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 i s 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 i s 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 i s 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.
This project is focused on the automated analysis of behavior in response to visual stimuli using zebrafish as a model system. The studies will contribute to a better basic understanding of behaviors that are influenced by visual stimuli and will provide high-throughput tools to evaluate novel treatments of blindness and low vision.
| Richendrfer, Holly; Creton, Robbert (2018) Cluster analysis profiling of behaviors in zebrafish larvae treated with antidepressants and pesticides. Neurotoxicol Teratol 69:54-62 |
| Thorn, Robert J; Clift, Danielle E; Ojo, Oladele et al. (2017) The loss and recovery of vertebrate vision examined in microplates. PLoS One 12:e0183414 |
