In contrast to the perception of images, which generally benefits from high spatial and temporal resolution, many visual functions collect photons over extended intervals of space and time to develop an accurate measure of the ambient light level. In mammals, these non-image visual functions are served by the intrinsically photosensitive retinal ganglion cells (ipRGCs), neurons that capture light using a receptor molecule called melanopsin. The overarching hypothesis of this proposal is that the mechanisms of light sensing by ipRGCs are specialized for encoding the overall, absolute light level (i.e., irradiance). Two key features of irradiance encoding are integration over space (thus averaging over variations in the visual scene) and signaling over a broad range of light intensities (which naturally span ten orders of magnitude). IpRGCs have the opportunity to use their entire surface area within the retina, including their axons, for sensing and integrating ligt. The hypothesis that axonal phototransduction extends the receptive field of ipRGCs will be tested in Aim 1.1 by mapping said receptive field at a high level of detail. Fundamental parameters of phototransduction will be measured directly from the axon in Aim 1.2, in order to test whether those parameters reflect the axon's distinct geometry and membrane properties. In addition, the task of irradiance encoding in ipRGCs is complicated by the fact that individual ipRGCs respond over a range of light intensities that is narrower than that attributed to them through in vivo studies of non-image visual functions. Preliminary data also show that for many ipRGCs, their spike rate is at best an ambiguous indicator of light intensity. One possible solution is that a diverse population of ipRGCs, with high variability in their response properties is required to cover the full range of intensities that drive non-image-forming visual behaviors. Indeed, preliminary experiments also indicate that there is substantial variation in the dynamic ranges of ipRGCs, even those that are anatomically indistinguishable. This hypothesis will be investigated in Aim 2.1 by defining the dynamic ranges of a large population of ipRGCs.
Aim 2. 2 will test the prediction that much of this observed variability is due to individual variation in te properties of intrinsic phototransduction. The proposed experiments will advance understanding of how ipRGCs support visual functions whose requirements are distinct from those of visual perception. For instance, ipRGCs are the principal regulators of the circadian clock-hence, a better understanding of the normal function of ipRGCs may inform the treatment and prevention of disorders related to circadian dysregulation, which include metabolic and affective disorders as well as cancer. The experiments proposed in Aim 1 are also directly relevant to the use of melanopsin as an optogenetic tool in the development of new therapies for vision loss. This research proposal is part of a broader training plan designed to hone the principal investigator's skills in experimental design and analysis, technical proficiency, and scholarship, and will proceed with close guidance from the principal investigator's sponsor and co-sponsor.
This proposal seeks to understand the basic function of cells in the mammalian eye that sense the ambient light level. This understanding will provide a foundation for the prevention and treatment of ailments that arise from a lack of synchrony between internal physiology and the external environment. These ailments include jet lag, seasonal affective disorder, cardiovascular disease, metabolic disorders, and cancer.
