Abstract

Adaptive optics scanning laser ophthalmoscopy (AO-SLO) has recently been used to achieve exquisite subcellular resolution imaging of the mouse retina. Wavefront sensing-based AO typically restricts the field of view to a few degrees of visual angle. As a consequence the relationship between AO-SLO data and larger scale retinal structures and cellular patterns can be difficult to assess. The retinal vasculature affords a large-scale 3D map on which cells and structures can be located during in vivo imaging. Phase-variance OCT (pv-OCT) can efficiently image the vasculature with near-infrared light in a label-free manner, allowing 3D vascular reconstruction with high precision. We combined widefield pv-OCT and SLO imaging with AO-SLO reflection and fluorescence imaging to localize two types of fluorescent cells within the retinal layers: GFP-expressing microglia, the resident macrophages of the retina, and GFP-expressing cone photoreceptor cells. We describe in detail a reflective afocal AO-SLO retinal imaging system designed for high resolution retinal imaging in mice. The optical performance of this instrument is compared to other state-of-the-art AO-based mouse retinal imaging systems. The spatial and temporal resolution of the new AO instrumentation was characterized with angiography of retinal capillaries, including blood-flow velocity analysis. Depth-resolved AO-SLO fluorescent images of microglia and cone photoreceptors are visualized in parallel with 469 nm and 663 nm reflectance images of the microvasculature and other structures. Additional applications of the new instrumentation are discussed.

© 2015 Optical Society of America

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2014 (7)

E. S. Levine, A. Zam, P. Zhang, A. Pechko, X. Wang, P. FitzGerald, E. N. Pugh, R. J. Zawadzki, and M. E. Burns, “Rapid light-induced activation of retinal microglia in mice lacking Arrestin-1,” Vision Res. 102, 71–79 (2014).
[Crossref] [PubMed]

A. Z. Zam, E. N. Pugh, and R. J. Zawadzki, “Evaluation of OCT for quantitative in vivo measurements of changes in neural tissue scattering in longitudinal studies of retinal degeneration in mice,” Proceedings of SPIE BiOS: Optical Coherence Tomography and Coherence Domain Optical Methods in Biomedicine 8934, 6 (2014).

D. M. Schwartz, J. Fingler, D. Y. Kim, R. J. Zawadzki, L. S. Morse, S. S. Park, S. E. Fraser, and J. S. Werner, “Phase-variance optical coherence tomography: a technique for noninvasive angiography,” Ophthalmology 121(1), 180–187 (2014).
[Crossref] [PubMed]

C. Alt, J. M. Runnels, L. J. Mortensen, W. Zaher, and C. P. Lin, “In vivo imaging of microglia turnover in the mouse retina after ionizing radiation and dexamethasone treatment,” Invest. Ophthalmol. Vis. Sci. 55(8), 5314–5319 (2014).
[Crossref] [PubMed]

R. S. Jonnal, O. P. Kocaoglu, R. J. Zawadzki, S. H. Lee, J. S. Werner, and D. T. Miller, “The cellular origins of the outer retinal bands in optical coherence tomography images,” Invest. Ophthalmol. Vis. Sci. 55(12), 7904–7918 (2014).
[Crossref] [PubMed]

A. Mishra, F. M. O’Farrell, C. Reynell, N. B. Hamilton, C. N. Hall, and D. Attwell, “Imaging pericytes and capillary diameter in brain slices and isolated retinae,” Nat. Protoc. 9(2), 323–336 (2014).
[Crossref] [PubMed]

Y. Jian, J. Xu, M. A. Gradowski, S. Bonora, R. J. Zawadzki, and M. V. Sarunic, “Wavefront sensorless adaptive optics optical coherence tomography for in vivo retinal imaging in mice,” Biomed. Opt. Express 5(2), 547–559 (2014).
[Crossref] [PubMed]

2013 (7)

R. Sharma, L. Yin, Y. Geng, W. H. Merigan, G. Palczewska, K. Palczewski, D. R. Williams, and J. J. Hunter, “In vivo two-photon imaging of the mouse retina,” Biomed. Opt. Express 4(8), 1285–1293 (2013).
[Crossref] [PubMed]

