局域性视网膜损伤所致的视路异常及功能重塑机制研究

Retinal damages occurring in eye diseases with sensory-loss are commonly regional. Multiple lines of evidence obtained from functional magnetic resonance imaging and electrophysiological studies suggest that, following regional retinal damages, visual functional abnormalities could be ameliorated via functional unaffected areas of the visual field due to remodeling of the visual cortex. It remains unclear whether cortical reorganization alone accounts for such functional remodeling of visual centers, nor has it been demonstrated whether functional remodeling also occurs in the retina and retinal remodeling may be a key driving factor of central remodeling. In this project with a working hypothesis that ‘functional remodeling of visual centers is based on the remodeling at the retina level’, using multi-disciplinary approaches, we will first work on rats, exploring morphological and functional changes/remodeling in both retina and visual centers, which are thought to be common and fundamental for understanding functional compensation following regional retinal damages. The study will then be extended to primates, which are closely similar to human beings in architecture of the visual pathway, investigating how unaffected retinal and cortical regions are remodeled following central vision impairment, a special and more clinically-oriented issue, and exploring how visual stimulation/training affects the functional remodeling of visual pathway. Meanwhile, we seek to elucidate visual pathway abnormalities and remodeling in human patients with central vision loss. This study will provide new insights into how retinal events could influence functional remodeling of the visual pathway after regional retinal damages, thus providing new strategies for low vision rehabilitation utilizing visual training.

感知损害性眼病的视网膜损伤常为局域性。功能磁共振及电生理研究提示，局域性损伤后，由于视皮层的功能重塑，健存视野表现出功能代偿。但视中枢的功能重塑是否完全为皮层源性、视网膜是否发生功能重塑并且是视中枢功能重塑的重要驱动因素，尚不清楚。本项目从作为视觉信号输入源的视网膜着手，以“视网膜水平发生的重塑可能是视中枢功能重塑的重要基础”作为工作假设，采用多学科技术，首先以大鼠为模型，对局域性损伤后视网膜和视中枢形态、功能变化和重塑作为关键的共性问题进行研究，进而拓展至视通路组构与人类更接近的灵长类动物，研究中心视觉受损时其它区域功能重塑这一与临床密切相关的特殊问题，探讨视觉训练对视通路形态功能重塑的影响。同时对中心视觉受损临床人群的视通路异常与重塑进行相关研究。本项目将为阐明局域性损伤后的视网膜在视通路功能重塑中的作用提供新认识，并为通过视觉训练最大程度发挥残存视功能的低视力康复治疗提供指导策略。

感知损害性眼病的视网膜损伤常为局域性，局域性视网膜损伤的患者可出现视觉认知的重建与视皮层的功能重塑。视网膜及视中枢在视通路的重塑过程中是否同时发生重塑及其机制尚不清楚；而视觉刺激或者认知训练是否可以促进重塑从而改善视功能也具有重要的临床应用价值。.课题组建立局域性视网膜光凝损伤小鼠模型，分别研究视网膜与视皮层的重塑。视网膜自感光神经节细胞在损伤早期表现为蛋白表达下降以及树突形态的萎缩；但随时间推移，蛋白表达升高、树突形态恢复，提示存在形态与功能的重塑。视皮层的研究同时观察了初级视皮层数百个神经元的方位调谐反应的重塑：损伤早期神经元的反应幅度显著下降；经过重塑反应，神经元的反应幅度显著回升，更重要的是发生重塑的神经元其最优反应方位仍保持与损毁前一致。功能磁共振研究则提示单侧视神经损伤小鼠健侧眼视觉通路主要结构较对照组出现信号减弱；双侧视神经损伤小鼠听觉系统出现跨感知觉重塑。.灵长类动物研究选取青光眼为疾病模型，研究急性眼内压升高造成不同视觉通路功能障碍的神经机制。急性眼内压升高降低了视觉皮层的视锐度反应，尤其对靠近中央区的精细视觉影响更重，提示对小细胞通路的影响较大细胞通路更严重。功能磁共振研究则进一步验证了双眼盲猕猴建立了听觉与视觉通路的跨感知觉重塑。.临床研究发现，不同于急性眼内压升高，慢性青光眼功能磁共振研究提示早期为大细胞选择性损伤。多模态磁共振发现青光眼患者大脑多个指标发生改变且与视功能有一定相关性，提示可作为一种疾病诊断及进展检测的客观有效手段。针对青光眼患者的视觉功能障碍的限制因素采取相应的认知训练，则可以有效提高患者的视功能。.本项目阐明了局域性视网膜损伤后视网膜、视中枢的结构与功能重塑机制，并为通过视觉训练提高残存视功能的低视力康复治疗提供指导策略。本项目已发表SCI论文65篇，授权专利2项，负责人获得国家级、省部级奖励各一项，培养了一批中青年科研骨干。