Automated analyses of behavior in response to visual stimuli

 视力障碍影响全球2.85亿人：3900万人失明，2.46亿人视力低下。目前迫切需要新的治疗方法，一些证据表明，通过再生光感受器和神经连接来恢复视力是可能的。美国国立卫生研究院国家眼科研究所的大胆目标突出了对这种再生过程的兴趣，即“再生眼睛和视觉系统中的神经元和神经连接”。然而，随着新方法的发展，一个关键的问题需要解决：我们如何在体内监测功能的成功？在动物模型系统中监测功能成功的一种有效方法是行为分析，因为行为分析可以揭示细微的功能缺陷，即使视觉系统根据形态学标准看起来正常。目前的项目集中在对视觉刺激的反应行为的自动分析，使用斑马鱼幼虫作为模型系统。斑马鱼幼体非常适合此类研究，因为高通量行为分析可以与遗传学，高分辨率成像和实验操作相结合。该项目的长期目标是通过对视觉刺激反应行为的深入了解，为预防和治疗视觉缺陷做出贡献。该项目的总体假设是，斑马鱼行为的自动分析是一种有效和敏感的方法来识别特定的视觉缺陷，并监测从这些缺陷的恢复。这一假设将在三个具体目标中得到检验。第一个目的是进一步提高斑马鱼幼虫行为的自动化分析响应视觉刺激，使用定制的成像系统。将开发新的算法和分析，并在不同的发育阶段检查对视觉刺激的行为反应。第二个目标是识别视觉系统中特定缺陷引起的行为特征变化。我们将分析具有影响视柄、光感受器、视网膜色素上皮、玻璃体脉管系统和透镜发育的基因突变的幼虫的行为。第三个目标是确定行为特征， 从视觉缺陷中恢复。斑马鱼具有显著的视觉系统再生能力，对视觉刺激的行为反应构成了视觉功能恢复的体内监测器。该项目还将研究小分子是否可以刺激功能恢复，这些小分子已经成功地刺激了其他系统的再生。这项工作的预期成果包括对视觉刺激影响的行为有更好的基本了解，以及评估失明和低视力治疗的高通量工具。开发的工具可用于未来的研究，以筛选导致视觉缺陷的广泛遗传和环境因素，并筛选小分子文库用于失明和低视力的新治疗。

 DESCRIPTION (provided by applicant): Visual impairments affect 285 million people worldwide: 39 million people are blind and 246 million people have low vision. Novel treatments are urgently needed and several lines of evidence suggest that it may be possible to restore vision by regenerating photoreceptors and neural connections. The interest in such regenerative processes is highlighted by the audacious goal of the National Eye Institute at the NIH to `regenerate neurons and neural connections in the eye and visual system'. However, as novel methodologies are developed, a critical question will need to be addressed: how do we monitor in vivo for functional success? An effective approach to monitor for functional success in animal model systems is the analysis of behavior, since behavioral analyses can reveal subtle functional defects, even if the visual system appears normal by morphological criteria. The current project is focused on the automated analysis of behavior in response to visual stimuli, using zebrafish larvae as a model system. Zebrafish larvae are ideally suited for such studies, since high-throughput analyses of behavior can be combined with genetics, high-resolution imaging and experimental manipulations. The long-term goal of the project is to contribute to the prevention and treatment of visual defects, through an in-depth understanding of behavior in response to visual stimuli. The project is guided by the overall hypothesis that the automated analysis of zebrafish behavior is an effective and sensitive approach to identify specific visual defects and monitor the recovery from such defects. This hypothesis will be tested in three specific aims. The first aim is to further improve the automated analysis of zebrafish larval behavior in response to visual stimuli, using a custom-built imaging system. Novel algorithms and assays will be developed and the behavioral responses to visual stimuli will be examined at different developmental stages. The second aim is to identify changes in behavioral profiles caused by specific defects in the visual system. We will analyze behavior in larvae with genetic mutations that affect development of the optic stalk, photoreceptors, retinal pigment epithelium, hyaloid vasculature and the lens. The third aim is to identify behavioral profiles which indicate a recovery from visual defects. Zebrafish have a remarkable capacity for regeneration of the visual system and the behavioral responses to visual stimuli constitute an in vivo monitor for the recovery of visual function. The project will also examine if functional recoveries can be stimulated by small molecules, which have been successful in stimulating regeneration in other systems. The expected outcome from this work includes a better basic understanding of behaviors that are influenced by visual stimuli and high-throughput tools to evaluate treatments of blindness and low vision. The developed tools may be used in future research to screen for a broad range of genetic and environmental factors that cause visual defects and to screen small molecule libraries for novel treatments of blindness and low vision.