S. H. Lee, J. S. Werner, and R. J. Zawadzki, “Improved visualization of outer retinal morphology with aberration cancelling reflective optical design for adaptive optics - optical coherence tomography,” Biomed. Opt. Express 4(11), 2508–2517 (2013).
[Crossref] [PubMed]

D. Dalkara, L. C. Byrne, R. R. Klimczak, M. Visel, L. Yin, W. H. Merigan, J. G. Flannery, and D. V. Schaffer, “In vivo-directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous,” Sci. Transl. Med. 5(189), 189ra76 (2013).
[Crossref] [PubMed]

D. Y. Kim, J. Fingler, R. J. Zawadzki, S. S. Park, L. S. Morse, D. M. Schwartz, S. E. Fraser, and J. S. Werner, “Optical imaging of the chorioretinal vasculature in the living human eye,” Proc. Natl. Acad. Sci. U.S.A. 110(35), 14354–14359 (2013).
[Crossref] [PubMed]

L. Yin, Y. Geng, F. Osakada, R. Sharma, A. H. Cetin, E. M. Callaway, D. R. Williams, and W. H. Merigan, “Imaging light responses of retinal ganglion cells in the living mouse eye,” J. Neurophysiol. 109(9), 2415–2421 (2013).
[Crossref] [PubMed]

J. Schallek, Y. Geng, H. Nguyen, and D. R. Williams, “Morphology and topography of retinal pericytes in the living mouse retina using in vivo adaptive optics imaging and ex vivo characterization,” Invest. Ophthalmol. Vis. Sci. 54(13), 8237–8250 (2013).
[Crossref] [PubMed]

Y. Jian, R. J. Zawadzki, and M. V. Sarunic, “Adaptive optics optical coherence tomography for in vivo mouse retinal imaging,” J. Biomed. Opt. 18(5), 056007 (2013).
[Crossref] [PubMed]

2012 (3)

2011 (7)

Y. Geng, L. A. Schery, R. Sharma, A. Dubra, K. Ahmad, R. T. Libby, and D. R. Williams, “Optical properties of the mouse eye,” Biomed. Opt. Express 2(4), 717–738 (2011).
[Crossref] [PubMed]

D. Y. Kim, J. Fingler, J. S. Werner, D. M. Schwartz, S. E. Fraser, and R. J. Zawadzki, “In vivo volumetric imaging of human retinal circulation with phase-variance optical coherence tomography,” Biomed. Opt. Express 2(6), 1504–1513 (2011).
[Crossref] [PubMed]

R. J. Zawadzki, S. M. Jones, S. Pilli, S. Balderas-Mata, D. Y. Kim, S. S. Olivier, and J. S. Werner, “Integrated adaptive optics optical coherence tomography and adaptive optics scanning laser ophthalmoscope system for simultaneous cellular resolution in vivo retinal imaging,” Biomed. Opt. Express 2(6), 1674–1686 (2011).
[PubMed]

Z. Zhong, H. Song, T. Y. Chui, B. L. Petrig, and S. A. Burns, “Noninvasive measurements and analysis of blood velocity profiles in human retinal vessels,” Invest. Ophthalmol. Vis. Sci. 52(7), 4151–4157 (2011).
[Crossref] [PubMed]

A. Roorda, “Adaptive optics for studying visual function: a comprehensive review,” J. Vis. 11(5), 6 (2011).
[Crossref] [PubMed]

L. L. Daniele, C. Insinna, R. Chance, J. Wang, S. S. Nikonov, and E. N. Pugh., “A mouse M-opsin monochromat: retinal cone photoreceptors have increased M-opsin expression when S-opsin is knocked out,” Vision Res. 51(4), 447–458 (2011).
[Crossref] [PubMed]

D. R. Williams, “Imaging single cells in the living retina,” Vision Res. 51(13), 1379–1396 (2011).
[Crossref] [PubMed]

2010 (2)

