Abstract

In vertebrate eyes, vision begins when the photoreceptor’s outer segment absorbs photons and generates a neural signal destined for the brain. The extreme optical and metabolic demands of this process of phototransduction necessitate continual renewal of the outer segment. Outer segment renewal has been long studied in post-mortem rods using autoradiography, but has been observed neither in living photoreceptors nor directly in cones. Using adaptive optics, which permits the resolution of cones, and temporally coherent illumination, which transforms the outer segment into a “biological interferometer,” we observed cone renewal in three subjects, manifesting as elongation of the cone outer segment, with rates ranging from 93 to 113 nm/hour (2.2 to 2.7 µm/day). In one subject we observed renewal occurring over 24 hours, with small but significant changes in renewal rate over the day. We determined that this novel method is sensitive to changes in outer segment length of 139 nm, more than 20 times better than the axial resolution of ultra-high resolution optical coherence tomography, the best existing method for depth imaging of the living retina.

© 2010 OSA

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2009 (2)

2008 (4)

2007 (1)

2006 (6)

M. D. Abràmoff, Y. H. Kwon, D. Ts’o, P. Soliz, B. Zimmerman, J. Pokorny, and R. Kardon, “Visual stimulus-induced changes in human near-infrared fundus reflectance,” Invest. Ophthalmol. Vis. Sci. 47(2), 715–721 (2006).
[CrossRef] [PubMed]

X. C. Yao and J. S. George, “Near-infrared imaging of fast intrinsic optical responses in visible light-activated amphibian retina,” J. Biomed. Opt. 11(6), 064030 (2006).
[CrossRef]

Y. Zhang, B. Cense, J. Rha, R. S. Jonnal, W. Gao, R. J. Zawadzki, J. S. Werner, S. Jones, S. Olivier, and D. T. Miller, “High-speed volumetric imaging of cone photoreceptors with adaptive optics spectral-domain optical coherence tomography,” Opt. Express 14(10), 4380–4394 (2006).
[CrossRef] [PubMed]

J. Rha, R. S. Jonnal, K. E. Thorn, J. Qu, Y. Zhang, and D. T. Miller, “Adaptive optics flood-illumination camera for high speed retinal imaging,” Opt. Express 14(10), 4552–4569 (2006).
[CrossRef] [PubMed]

V. J. Srinivasan, M. Wojtkowski, J. G. Fujimoto, and J. S. Duker, “In vivo measurement of retinal physiology with high-speed ultrahigh-resolution optical coherence tomography,” Opt. Lett. 31(15), 2308–2310 (2006).
[CrossRef] [PubMed]

K. Bizheva, R. Pflug, B. Hermann, B. Povazay, H. Sattmann, P. Qiu, E. Anger, H. Reitsamer, S. Popov, J. R. Taylor, A. Unterhuber, P. Ahnelt, and W. Drexler, “Optophysiology: depth-resolved probing of retinal physiology with functional ultrahigh-resolution optical coherence tomography,” Proc. Natl. Acad. Sci. U.S.A. 103(13), 5066–5071 (2006).
[CrossRef] [PubMed]

2005 (4)

2004 (3)

K. Tsunoda, Y. Oguchi, G. Hanazono, and M. Tanifuji, “Mapping cone- and rod-induced retinal responsiveness in macaque retina by optical imaging,” Invest. Ophthalmol. Vis. Sci. 45(10), 3820–3826 (2004).
[CrossRef] [PubMed]

B. Cense, N. Nassif, T. Chen, M. Pierce, S. H. Yun, B. Park, B. Bouma, G. Tearney, and J. de Boer, “Ultrahigh-resolution high-speed retinal imaging using spectral-domain optical coherence tomography,” Opt. Express 12(11), 2435–2447 (2004).
[CrossRef] [PubMed]

A. L. Kindzelskii, V. M. Elner, S. G. Elner, D. Yang, B. A. Hughes, and H. R. Petty, “Toll-like receptor 4 (TLR4) of retinal pigment epithelial cells participates in transmembrane signaling in response to photoreceptor outer segments,” J. Gen. Physiol. 124(2), 139–149 (2004).
[CrossRef] [PubMed]

2003 (1)

A. Pallikaris, D. R. Williams, and H. Hofer, “The reflectance of single cones in the living human eye,” Invest. Ophthalmol. Vis. Sci. 44(10), 4580–4592 (2003).
[CrossRef] [PubMed]

2002 (1)

