treated mice after observational fear learning. Finally, we found that pretreatment with L-368899, an antagonist of the oxytocin receptor, repressed the empathetic behavior in VPA-treated mice. These results suggest that VPA-treated ASD model animals showed increased emotional empathy-like behaviors through the hyperactivation of PVN oxytocinergic neurons for the first time. Further investigation of this hyperactivity will help to identify extrinsic stimuli and the condition which are capable of activation of PVN oxytocinergic neurons and to identify novel approach to enhance oxytocin signaling, which ultimately pave the way to development of novel therapy for ASD.
自闭症谱系障碍（ASD）是一种神经发育障碍，其特征是存在核心症状，包括社交行为和重复兴趣方面的障碍。最近的研究表明，自闭症患者还表现出同理心的降低，最终导致社交关系的困难；然而，另一份报告表明，自闭症患者具有增强的情绪同理心。然而，自闭症患者同理心改变的神经生物学机制仍不清楚。在这项研究中，我们评估了丙戊酸（VPA）处理的小鼠（一种具有观察性恐惧学习的 ASD 小鼠模型）中的类同理心行为。然后，我们研究了负责 VPA 处理的小鼠类同理心行为改变的大脑区域和信号系统。结果显示，产前暴露于 VPA 的小鼠表现出增加的类同理心行为，这不是由于听觉刺激敏感性改变或与疼痛相关的上下文记忆增强所致。免疫组织化学分析显示，在观察性恐惧学习后，下丘脑室旁核（PVN）中催产素能神经元的 c-Fos 阳性细胞数量在 VPA 处理的小鼠中显著增加。最后，我们发现，催产素受体拮抗剂 L-368899 的预处理抑制了 VPA 处理的小鼠的同理心行为。这些结果表明，VPA 处理的 ASD 模型动物首次通过 PVN 催产素能神经元的过度激活表现出增强的情绪类同理心行为。进一步研究这种过度活跃将有助于确定能够激活 PVN 催产素能神经元的外在刺激和条件，并确定增强催产素信号的新方法，这最终为 ASD 的新型治疗方法的发展铺平了道路。