J. Tam, J. A. Martin, and A. Roorda, “Noninvasive visualization and analysis of parafoveal capillaries in humans,” Invest. Ophthalmol. Vis. Sci. 51(3), 1691–1698 (2010).
[Crossref] [PubMed]

F. Naarendorp, T. M. Esdaille, S. M. Banden, J. Andrews-Labenski, O. P. Gross, and E. N. Pugh., “Dark light, rod saturation, and the absolute and incremental sensitivity of mouse cone vision,” J. Neurosci. 30(37), 12495–12507 (2010).
[Crossref] [PubMed]

2009 (1)

2007 (2)

2006 (2)

S. S. Nikonov, R. Kholodenko, J. Lem, and E. N. Pugh., “Physiological features of the S- and M-cone photoreceptors of wild-type mice from single-cell recordings,” J. Gen. Physiol. 127(4), 359–374 (2006).
[Crossref] [PubMed]

B. N. Giepmans, S. R. Adams, M. H. Ellisman, and R. Y. Tsien, “The fluorescent toolbox for assessing protein location and function,” Science 312(5771), 217–224 (2006).
[Crossref] [PubMed]

2005 (1)

2004 (3)

M. Wojtkowski, V. Srinivasan, T. Ko, J. Fujimoto, A. Kowalczyk, and J. Duker, “Ultrahigh-resolution, high-speed, Fourier domain optical coherence tomography and methods for dispersion compensation,” Opt. Express 12(11), 2404–2422 (2004).
[Crossref] [PubMed]

J. A. Peet, A. Bragin, P. D. Calvert, S. S. Nikonov, S. Mani, X. Zhao, J. C. Besharse, E. A. Pierce, B. E. Knox, and E. N. Pugh., “Quantification of the cytoplasmic spaces of living cells with EGFP reveals arrestin-EGFP to be in disequilibrium in dark adapted rod photoreceptors,” J. Cell Sci. 117(14), 3049–3059 (2004).
[Crossref] [PubMed]

M. Jacob and M. Unser, “Design of steerable filters for feature detection using canny-like criteria,” IEEE Trans. Pattern Anal. Mach. Intell. 26(8), 1007–1019 (2004).
[Crossref] [PubMed]

2002 (1)

2001 (1)

Y. Fei and T. E. Hughes, “Transgenic expression of the jellyfish green fluorescent protein in the cone photoreceptors of the mouse,” Vis. Neurosci. 18(4), 615–623 (2001).
[Crossref] [PubMed]

2000 (2)

S. Jung, J. Aliberti, P. Graemmel, M. J. Sunshine, G. W. Kreutzberg, A. Sher, and D. R. Littman, “Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion,” Mol. Cell. Biol. 20(11), 4106–4114 (2000).
[Crossref] [PubMed]

M. L. Applebury, M. P. Antoch, L. C. Baxter, L. L. Chun, J. D. Falk, F. Farhangfar, K. Kage, M. G. Krzystolik, L. A. Lyass, and J. T. Robbins, “The murine cone photoreceptor: a single cone type expresses both S and M opsins with retinal spatial patterning,” Neuron 27(3), 513–523 (2000).
[Crossref] [PubMed]

1992 (1)

Y. Wang, J. P. Macke, S. L. Merbs, D. J. Zack, B. Klaunberg, J. Bennett, J. Gearhart, and J. Nathans, “A locus control region adjacent to the human red and green visual pigment genes,” Neuron 9(3), 429–440 (1992).
[Crossref] [PubMed]

1991 (1)

W. T. Freeman and E. H. Adelson, “The Design and Use of Steerable Filters,” IEEE Trans. Pattern Anal. Mach. Intell. 13(9), 891–906 (1991).
[Crossref]

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)

1986 (1)

J. Canny, “A computational approach to edge detection,” IEEE Trans. Pattern Anal. Mach. Intell. 8(6), 679–698 (1986).
[Crossref] [PubMed]

1983 (1)

D. A. Hume, V. H. Perry, and S. Gordon, “Immunohistochemical localization of a macrophage-specific antigen in developing mouse retina: phagocytosis of dying neurons and differentiation of microglial cells to form a regular array in the plexiform layers,” J. Cell Biol. 97(1), 253–257 (1983).
[Crossref] [PubMed]

1979 (1)

L. D. Carter-Dawson and M. M. LaVail, “Rods and cones in the mouse retina. I. Structural analysis using light and electron microscopy,” J. Comp. Neurol. 188(2), 245–262 (1979).
[Crossref] [PubMed]

Adams, S. R.

