Vision is the result of billions of neurons working in tandem to extract ecologically meaningful information from the external world. In contrast, only a few million cone photoreceptors serve as the gatekeepers for vision, by initiating light absorption and converting it into a language that the rest of the visual system can decode. In the retina, cone photoreceptors are also among the most vulnerable to disease. If therapies aimed at their rescue are to evolve in the future and restore normal vision with all its exquisite features, the underlying neural substrates for vision need to be detailed on a cellular scale. The properties of the trichromatic cone mosaic pose few well recognized ambiguities for visual processing. The photoisomerization in one cone alone, for instance, can arise from numerous combinations of intensity and wavelength leaving the visual system to rely on comparisons in postreceptoral circuitry to divorce these two elementary aspects of physical stimuli. Postreceptoral pathways encode intensity and wavelength variations in the retinal image by comparing trichromatic cone signals in a local region of space, the mechanisms of which remain mysterious. This, yet unknown, spatiochromatic code initiated at the level of the cone mosaic is inherited by, and consequently constrains the information available to downstream neurons responsible for decoding chromatic and achromatic properties of the visual scene. The lack of information on the natural variation in cone topography within and between individuals is a source of ambiguity for models of spectral processing in downstream neurons. Furthermore, the general lack of tools to directly link the outputs of the cones and their ensuing circuits onto behavior has hindered progress in outlining the neural substrates for color appearance and detection. We have recently developed tools to a) efficiently map the topography of the cone mosaic with adaptive optics assisted densitometry and b) test the visual sensations elicited by targeted stimulation of the retina with help of cellular-scale eye tracking. With knowledge of the spectral organization in the central retina across a range of individuals, we will establish the genetic and developmental mechanisms shaping the adult human retina in Aim 1. By undertaking concomitant chromatic and luminance detection measurements in the same retinae with optical aberrations removed, we will outline the postreceptoral wiring strategies that dictate the underlying limits for these classical perceptual tasks.
In Aim 2, we will map the output of individual and collection of cone cells of known spectral type onto perception. We will first test hypotheses that characterize the rules by which cone signals are integrated to mediate detection and appearance. Next, we will detail the spatial grain of color signaling across the central retina and test whether they fall in line with standard models of center-surround opponency. Together, this work will lay the foundation for computational models of visual processing, establish a new line of experiments to test model predictions linking physiology and perception; and eventually set the stage for a wider application of these tools to cellular-scale behavioral testing in retinal disease and their therapies.
The study of visual processing on a cellular scale is central to understanding not only how we see colors, patterns and shapes but also to decipher the etiology and mechanisms of retinal diseases. This proposal is aimed at advancing our fundamental understanding of retinal processing and the central role cone photoreceptors play within it. The outcomes of this proposal will guide the next generation of prosthetics and enable sensitive, early markers of structural and functional abnormalities in retinal disease. Finally, it will establish a clinical protocol in humans where the next generation of treatments can be tested and refined in a safe, effective manner.
