Animal models enable targeting autism-associated genes, such as the shank3 gene, to assess their impact on behavioural phenotypes. However, this is often limited to simple behaviours relevant for social interaction. Social contagion is a complex phenotype forming the basis of human empathic behaviour and involves attention to the behaviour of others for recognizing and sharing their emotional or affective state. Thus, it is a form of social communication, which constitutes the most common developmental impairment across autism spectrum disorders (ASD). Here we describe the development of a zebrafish model that identifies the neurocognitive mechanisms by which shank3 mutation drives deficits in social contagion. We used a CRISPR-Cas9 technique to generate mutations to the shank3a gene, a zebrafish paralogue found to present greater orthology and functional conservation relative to the human gene. Mutants were first compared to wild types during a two-phase protocol that involves the observation of two conflicting states, distress and neutral, and the later recall and discrimination of others when no longer presenting such differences. Then, the whole-brain expression of different neuroplasticity markers was compared between genotypes and their contribution to cluster-specific phenotypic variation was assessed. The shank3 mutation markedly reduced social contagion via deficits in attention contributing to difficulties in recognising affective states. Also, the mutation changed the expression of neuronal plasticity genes. However, only downregulated neuroligins clustered with shank3a expression under a combined synaptogenesis component that contributed specifically to variation in attention. While zebrafish are extremely useful in identifying the role of shank3 mutations to composite social behaviour, they are unlikely to represent the full complexity of socio-cognitive and communication deficits presented by human ASD pathology. Moreover, zebrafish cannot represent the scaling up of these deficits to higher-order empathic and prosocial phenotypes seen in humans. We demonstrate a causal link between the zebrafish orthologue of an ASD-associated gene and the attentional control of affect recognition and consequent social contagion. This models autistic affect-communication pathology in zebrafish and reveals a genetic attention-deficit mechanism, addressing the ongoing debate for such mechanisms accounting for emotion recognition difficulties in autistic individuals.

中文翻译：

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自闭症相关基因 shank3 对于斑马鱼的社会传染是必需的

动物模型能够针对自闭症相关基因（例如 shank3 基因）来评估其对行为表型的影响。然而，这通常仅限于与社交互动相关的简单行为。社会传染是一种复杂的表型，形成人类共情行为的基础，涉及对他人行为的关注，以识别和分享他们的情绪或情感状态。因此，它是一种社会交流形式，构成自闭症谱系障碍 (ASD) 中最常见的发育障碍。在这里，我们描述了斑马鱼模型的开发，该模型确定了 shank3 突变驱动社会传染缺陷的神经认知机制。我们使用 CRISPR-Cas9 技术对 shank3a 基因产生突变，一种斑马鱼旁系同源物，被发现与人类基因相比具有更大的直系同源性和功能保守性。首先在一个两阶段协议中将突变体与野生型进行比较，该协议涉及观察两种冲突状态，即痛苦状态和中性状态，以及当不再呈现这种差异时对其他状态的回忆和歧视。然后，比较基因型之间不同神经可塑性标记物的全脑表达，并评估它们对簇特异性表型变异的贡献。shank3突变通过注意力缺陷显着减少了社会传染，导致难以识别情感状态。此外，突变改变了神经元可塑性基因的表达。然而，只有在联合突触发生成分下与 shank3a 表达聚集的神经连接蛋白下调，该成分特别有助于注意力的变化。虽然斑马鱼在识别 shank3 突变对复合社会行为的作用方面非常有用，但它们不太可能代表人类 ASD 病理学所呈现的社会认知和沟通缺陷的全部复杂性。此外，斑马鱼不能代表这些缺陷扩大到人类中看到的高阶共情和亲社会表型。我们证明了自闭症谱系障碍相关基因的斑马鱼直系同源物与情感识别和随之而来的社会传染的注意力控制之间的因果关系。该模型模拟了斑马鱼的自闭症情感交流病理学，并揭示了遗传性注意力缺陷机制，