B. N. Giepmans, S. R. Adams, M. H. Ellisman, and R. Y. Tsien, “The fluorescent toolbox for assessing protein location and function,” Science 312(5771), 217–224 (2006).
[Crossref] [PubMed]

Adelson, E. H.

W. T. Freeman and E. H. Adelson, “The Design and Use of Steerable Filters,” IEEE Trans. Pattern Anal. Mach. Intell. 13(9), 891–906 (1991).
[Crossref]

Ahmad, K.

Aliberti, J.

S. Jung, J. Aliberti, P. Graemmel, M. J. Sunshine, G. W. Kreutzberg, A. Sher, and D. R. Littman, “Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion,” Mol. Cell. Biol. 20(11), 4106–4114 (2000).
[Crossref] [PubMed]

Alt, C.

C. Alt, J. M. Runnels, L. J. Mortensen, W. Zaher, and C. P. Lin, “In vivo imaging of microglia turnover in the mouse retina after ionizing radiation and dexamethasone treatment,” Invest. Ophthalmol. Vis. Sci. 55(8), 5314–5319 (2014).
[Crossref] [PubMed]

Andrews-Labenski, J.

F. Naarendorp, T. M. Esdaille, S. M. Banden, J. Andrews-Labenski, O. P. Gross, and E. N. Pugh., “Dark light, rod saturation, and the absolute and incremental sensitivity of mouse cone vision,” J. Neurosci. 30(37), 12495–12507 (2010).
[Crossref] [PubMed]

Antoch, M. P.

M. L. Applebury, M. P. Antoch, L. C. Baxter, L. L. Chun, J. D. Falk, F. Farhangfar, K. Kage, M. G. Krzystolik, L. A. Lyass, and J. T. Robbins, “The murine cone photoreceptor: a single cone type expresses both S and M opsins with retinal spatial patterning,” Neuron 27(3), 513–523 (2000).
[Crossref] [PubMed]

Applebury, M. L.

M. L. Applebury, M. P. Antoch, L. C. Baxter, L. L. Chun, J. D. Falk, F. Farhangfar, K. Kage, M. G. Krzystolik, L. A. Lyass, and J. T. Robbins, “The murine cone photoreceptor: a single cone type expresses both S and M opsins with retinal spatial patterning,” Neuron 27(3), 513–523 (2000).
[Crossref] [PubMed]

Attwell, D.

A. Mishra, F. M. O’Farrell, C. Reynell, N. B. Hamilton, C. N. Hall, and D. Attwell, “Imaging pericytes and capillary diameter in brain slices and isolated retinae,” Nat. Protoc. 9(2), 323–336 (2014).
[Crossref] [PubMed]

Balderas-Mata, S.

Banden, S. M.

F. Naarendorp, T. M. Esdaille, S. M. Banden, J. Andrews-Labenski, O. P. Gross, and E. N. Pugh., “Dark light, rod saturation, and the absolute and incremental sensitivity of mouse cone vision,” J. Neurosci. 30(37), 12495–12507 (2010).
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Baxter, L. C.

M. L. Applebury, M. P. Antoch, L. C. Baxter, L. L. Chun, J. D. Falk, F. Farhangfar, K. Kage, M. G. Krzystolik, L. A. Lyass, and J. T. Robbins, “The murine cone photoreceptor: a single cone type expresses both S and M opsins with retinal spatial patterning,” Neuron 27(3), 513–523 (2000).
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Bennett, J.

