Visual experience begins with electrical responses of retinal photoreceptors. Only light detected by rods and cones can be analyzed by higher visual centers to alter our behavior. It is therefore essential that we understand how photoreceptors convert light into changes in membrane potential and how the mechanism of transduction is modulated in steady illumination. Although research during the last 30 years has clarified many features of photoreceptor biochemistry and physiology, most of this work has been done on rods, even though cones respond over a much wider range of intensities and are more important for visual perception. Cones have the remarkable ability to continue to respond even in bright light; unlike rods, cones never saturate no matter how strong the background illumination. Cones can continue to adjust sensitivity so that it remains proportional to ambient illumination, maximizing the detection of contrast even in light bleaching a significant fraction of the visual pigment. Moreover background light accelerates the recovery of the cone response, enhancing the sensitivity of the visual system to change and motion when light is no longer limiting. An understanding of adaptation is essential to any effort to replace visual function in degenerated retina with some form of extrinsic light detector. We cannot hope to restore the ability of vision to operate over an extensive range of light intensities unless sensitivity and response kinetics can be made to adapt to the ambient light intensity. Failure of photoreceptors to adapt or recover normally can lead to genetically inherited retinal diseases including night blindness, bradyopsia, Oguchi disease, and Leber?s amaurosis. For this reason, the Retinal Disease Program of the NEI has as one of its program objectives to ?analyze the mechanisms underlying light adaptation and recovery following phototransduction?. The goal of this research is to understand the effects of steady background light and bleaching on sensitivity and response recovery in mammalian cones, in order to test mechanisms previously postulated for rods and to reveal major gaps in our understanding. These experiments will exploit an unusually bright LED-based optical stimulator and transgenic animals to investigate basic properties of mammalian cone physiology; and to combine measurements of sensitivity modulation by bleaching and steady background light into a comprehensive explanation of light adaptation.

Public Health Relevance

The great majority of diseases of the retina are caused by disorder or degeneration of the photoreceptors, the cells in the eye that convert light into an electrical signal. This proposal seeks to understand basic mechanisms of photoreceptor function, particularly recovery after exposure to light and adaptation to maintained illumination, which are known to be implicated in genetically inherited retinal diseases including night blindness, bradyopsin, and Leber's amaurosis. This study will support an important program objective of the National Eye Institute of the NIH to ?analyze the mechanisms underlying light adaptation and recovery following phototransduction?, and this work will also contribute to a more detailed understanding of the physiology of signal transduction throughout the body.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY001844-41
Application #
9237856
Study Section
Biology of the Visual System Study Section (BVS)
Program Officer
Neuhold, Lisa
Project Start
1984-07-01
Project End
2021-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
41
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Morshedian, Ala; Woodruff, Michael L; Fain, Gordon L (2018) Role of recoverin in rod photoreceptor light adaptation. J Physiol 596:1513-1526
Wang, Tian; Reingruber, J├╝rgen; Woodruff, Michael L et al. (2018) The PDE6 mutation in the rd10 retinal degeneration mouse model causes protein mislocalization and instability and promotes cell death through increased ion influx. J Biol Chem 293:15332-15346
Morshedian, Ala; Fain, Gordon L (2017) Light adaptation and the evolution of vertebrate photoreceptors. J Physiol 595:4947-4960
Morshedian, Ala; Toomey, Matthew B; Pollock, Gabriel E et al. (2017) Cambrian origin of the CYP27C1-mediated vitamin A1-to-A2 switch, a key mechanism of vertebrate sensory plasticity. R Soc Open Sci 4:170362
Morshedian, Ala; Fain, Gordon L (2017) The evolution of rod photoreceptors. Philos Trans R Soc Lond B Biol Sci 372:
Kaylor, Joanna J; Xu, Tongzhou; Ingram, Norianne T et al. (2017) Blue light regenerates functional visual pigments in mammals through a retinyl-phospholipid intermediate. Nat Commun 8:16
Ingram, Norianne T; Sampath, Alapakkam P; Fain, Gordon L (2016) Why are rods more sensitive than cones? J Physiol 594:5415-26
Morshedian, Ala; Fain, Gordon L (2015) Single-photon sensitivity of lamprey rods with cone-like outer segments. Curr Biol 25:484-7
Fain, Gordon L (2015) Phototransduction: Making the Chromophore to See Through the Murk. Curr Biol 25:R1126-7
Woodruff, Michael L; Rajala, Ammaji; Fain, Gordon L et al. (2015) Effect of knocking down the insulin receptor on mouse rod responses. Sci Rep 5:7858

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