Environmental context modulates sociability in ube3a zebrafish mutants via alterations in sensory pathways

Individuals with autism spectrum disorder (ASD) have a greater prevalence of deficits in social interactions and repetitive behaviours, which are influenced by hereditary and environmental factors. How environmental factors influence genetically predisposed individuals remains unknown. Here, we provide new evidence of the interplay between social behaviour and environmental influences, by manipulating perceived safety and threat levels in ube3a mutant zebrafish, a mutation that is linked to Angelman syndrome and ASD. Mutant fish demonstrated abnormal social behaviour in an aversive custom-made Styrofoam container, whereas these abnormalities ameliorated in a preferred Plexiglass setting. Our findings were further supported by elevated anxiety levels in the mutants when they performed conventional anxiety-related tests, such as the light‒dark test (LDT) and the novel tank diving test (NTT). Additionally, neural activity mapping using c-Fos in situ hybridization revealed differences in activation patterns in the brains of the mutants. Importantly, we performed an overrepresentation analysis (ORA) using RNA sequencing data from ube3a mutants and integrating datasets from human diseases. We identified the upregulation of vision- and comorbidity-related genes in ube3a mutants and alterations in sensory pathways, highlighting that abnormal processing of visual information is the cause of increased anxiety levels, resulting in decreased social interaction in a stressful Styrofoam environment. Our findings underscore the crucial impact of environmental factors on social behaviour and indicate that therapeutic options for ASD that focus on adjusting environmental contexts to modify perceived stimuli may ameliorate ASD-like behaviours.自闭症谱系障碍（autism spectrum disorder, ASD）患者在社交互动缺陷与重复行为方面的患病率更高，此类症状受遗传与环境因素共同影响。然而，环境因素如何作用于具有遗传易感性的个体，目前仍尚不明确。本研究通过调控UBE3A突变斑马鱼的感知安全与威胁水平，为社交行为与环境影响之间的相互作用提供了新证据——该UBE3A突变与安格曼综合征（Angelman syndrome）及ASD相关。突变型斑马鱼在定制的厌恶性聚苯乙烯泡沫（Styrofoam）容器中表现出异常社交行为，而在偏好的有机玻璃（Plexiglass）环境中，此类异常行为得到改善。本研究进一步通过经典焦虑相关实验验证了上述发现：突变体在明暗箱实验（light‒dark test, LDT）与新水箱跳水实验（novel tank diving test, NTT）中均表现出焦虑水平升高。此外，利用c-Fos原位杂交（c-Fos in situ hybridization）进行的神经活动图谱分析显示，突变体大脑的激活模式存在显著差异。尤为重要的是，本研究针对UBE3A突变体的RNA测序（RNA sequencing）数据开展了富集分析（overrepresentation analysis, ORA），并整合了人类疾病相关数据集。我们发现UBE3A突变体中视觉相关基因与共病相关基因表达上调，且感觉通路存在异常改变，这表明视觉信息加工异常是焦虑水平升高的诱因，进而导致在应激性聚苯乙烯泡沫环境中社交互动减少。本研究结果强调了环境因素对社交行为的关键影响，并提示针对ASD的治疗方案可通过调整环境背景以改变感知刺激，从而改善类ASD行为。