Y. Wang, J. P. Macke, S. L. Merbs, D. J. Zack, B. Klaunberg, J. Bennett, J. Gearhart, and J. Nathans, “A locus control region adjacent to the human red and green visual pigment genes,” Neuron 9(3), 429–440 (1992).
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Besharse, J. C.

J. A. Peet, A. Bragin, P. D. Calvert, S. S. Nikonov, S. Mani, X. Zhao, J. C. Besharse, E. A. Pierce, B. E. Knox, and E. N. Pugh., “Quantification of the cytoplasmic spaces of living cells with EGFP reveals arrestin-EGFP to be in disequilibrium in dark adapted rod photoreceptors,” J. Cell Sci. 117(14), 3049–3059 (2004).
[Crossref] [PubMed]

Bifano, T. G.

Biss, D. P.

Bonora, S.

Bower, B. A.

Bragin, A.

J. A. Peet, A. Bragin, P. D. Calvert, S. S. Nikonov, S. Mani, X. Zhao, J. C. Besharse, E. A. Pierce, B. E. Knox, and E. N. Pugh., “Quantification of the cytoplasmic spaces of living cells with EGFP reveals arrestin-EGFP to be in disequilibrium in dark adapted rod photoreceptors,” J. Cell Sci. 117(14), 3049–3059 (2004).
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Burns, M. E.

E. S. Levine, A. Zam, P. Zhang, A. Pechko, X. Wang, P. FitzGerald, E. N. Pugh, R. J. Zawadzki, and M. E. Burns, “Rapid light-induced activation of retinal microglia in mice lacking Arrestin-1,” Vision Res. 102, 71–79 (2014).
[Crossref] [PubMed]

Burns, S. A.

Byrne, L. C.

D. Dalkara, L. C. Byrne, R. R. Klimczak, M. Visel, L. Yin, W. H. Merigan, J. G. Flannery, and D. V. Schaffer, “In vivo-directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous,” Sci. Transl. Med. 5(189), 189ra76 (2013).
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Callaway, E. M.

L. Yin, Y. Geng, F. Osakada, R. Sharma, A. H. Cetin, E. M. Callaway, D. R. Williams, and W. H. Merigan, “Imaging light responses of retinal ganglion cells in the living mouse eye,” J. Neurophysiol. 109(9), 2415–2421 (2013).
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Calvert, P. D.

J. A. Peet, A. Bragin, P. D. Calvert, S. S. Nikonov, S. Mani, X. Zhao, J. C. Besharse, E. A. Pierce, B. E. Knox, and E. N. Pugh., “Quantification of the cytoplasmic spaces of living cells with EGFP reveals arrestin-EGFP to be in disequilibrium in dark adapted rod photoreceptors,” J. Cell Sci. 117(14), 3049–3059 (2004).
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Campbell, M.

Canny, J.

J. Canny, “A computational approach to edge detection,” IEEE Trans. Pattern Anal. Mach. Intell. 8(6), 679–698 (1986).
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Carter-Dawson, L. D.

L. D. Carter-Dawson and M. M. LaVail, “Rods and cones in the mouse retina. I. Structural analysis using light and electron microscopy,” J. Comp. Neurol. 188(2), 245–262 (1979).
[Crossref] [PubMed]

Cetin, A. H.

L. Yin, Y. Geng, F. Osakada, R. Sharma, A. H. Cetin, E. M. Callaway, D. R. Williams, and W. H. Merigan, “Imaging light responses of retinal ganglion cells in the living mouse eye,” J. Neurophysiol. 109(9), 2415–2421 (2013).
[Crossref] [PubMed]

Chance, R.

L. L. Daniele, C. Insinna, R. Chance, J. Wang, S. S. Nikonov, and E. N. Pugh., “A mouse M-opsin monochromat: retinal cone photoreceptors have increased M-opsin expression when S-opsin is knocked out,” Vision Res. 51(4), 447–458 (2011).
[Crossref] [PubMed]

Choi, S.

Chui, T. Y.