G. Tosini and C. Fukuhara, “The mammalian retina as a clock,” Cell Tissue Res. 309(1), 119–126 (2002).
[CrossRef] [PubMed]

2000 (2)

P. J. DeLint, T. T. Berendschot, J. van de Kraats, and D. van Norren, “Slow optical changes in human photoreceptors induced by light,” Invest. Ophthalmol. Vis. Sci. 41(1), 282–289 (2000).
[PubMed]

D. Vollrath, A. Gal, Y. Li, D. A. Thompson, J. Weir, U. Orth, S. G. Jacobson, and E. Apfelstedt-Sylla, “Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa,” Nat. Genet. 26(3), 270–271 (2000).
[CrossRef] [PubMed]

1999 (1)

M. S. Grace, A. Chiba, and M. Menaker, “Circadian control of photoreceptor outer segment membrane turnover in mice genetically incapable of melatonin synthesis,” Vis. Neurosci. 16(5), 909–918 (1999).
[CrossRef] [PubMed]

1994 (1)

D. T. Organisciak and B. S. Winkler, “Retinal light damage: practical and theoretical considerations,” Prog. Retin. Eye Res. 13(1), 1–29 (1994).
[CrossRef]

1993 (1)

C. J. Guérin, G. P. Lewis, S. K. Fisher, and D. H. Anderson, “Recovery of photoreceptor outer segment length and analysis of membrane assembly rates in regenerating primate photoreceptor outer segments,” Invest. Ophthalmol. Vis. Sci. 34(1), 175–183 (1993).
[PubMed]

1990 (1)

C. A. Curcio, K. R. Sloan, R. E. Kalina, and A. E. Hendrickson, “Human photoreceptor topography,” J. Comp. Neurol. 292(4), 497–523 (1990).
[CrossRef] [PubMed]

1987 (1)

G. D. Aguirre and L. Andrews, “Nomarski evaluation of rod outer segment renewal in a hereditary retinal degeneration. Comparison with autoradiographic evaluation,” Invest. Ophthalmol. Vis. Sci. 28(7), 1049–1058 (1987).
[PubMed]

1986 (1)

A. Grinvald, E. Lieke, R. D. Frostig, C. D. Gilbert, and T. N. Wiesel, “Functional architecture of cortex revealed by optical imaging of intrinsic signals,” Nature 324(6095), 361–364 (1986).
[CrossRef] [PubMed]

1985 (1)

D. Bok, “Retinal photoreceptor-pigment epithelium interactions. Friedenwald lecture,” Invest. Ophthalmol. Vis. Sci. 26(12), 1659–1694 (1985).
[PubMed]

1984 (1)

D. G. Birch, E. L. Berson, and M. A. Sandberg, “Diurnal rhythm in the human rod ERG,” Invest. Ophthalmol. Vis. Sci. 25(2), 236–238 (1984).
[PubMed]

1983 (1)

S. K. Fisher, B. A. Pfeffer, and D. H. Anderson, “Both rod and cone disc shedding are related to light onset in the cat,” Invest. Ophthalmol. Vis. Sci. 24(7), 844–856 (1983).
[PubMed]

1981 (1)

M. M. LaVail, “Photoreceptor characteristics in congenic strains of RCS rats,” Invest. Ophthalmol. Vis. Sci. 20(5), 671–675 (1981).
[PubMed]

1980 (3)

D. H. Anderson, S. K. Fisher, P. A. Erickson, and G. A. Tabor, “Rod and cone disc shedding in the rhesus monkey retina: a quantitative study,” Exp. Eye Res. 30(5), 559–574 (1980).
[CrossRef] [PubMed]

M. M. LaVail, “Circadian nature of rod outer segment disc shedding in the rat,” Invest. Ophthalmol. Vis. Sci. 19(4), 407–411 (1980).
[PubMed]

A. I. Goldman, P. S. Teirstein, and P. J. O’Brien, “The role of ambient lighting in circadian disc shedding in the rod outer segment of the rat retina,” Invest. Ophthalmol. Vis. Sci. 19(11), 1257–1267 (1980).
[PubMed]

1978 (1)

R. W. Young, “The daily rhythm of shedding and degradation of rod and cone outer segment membranes in the chick retina,” Invest. Ophthalmol. Vis. Sci. 17(2), 105–116 (1978).
[PubMed]

1976 (2)

N. Buyukmihci and G. D. Aguirre, “Rod disc turnover in the dog,” Invest. Ophthalmol. Vis. Sci. 15, 579–584 (1976).

M. M. LaVail, “Rod outer segment disk shedding in rat retina: relationship to cyclic lighting,” Science 194(4269), 1071–1074 (1976).
[CrossRef] [PubMed]

