The contribution of inner retinal photoreception to mouse visual function

Sight is our most valued sense, and has been a perennial subject of scientific investigation over the centauries. Nonetheless, we continue to find out exciting new things about it. Among the most surprising of these has been that the rod and cone cells in the retina are not our only photoreceptors. In fact, we now know that another group of cells, called mRGCs, are capable of responding directly to light. These mRGCs work fairly well even when rods and cones are absent, and thus provide residual photosensitivity in some blind people. Until now, however, mRGCs have been thought to mainly provide input to crude 'sub conscious' responses to light, such as setting the size of the pupil in our eyes and ensuring that our internal biological clocks are set to local time. There has been little indication that they could also help us to see. We have recently shown that, in fact, signals from mRGCs appear throughout those parts of the brain responsible for visual perception. How then do mRGCs help us to see? Answering that question is the subject of this proposal. We will achieve this by providing visual stimuli capable of selectively activating mRGCs to several lines of transgenic mice. We will then be able to determine whether mice can use these stimuli to navigate a maze, and also what impact they have on the electrical activity of neurons in parts of the brain responsible for vision. Our work has the capacity to provide a new understanding of how we perceive the world. Because mRGCs survive in people with rod and cone degeneration, this information may be particularly pertinent for the blind and partially sighted.

We have recently shown that, far from being largely segregated from the primary visual pathways as previously thought, signals from mRGC photoreceptors are extraordinarily widespread across the visual thalamus and cortex. This implies a substantial contribution to pattern vision and perception, but at present the nature of this contribution is unknown. Our electrophysiological recordings from the mouse dorsal lateral geniculate nucleus (dLGN) reveal melanopsin signals in the ~40% of neurons showing sustained activation to a light step. It allows this sub-population of neurons to maintain firing under extended light exposure, and to trace the irradiance of a full field light stimulus over at least 6 decimal orders. Our first hypothesis regarding melanopsin's visual functions is therefore that it helps encode levels of ambient light for perceptions of global 'brightness'. We next propose that this system also conveys some spatial information, allowing mRGCs to contribute a spatial map of brightness. As our new data reveals that the melanopsin signal is merged with conventional visual input by the level of the thalamus, a final possibility is that these information streams interact, allowing mRGCs to modulate the activity of rod/cone based visual processes. We propose behavioural and in vivo electrophysiological experiments that, in combination with advanced informatics techniques, will allow us to define mRGC contributions to encoding a wide range of visual stimuli from simple full field illumination to 'natural' visual scenes. We will take advantage of the difference in spectral sensitivity of melanopsin vs rod/cone photoreceptors to selectively evoke melanopsin-based visual responses. Importantly, this approach will allow us to study melanopsin vision in animals with an intact visual system, which is a prerequisite for approaching an accurate and complete view of mRGC influence.

This project will reveal how the visual system uses melanopsin photoreception. We see two potential practical applications of this knowledge. 1.) Lighting design and electronics industries. At present, artificial lighting and visual display units are designed solely with cone photoreceptors in mind. New lighting technologies (OLED, QD-LED) have the capacity to provide a closer approximation of the spectral and brightness ranges of natural scenes. Our experiments will reveal whether this technology could be utilised to provide information to the melanopsin system, and thus bring the viewer experience closer to that in natural (outdoor) visual environments. Our plan for dissemination of this knowledge will initially be to use our contacts within the lighting industry. This will be achieved by speaking at industry forums organised by the main lighting standards organisations at national (National Physical Laboratory) and international (Committee International de l'Eclairage) levels, and contributing articles to trade publications. Should our discoveries suggest immediate practical applications we will work with UMIP (our University's knowledge and technology transfer organisation) to seek protection for intellectual property, and to identify suitable industrial partners for product testing and development. 2.) New approaches to blindness. Millions around the world suffer varying degrees of blindness thanks to rod/cone degeneration. At present these conditions are largely untreatable. However, we know that melanopsin photoreception survives even complete rod/cone degeneration. Could this explain why complete loss of light perception is so rare in these subjects? If so, could strategies to support mRGC survival and function under these conditions present a simple new option for improving vision? At earlier stages of degeneration does melanopsin help to support vision? If so, could new visual aides designed to optimise melanopsin vision improve sight in these patients? Determining melanopsin's contribution to vision in sighted individuals represents the first step to answering these important questions. Should our findings indicate that the answer to any of them is likely to be 'yes', then we will move forward to parallel animal and clinical studies of melanopsin vision in retinal disease. For this task, we are fortunate to have The Manchester Royal Eye Hospital in an adjoining building. The principle applicant has active collaborations with clinicians in this unit (Profs Paul Bishop and Graeme Black), and will aim to work with them to study melanopsin's contribution to vision in subjects with retinal degeneration and to test potential clinical interventions. This strategy should allow us to realise any clinical benefits arising from our studies within 5-8 years. Training This project represents an excellent opportunity for the researcher coapplicant to obtain training in computational and informatics techniques to complement his current expertise in electrophysiology. This will make him well placed to contribute to the coming era in biology in which higher-level analyses of large datasets will be so important.