T. Y. Chui, D. A. Vannasdale, and S. A. Burns, “The use of forward scatter to improve retinal vascular imaging with an adaptive optics scanning laser ophthalmoscope,” Biomed. Opt. Express 3(10), 2537–2549 (2012).
[Crossref] [PubMed]

Z. Zhong, H. Song, T. Y. Chui, B. L. Petrig, and S. A. Burns, “Noninvasive measurements and analysis of blood velocity profiles in human retinal vessels,” Invest. Ophthalmol. Vis. Sci. 52(7), 4151–4157 (2011).
[Crossref] [PubMed]

Chun, L. L.

M. L. Applebury, M. P. Antoch, L. C. Baxter, L. L. Chun, J. D. Falk, F. Farhangfar, K. Kage, M. G. Krzystolik, L. A. Lyass, and J. T. Robbins, “The murine cone photoreceptor: a single cone type expresses both S and M opsins with retinal spatial patterning,” Neuron 27(3), 513–523 (2000).
[Crossref] [PubMed]

Côté, D.

Curcio, C. A.

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]

D’Anna, S. A.

Dalkara, D.

D. Dalkara, L. C. Byrne, R. R. Klimczak, M. Visel, L. Yin, W. H. Merigan, J. G. Flannery, and D. V. Schaffer, “In vivo-directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous,” Sci. Transl. Med. 5(189), 189ra76 (2013).
[Crossref] [PubMed]

Daniele, L. L.

L. L. Daniele, C. Insinna, R. Chance, J. Wang, S. S. Nikonov, and E. N. Pugh., “A mouse M-opsin monochromat: retinal cone photoreceptors have increased M-opsin expression when S-opsin is knocked out,” Vision Res. 51(4), 447–458 (2011).
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Donnelly Iii, W.

Dubra, A.

Duker, J.

Ellisman, M. H.

B. N. Giepmans, S. R. Adams, M. H. Ellisman, and R. Y. Tsien, “The fluorescent toolbox for assessing protein location and function,” Science 312(5771), 217–224 (2006).
[Crossref] [PubMed]

Esdaille, T. M.

F. Naarendorp, T. M. Esdaille, S. M. Banden, J. Andrews-Labenski, O. P. Gross, and E. N. Pugh., “Dark light, rod saturation, and the absolute and incremental sensitivity of mouse cone vision,” J. Neurosci. 30(37), 12495–12507 (2010).
[Crossref] [PubMed]

Falk, J. D.

M. L. Applebury, M. P. Antoch, L. C. Baxter, L. L. Chun, J. D. Falk, F. Farhangfar, K. Kage, M. G. Krzystolik, L. A. Lyass, and J. T. Robbins, “The murine cone photoreceptor: a single cone type expresses both S and M opsins with retinal spatial patterning,” Neuron 27(3), 513–523 (2000).
[Crossref] [PubMed]

Farhangfar, F.

M. L. Applebury, M. P. Antoch, L. C. Baxter, L. L. Chun, J. D. Falk, F. Farhangfar, K. Kage, M. G. Krzystolik, L. A. Lyass, and J. T. Robbins, “The murine cone photoreceptor: a single cone type expresses both S and M opsins with retinal spatial patterning,” Neuron 27(3), 513–523 (2000).
[Crossref] [PubMed]

Fei, Y.

Y. Fei and T. E. Hughes, “Transgenic expression of the jellyfish green fluorescent protein in the cone photoreceptors of the mouse,” Vis. Neurosci. 18(4), 615–623 (2001).
[Crossref] [PubMed]

Fingler, J.

FitzGerald, P.

E. S. Levine, A. Zam, P. Zhang, A. Pechko, X. Wang, P. FitzGerald, E. N. Pugh, R. J. Zawadzki, and M. E. Burns, “Rapid light-induced activation of retinal microglia in mice lacking Arrestin-1,” Vision Res. 102, 71–79 (2014).
[Crossref] [PubMed]

Flannery, J. G.