1975 (1)

D. H. Anderson and S. K. Fisher, “Disc shedding in rodlike and conelike photoreceptors of tree squirrels,” Science 187(4180), 953–955 (1975).
[CrossRef] [PubMed]

1974 (1)

R. H. Steinberg, I. Wood, and R. H. Steinberg, “Phagocytosis by pigment epithelium of human retinal cones,” Nature 252(5481), 305–307 (1974).
[CrossRef] [PubMed]

1973 (3)

F. J. M. Daemen, “Vertebrate rod outer segment membranes,” Biochim. Biophys. Acta 300(3), 255–288 (1973).
[PubMed]

M. M. LaVail, “Kinetics of rod outer segment renewal in the developing mouse retina,” J. Cell Biol. 58(3), 650–661 (1973).
[CrossRef] [PubMed]

W. Snyder and C. Pask, “Stiles-crawford effect-explanation and consequences,” Vision Res. 13(6), 1115–1137 (1973).
[CrossRef] [PubMed]

1971 (1)

R. W. Young, “The renewal of rod and cone outer segments in the rhesus monkey,” J. Cell Biol. 49(2), 303–318 (1971).
[CrossRef] [PubMed]

1969 (1)

R. W. Young and D. Bok, “Participation of the retinal pigment epithelium in the rod outer segment renewal process,” J. Cell Biol. 42(2), 392–403 (1969).
[CrossRef] [PubMed]

1968 (1)

B. Anderson., “Ocular effects of changes in oxygen and carbon dioxide tension,” Trans. Am. Ophthalmol. Soc. 66, 423–474 (1968).
[PubMed]

1967 (1)

R. W. Young, “The renewal of photoreceptor cell outer segments,” J. Cell Biol. 33(1), 61–72 (1967).
[CrossRef] [PubMed]

1966 (1)

W. K. Noell, V. S. Walker, B. O. K. S. Kang, and S. Berman, “Retinal damage by light in rats,” Invest. Ophthalmol. Vis. Sci. 5, 450–473 (1966).

1957 (1)

K. F. A. Ross and J. T. Y. Chou, “The physical nature of the lipid globules in the living neurones of Helix aspersa as indicated by measurements of refractive index,” J. Cell Sci. 3, 341 (1957).

Abecasis, G. R.

S. Zareparsi, M. Buraczynska, K. E. H. Branham, S. Shah, D. Eng, M. Li, H. Pawar, B. M. Yashar, S. E. Moroi, P. R. Lichter, H. R. Petty, J. E. Richards, G. R. Abecasis, V. M. Elner, and A. Swaroop, “Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration,” Hum. Mol. Genet. 14(11), 1449–1455 (2005).
[CrossRef] [PubMed]

Abràmoff, M. D.

M. D. Abràmoff, Y. H. Kwon, D. Ts’o, P. Soliz, B. Zimmerman, J. Pokorny, and R. Kardon, “Visual stimulus-induced changes in human near-infrared fundus reflectance,” Invest. Ophthalmol. Vis. Sci. 47(2), 715–721 (2006).
[CrossRef] [PubMed]

Aguirre, G. D.

G. D. Aguirre and L. Andrews, “Nomarski evaluation of rod outer segment renewal in a hereditary retinal degeneration. Comparison with autoradiographic evaluation,” Invest. Ophthalmol. Vis. Sci. 28(7), 1049–1058 (1987).
[PubMed]

N. Buyukmihci and G. D. Aguirre, “Rod disc turnover in the dog,” Invest. Ophthalmol. Vis. Sci. 15, 579–584 (1976).

Ahnelt, P.

K. Bizheva, R. Pflug, B. Hermann, B. Povazay, H. Sattmann, P. Qiu, E. Anger, H. Reitsamer, S. Popov, J. R. Taylor, A. Unterhuber, P. Ahnelt, and W. Drexler, “Optophysiology: depth-resolved probing of retinal physiology with functional ultrahigh-resolution optical coherence tomography,” Proc. Natl. Acad. Sci. U.S.A. 103(13), 5066–5071 (2006).
[CrossRef] [PubMed]

Ahnelt, P. K.

Anderson, B.

B. Anderson., “Ocular effects of changes in oxygen and carbon dioxide tension,” Trans. Am. Ophthalmol. Soc. 66, 423–474 (1968).
[PubMed]

Anderson, D. H.

