Defects and asymmetries in the visual pathway of non-human primates with natural strabismus and amblyopia

Strabismus and amblyopia are common ophthalmologic developmental diseases caused by abnormal visual experiences. However, the underlying pathogenesis and visual defects are still not fully understood. Most studies have used experimental interference to establish disease-associated animal models, while ignoring the natural pathophysiological mechanisms. This study was designed to investigate whether natural strabismus and amblyopia are associated with abnormal neurological defects. We screened one natural strabismic monkey ( Macaca fascicularis) and one natural amblyopic monkey from hundreds of monkeys, and retrospectively analyzed one human strabismus case. Neuroimaging, behavioral, neurophysiological, neurostructural, and genovariation features were systematically evaluated using magnetic resonance imaging (MRI), behavioral tasks, flash visual evoked potentials (FVEP), electroretinogram (ERG), optical coherence tomography (OCT), and whole-genome sequencing (WGS), respectively. Results showed that the strabismic patient and natural strabismic and amblyopic monkeys exhibited similar abnormal asymmetries in brain structure, i.e., ipsilateral impaired right hemisphere. Visual behavior, visual function, retinal structure, and fundus of the monkeys were impaired. Aberrant asymmetry in binocular visual function and structure between the strabismic and amblyopic monkeys was closely related, with greater impairment of the left visual pathway. Several similar known mutant genes for strabismus and amblyopia were also identified. In conclusion, natural strabismus and amblyopia are accompanied by abnormal asymmetries of the visual system, especially visual neurophysiological and neurostructural defects. Our results suggest that future therapeutic and mechanistic studies should consider defects and asymmetries throughout the entire visual system.斜视和弱视是由异常视觉体验引起的常见眼科发育性疾病。然而，其潜在的发病机制与视觉缺陷仍未完全发现。既往绝大多数研究集中于利用实验干扰而建立的疾病动物模型，却忽略了疾病的天然病理生理机制。该研究旨在全面系统地探讨天然斜视和弱视是否与神经功能的异常缺损相关。我们从数百只食蟹猴中大规模筛选出一只天然斜视和一只天然弱视食蟹猴，并对一例临床特征相似的人类斜视病例进行回顾性分析。接着，采取磁共振成像、行为任务、闪光视觉诱发电位、视网膜电图、光学相干断层扫描和全基因组测序方法，分别系统地评估其神经成像、视觉行为、神经电生理、神经结构和基因变异的特征变化。我们的研究结果显示，斜视患者、天然斜视食蟹猴与天然弱视食蟹猴均表现出相似的异常不对称的大脑结构，即均为右半球脑部受损。天然斜视与弱视食蟹猴的视觉行为、视觉功能、视网膜结构和眼底结构均受损。斜视与弱视食蟹猴在双眼视觉功能和结构的异常不对称性方面，呈现显著的相关，表明两者左侧视觉通路均受损更严重。此外，一些与斜视和弱视疾病相关且相似的已知突变基因也被成功地辨别。综上所述，天然斜视和弱视均伴随着视觉系统的异常不对称，尤其是视觉神经电生理和神经结构的缺陷。因此，我们的数据表明，未来的治疗和机制研究均应考虑整个视觉系统的缺陷和不对称性。.