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      The optoretinogram reveals the primary steps of phototransduction in the living human eye

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          Abstract

          Human cone photoreceptors undergo rapid nanometer-scale mechanical deformations during the first step of phototransduction.

          Abstract

          Photoreceptors initiate vision by converting photons to electrical activity. The onset of the phototransduction cascade is marked by the isomerization of photopigments upon light capture. We revealed that the onset of phototransduction is accompanied by a rapid (<5 ms), nanometer-scale electromechanical deformation in individual human cone photoreceptors. Characterizing this biophysical phenomenon associated with phototransduction in vivo was enabled by high-speed phase-resolved optical coherence tomography in a line-field configuration that allowed sufficient spatiotemporal resolution to visualize the nanometer/millisecond-scale light-induced shape change in photoreceptors. The deformation was explained as the optical manifestation of electrical activity, caused due to rapid charge displacement following isomerization, resulting in changes of electrical potential and surface tension within the photoreceptor disc membranes. These all-optical recordings of light-induced activity in the human retina constitute an optoretinogram and hold remarkable potential to reveal the biophysical correlates of neural activity in health and disease.

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          Most cited references54

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          SciPy 1.0: fundamental algorithms for scientific computing in Python

          SciPy is an open-source scientific computing library for the Python programming language. Since its initial release in 2001, SciPy has become a de facto standard for leveraging scientific algorithms in Python, with over 600 unique code contributors, thousands of dependent packages, over 100,000 dependent repositories and millions of downloads per year. In this work, we provide an overview of the capabilities and development practices of SciPy 1.0 and highlight some recent technical developments.
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            Genetic reactivation of cone photoreceptors restores visual responses in retinitis pigmentosa.

            Retinitis pigmentosa refers to a diverse group of hereditary diseases that lead to incurable blindness, affecting two million people worldwide. As a common pathology, rod photoreceptors die early, whereas light-insensitive, morphologically altered cone photoreceptors persist longer. It is unknown if these cones are accessible for therapeutic intervention. Here, we show that expression of archaebacterial halorhodopsin in light-insensitive cones can substitute for the native phototransduction cascade and restore light sensitivity in mouse models of retinitis pigmentosa. Resensitized photoreceptors activate all retinal cone pathways, drive sophisticated retinal circuit functions (including directional selectivity), activate cortical circuits, and mediate visually guided behaviors. Using human ex vivo retinas, we show that halorhodopsin can reactivate light-insensitive human photoreceptors. Finally, we identified blind patients with persisting, light-insensitive cones for potential halorhodopsin-based therapy.
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              The arrangement of the three cone classes in the living human eye.

              Human colour vision depends on three classes of receptor, the short- (S), medium- (M), and long- (L) wavelength-sensitive cones. These cone classes are interleaved in a single mosaic so that, at each point in the retina, only a single class of cone samples the retinal image. As a consequence, observers with normal trichromatic colour vision are necessarily colour blind on a local spatial scale. The limits this places on vision depend on the relative numbers and arrangement of cones. Although the topography of human S cones is known, the human L- and M-cone submosaics have resisted analysis. Adaptive optics, a technique used to overcome blur in ground-based telescopes, can also overcome blur in the eye, allowing the sharpest images ever taken of the living retina. Here we combine adaptive optics and retinal densitometry to obtain what are, to our knowledge, the first images of the arrangement of S, M and L cones in the living human eye. The proportion of L to M cones is strikingly different in two male subjects, each of whom has normal colour vision. The mosaics of both subjects have large patches in which either M or L cones are missing. This arrangement reduces the eye's ability to recover colour variations of high spatial frequency in the environment but may improve the recovery of luminance variations of high spatial frequency.
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                Author and article information

                Journal
                Sci Adv
                Sci Adv
                sciadv
                advances
                Science Advances
                American Association for the Advancement of Science
                2375-2548
                September 2020
                09 September 2020
                : 6
                : 37
                : eabc1124
                Affiliations
                [1 ]Department of Ophthalmology, University of Washington, Seattle, WA 98109, USA.
                [2 ]Hansen Experimental Physics Laboratory, Stanford, CA 94305, USA.
                [3 ]Department of Electrical Engineering, Stanford University, Stanford, CA 94305, USA.
                [4 ]Department of Ophthalmology, Stanford University, Stanford, CA 94305, USA.
                [5 ]Department of Bioengineering, University of California, Riverside, CA 92521, USA.
                [6 ]School of Optometry, University of California, Berkeley, CA 94720, USA.
                Author notes
                [ * ]Corresponding author. Email: rsabesan@ 123456uw.edu
                Author information
                https://orcid.org/0000-0002-6996-0355
                https://orcid.org/0000-0002-9958-4119
                https://orcid.org/0000-0002-8603-7693
                https://orcid.org/0000-0002-9539-6786
                https://orcid.org/0000-0001-9009-7966
                https://orcid.org/0000-0003-2705-065X
                https://orcid.org/0000-0002-0282-7162
                https://orcid.org/0000-0002-3785-0848
                https://orcid.org/0000-0002-0480-3025
                https://orcid.org/0000-0003-0895-7037
                Article
                abc1124
                10.1126/sciadv.abc1124
                9222118
                32917686
                05d85063-78ff-4d08-a2b5-0fe5ad4ab95d
                Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                History
                : 07 April 2020
                : 24 July 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000053, National Eye Institute;
                Award ID: U01EY025501, EY027941, EY029710, EY025501, P30EY001730
                Funded by: FundRef http://dx.doi.org/10.13039/100000861, Burroughs Wellcome Fund;
                Funded by: FundRef http://dx.doi.org/10.13039/100000937, MJ Murdock Charitable Trust;
                Funded by: FundRef http://dx.doi.org/10.13039/100001116, Foundation Fighting Blindness;
                Funded by: FundRef http://dx.doi.org/10.13039/100001818, Research to Prevent Blindness;
                Categories
                Research Article
                Research Articles
                SciAdv r-articles
                Cellular Neuroscience
                Neuroscience
                Cellular Neuroscience
                Custom metadata
                Sef Rio

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