C. J. Guérin, G. P. Lewis, S. K. Fisher, and D. H. Anderson, “Recovery of photoreceptor outer segment length and analysis of membrane assembly rates in regenerating primate photoreceptor outer segments,” Invest. Ophthalmol. Vis. Sci. 34(1), 175–183 (1993).
[PubMed]

S. K. Fisher, B. A. Pfeffer, and D. H. Anderson, “Both rod and cone disc shedding are related to light onset in the cat,” Invest. Ophthalmol. Vis. Sci. 24(7), 844–856 (1983).
[PubMed]

D. H. Anderson, S. K. Fisher, P. A. Erickson, and G. A. Tabor, “Rod and cone disc shedding in the rhesus monkey retina: a quantitative study,” Exp. Eye Res. 30(5), 559–574 (1980).
[CrossRef] [PubMed]

D. H. Anderson and S. K. Fisher, “Disc shedding in rodlike and conelike photoreceptors of tree squirrels,” Science 187(4180), 953–955 (1975).
[CrossRef] [PubMed]

Andrews, L.

G. D. Aguirre and L. Andrews, “Nomarski evaluation of rod outer segment renewal in a hereditary retinal degeneration. Comparison with autoradiographic evaluation,” Invest. Ophthalmol. Vis. Sci. 28(7), 1049–1058 (1987).
[PubMed]

Anger, E.

K. Bizheva, R. Pflug, B. Hermann, B. Povazay, H. Sattmann, P. Qiu, E. Anger, H. Reitsamer, S. Popov, J. R. Taylor, A. Unterhuber, P. Ahnelt, and W. Drexler, “Optophysiology: depth-resolved probing of retinal physiology with functional ultrahigh-resolution optical coherence tomography,” Proc. Natl. Acad. Sci. U.S.A. 103(13), 5066–5071 (2006).
[CrossRef] [PubMed]

Apfelstedt-Sylla, E.

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A. L. Kindzelskii, V. M. Elner, S. G. Elner, D. Yang, B. A. Hughes, and H. R. Petty, “Toll-like receptor 4 (TLR4) of retinal pigment epithelial cells participates in transmembrane signaling in response to photoreceptor outer segments,” J. Gen. Physiol. 124(2), 139–149 (2004).
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J. Opt. Soc. Am. A (1)

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D. Vollrath, A. Gal, Y. Li, D. A. Thompson, J. Weir, U. Orth, S. G. Jacobson, and E. Apfelstedt-Sylla, “Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa,” Nat. Genet. 26(3), 270–271 (2000).
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Y. Zhang, B. Cense, J. Rha, R. S. Jonnal, W. Gao, R. J. Zawadzki, J. S. Werner, S. Jones, S. Olivier, and D. T. Miller, “High-speed volumetric imaging of cone photoreceptors with adaptive optics spectral-domain optical coherence tomography,” Opt. Express 14(10), 4380–4394 (2006).
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W. Gao, B. Cense, Y. Zhang, R. S. Jonnal, D. T. Miller, and D. T. Miller, “Measuring retinal contributions to the optical Stiles-Crawford effect with optical coherence tomography,” Opt. Express 16(9), 6486–6501 (2008).
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Y. Zhang, J. Rha, R. S. Jonnal, and D. T. Miller, “Adaptive optics parallel spectral domain optical coherence tomography for imaging the living retina,” Opt. Express 13(12), 4792–4811 (2005).
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Proc. Natl. Acad. Sci. U.S.A. (1)

K. Bizheva, R. Pflug, B. Hermann, B. Povazay, H. Sattmann, P. Qiu, E. Anger, H. Reitsamer, S. Popov, J. R. Taylor, A. Unterhuber, P. Ahnelt, and W. Drexler, “Optophysiology: depth-resolved probing of retinal physiology with functional ultrahigh-resolution optical coherence tomography,” Proc. Natl. Acad. Sci. U.S.A. 103(13), 5066–5071 (2006).
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Supplementary Material (1)

» Media 1: AVI (6425 KB)     

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Figures (6)

