Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34126, South Korea.
Department of Bio-Health Technology, College of Biomedicine Science, Kangwon National University, Chuncheon 24341, South Korea; Multidimensional Genomics Research Center, Kangwon National University, Chuncheon 24341, South Korea.
Cell Rep. 2024 Sep 24;43(9):114659. doi: 10.1016/j.celrep.2024.114659. Epub 2024 Aug 24.
Empathy, crucial for social interaction, is impaired across various neuropsychiatric conditions. However, the genetic and neural underpinnings of empathy variability remain elusive. By combining forward genetic mapping with transcriptome analysis, we discover that aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) is a key driver modulating observational fear, a basic form of affective empathy. Disrupted ARNT2 expression in the anterior cingulate cortex (ACC) reduces affect sharing in mice. Specifically, selective ARNT2 ablation in somatostatin (SST)-expressing interneurons leads to decreased pyramidal cell excitability, increased spontaneous firing, aberrant Ca dynamics, and disrupted theta oscillations in the ACC, resulting in reduced vicarious freezing. We further demonstrate that ARNT2-expressing SST interneurons govern affective state discrimination, uncovering a potential mechanism by which ARNT2 polymorphisms associate with emotion recognition in humans. Our findings advance our understanding of the molecular mechanism controlling empathic capacity and highlight the neural substrates underlying social affective dysfunctions in psychiatric disorders.
同理心对于社会互动至关重要，但在各种神经精神疾病中都受到损害。然而，同理心变异性的遗传和神经基础仍然难以捉摸。通过将正向遗传作图与转录组分析相结合，我们发现芳香烃受体核转位蛋白 2（ARNT2）是调节观察性恐惧（一种基本形式的情感同理心）的关键驱动因素。前扣带皮层（ACC）中 ARNT2 表达的中断会减少小鼠的情感共享。具体而言，选择性 ARNT2 消融在表达生长抑素（SST）的中间神经元中导致锥体神经元兴奋性降低、自发放电增加、钙动力学异常和 ACC 中的θ振荡中断，导致替代性冻结减少。我们进一步证明，表达 ARNT2 的 SST 中间神经元控制情感状态的区分，揭示了 ARNT2 多态性与人类情绪识别相关的潜在机制。我们的研究结果增进了我们对控制同理心能力的分子机制的理解，并强调了神经基础在精神障碍中的社交情感功能障碍中的作用。
