Zebrafish studies reel in answers on how humans see during daytime

Many daily tasks are dependent on the ability of the eye to adapt to changes in light. Cone photoreceptors in the retina play a key role in enabling vision over a wide range of light intensities. Currently, the process that enables cone vision in bright or well-lit environments, also known as photopic vision, is poorly understood.

A team of researchers at University College Dublin (UCD), led Prof Breandán Kennedy, has dedicated significant efforts to understanding how the visual cycle works inside retinal cells.

The outcomes of their studies, recently published in the Journal of Biological Chemistry, have provided further insight into the different mechanisms within cone cells that are responsible for enabling vision in bright light.

This research team used a zebrafish – a small tropical fish – as their eyes are very similar to humans. Specifically, they used a strain of zebrafish that has been shown to rely exclusively on cones for their vision. They then blocked the function of some proteins known to play a role in the visual cycle.

For example, they blocked the function of RPE65 in zebrafish using Emixustat, a drug currently in phase 3 clinical trials for use in Stargardt disease. Within the retina, RPE65 has an important job in switching ‘inactive’ dietary vitamin A to ‘active’ light sensitive vitamin A.

The zebrafish were then placed in the dark for a period of time and their responses measured immediately following exposure to light, 30 minutes after light adaptation and 4-6 hours after light adaptation. This enabled the scientists to understand what is regulating immediate, early or late phases of cone phototopic vision.

The study found that when RPE65 is blocked, zebrafish had poorer vision when exposed to light immediately after a period in the dark.

Rebecca Ward, a PhD student on this study explains, “This means that when we are in darkness and move to a well-lit environment, RPE65 protein is important for our eyes to adapt to these changing levels of light. However, when zebrafish were exposed to light for 30 minutes or longer, they had full visual responses, whether or not RPE65 was blocked.”

Professor Breandán Kennedy who led this research consortium said, “A puzzle for vision researchers is to understand how cone photoreceptors continuously recharge with light-sensitive vitamin A during daylight conditions. Surprisingly, we discovered that if the zebrafish with impaired vision due to emixustat treatment, were exposed to light for 30 minutes or longer, they regained full vision. This indicates that RPE65 is required at night to provide light-sensitive vitamin A for vision in the morning. But, during the day, RPE65 is not required, and the eye uses light to regenerate the light-sensitive vitamin A – a clever, efficient solution.”

Through the incorporation of strong public and patient involvement in research, this is a motivating example of how the priorities and lived experience of those affected by visual impairment can complement the scientific expertise and demonstrates the essential integration of all perspectives to yield more relevant and impactful research.

By knowing how vision works, it becomes much easier for us to fix, and in our case to develop treatments that will prevent or restore vision.

This full research study has now been published in the Journal of Biological Chemistry.

Meet Prof Breandan Kennedy and Rebecca Ward and learn more about what attracted them to retinal research.