Fig. 1
Fig. 1

The reflective structure of the retina. (a) A diagram depicting the major layers of the neural retina, consisting of the inner limiting membrane (ILM), nerve fiber layer (NFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), external limiting membrane (ELM), the inner segments (IS) and outer segments (OS) (which make up the photoreceptor layer), the connecting cilia (CC) and posterior tip (PT) layers (which bound the outer segment), the retinal pigment epithelium (RPE), and the choroid (CH). (b) An AO-OCT B-scan (log intensity) from Subject 1, showing a cross-section of the full retinal thickness, aligned with the layers depicted in (a), and an enlarged view (linear intensity) of the cone outer segments. While OCT images are typically shown in log intensity, the linear intensity view of the outer segments demonstrates vividly that the bulk of the cone reflection originates at the CC and PT layers: the bright, patterned reflections at the CC and PT layers are the most visible structures in the linear intensity image; their peak intensity is more than two orders of magnitude greater than the average intensity of all other layers in the image. Each distinct reflection in the pattern represents a single cone cell. (c) A model of light propagation through the OS. Two bright reflections ( Ψ 1 and Ψ 2 ) originate from the CC and PT layers, creating a biological interferometer in the retina that is sensitive to small ( < < λ ) changes in the outer segment length L whenever the temporal coherence length of the illumination source L c is longer than L.

Fig. 2
Fig. 2

Schematic diagram of the adaptive optics (AO) retina camera. Abbreviations used: superluminescent diode (SLD), laser diode (LD), multimode fiber (MMF), mirror (M), dichroic beam splitter (DBS), pellicle beam splitter (PBS), and charge-coupled device (CCD). The AO system consists of the 788 nm SLD, the Shack-Hartmann wavefront sensor, and the deformable mirror. The imaging system consists of the 810 nm LD, the 842 nm SLD, and the science CCD.

Fig. 6
Fig. 6

Plot of the average frequency of oscillation over 24 hour period. Each data point was generated by computing the power spectrum of every cone reflectance series over a four hour window, locating the peak in each power spectrum, and averaging those peak frequencies together. The data point at 2pm, for instance, is the average frequency between the hours of noon and 4pm. Standard deviation (σ) of peak frequencies was computed. Error bars show one standard error of the mean in the distribution of frequencies, (σ/√N, with N = 806). Oscillations in reflectance were present throughout the 24 hour experiment.

Fig. 3
Fig. 3

Visible oscillations in cone reflectance over hours. (a) Cone mosaic image acquired from subject 1 with the AO retina camera. The image, an average of 21 images acquired over five hours, is 324x264 μm and each bright spot is a single cone cell. (b-f) Enlarged images of a sample region (location indicated by white box in (a)), acquired at 0h, 0.75h, 1.5h, 2.25h, and 3h. Most of the cones can be observed to go through approximately one full cycle of reflectance change. For example, cone 1 is bright at times 0h and 3h, but dark at time 1.5h, while cone 5 is dark at times 0h and 3h, but bright at time 1.5h.

Fig. 4
Fig. 4

Video showing the visible oscillations in cone reflectance over five hours (Media 1). The clock in the upper right shows the time each image in the video was acquired. In order to emphasize oscillations at the peak frequency while reducing the visible effects of noise near the sampling frequency, a Gaussian temporal lowpass filter (σ = 12 min) was used. Most cones appear to go through nearly two full cycles of reflectance oscillation. The amplitude and phase of oscillation appear to vary randomly among cones.

Fig. 5
Fig. 5

Cone reflectances and their power spectra (plots offset vertically for ease of viewing). (a) Reflectance as a function of time of eight sample cones taken from trial 4. Superimposed on each plot is a cosine fit (gray line). The black bar in the upper left shows 1/10th of the average DC component, I0, of cone reflectance. The oscillation of reflectance in all cones had a visible period of 2.5 – 3 hours, while the amplitudes and phases appeared to vary randomly. At the bottom is a plot of the average reflectance of all cones (diamonds), nearly flat (contrast 0.18%), which is predicted by the model shown in Fig. 1(c) and Eq. (1). (b) Power spectra of mean-subtracted cone reflectance traces shown in a, and the average spectrum of all 1626 cones (dark line). Most cones in this trial had a visible peak in the power spectrum around 0.37 cyc/hr, and this peak is visible in the average power spectrum as well. Similar peaks were seen in power spectra of individual cones, and the average power spectrum, in all trials in which the long coherence source was used (these frequencies are summarized in Table 1). When the short coherence source was used, neither the power spectra of individual cones nor the average power spectrum showed comparable peaks.

Tables (1)

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Table 1 Summary of experimental trials and average renewal velocities measured (see text for details).

Equations (2)

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I = I 0 + 2 | Ψ 1 | | Ψ 2 | cos ( 2 π λ 2 n L )
v P T = f λ 2 n

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