D. Dalkara, L. C. Byrne, R. R. Klimczak, M. Visel, L. Yin, W. H. Merigan, J. G. Flannery, and D. V. Schaffer, “In vivo-directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous,” Sci. Transl. Med. 5(189), 189ra76 (2013).
[Crossref] [PubMed]

Fraser, S. E.

Freeman, W. T.

W. T. Freeman and E. H. Adelson, “The Design and Use of Steerable Filters,” IEEE Trans. Pattern Anal. Mach. Intell. 13(9), 891–906 (1991).
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Fujimoto, J.

Gearhart, J.

Y. Wang, J. P. Macke, S. L. Merbs, D. J. Zack, B. Klaunberg, J. Bennett, J. Gearhart, and J. Nathans, “A locus control region adjacent to the human red and green visual pigment genes,” Neuron 9(3), 429–440 (1992).
[Crossref] [PubMed]

Geng, Y.

L. Yin, Y. Geng, F. Osakada, R. Sharma, A. H. Cetin, E. M. Callaway, D. R. Williams, and W. H. Merigan, “Imaging light responses of retinal ganglion cells in the living mouse eye,” J. Neurophysiol. 109(9), 2415–2421 (2013).
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R. Sharma, L. Yin, Y. Geng, W. H. Merigan, G. Palczewska, K. Palczewski, D. R. Williams, and J. J. Hunter, “In vivo two-photon imaging of the mouse retina,” Biomed. Opt. Express 4(8), 1285–1293 (2013).
[Crossref] [PubMed]

J. Schallek, Y. Geng, H. Nguyen, and D. R. Williams, “Morphology and topography of retinal pericytes in the living mouse retina using in vivo adaptive optics imaging and ex vivo characterization,” Invest. Ophthalmol. Vis. Sci. 54(13), 8237–8250 (2013).
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Y. Geng, A. Dubra, L. Yin, W. H. Merigan, R. Sharma, R. T. Libby, and D. R. Williams, “Adaptive optics retinal imaging in the living mouse eye,” Biomed. Opt. Express 3(4), 715–734 (2012).
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Y. Geng, L. A. Schery, R. Sharma, A. Dubra, K. Ahmad, R. T. Libby, and D. R. Williams, “Optical properties of the mouse eye,” Biomed. Opt. Express 2(4), 717–738 (2011).
[Crossref] [PubMed]

Giepmans, B. N.

B. N. Giepmans, S. R. Adams, M. H. Ellisman, and R. Y. Tsien, “The fluorescent toolbox for assessing protein location and function,” Science 312(5771), 217–224 (2006).
[Crossref] [PubMed]

Gordon, S.

D. A. Hume, V. H. Perry, and S. Gordon, “Immunohistochemical localization of a macrophage-specific antigen in developing mouse retina: phagocytosis of dying neurons and differentiation of microglial cells to form a regular array in the plexiform layers,” J. Cell Biol. 97(1), 253–257 (1983).
[Crossref] [PubMed]

Gradowski, M. A.

Graemmel, P.

S. Jung, J. Aliberti, P. Graemmel, M. J. Sunshine, G. W. Kreutzberg, A. Sher, and D. R. Littman, “Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion,” Mol. Cell. Biol. 20(11), 4106–4114 (2000).
[Crossref] [PubMed]

Gross, O. P.

F. Naarendorp, T. M. Esdaille, S. M. Banden, J. Andrews-Labenski, O. P. Gross, and E. N. Pugh., “Dark light, rod saturation, and the absolute and incremental sensitivity of mouse cone vision,” J. Neurosci. 30(37), 12495–12507 (2010).
[Crossref] [PubMed]

Hall, C. N.

A. Mishra, F. M. O’Farrell, C. Reynell, N. B. Hamilton, C. N. Hall, and D. Attwell, “Imaging pericytes and capillary diameter in brain slices and isolated retinae,” Nat. Protoc. 9(2), 323–336 (2014).
[Crossref] [PubMed]

Hamilton, N. B.

A. Mishra, F. M. O’Farrell, C. Reynell, N. B. Hamilton, C. N. Hall, and D. Attwell, “Imaging pericytes and capillary diameter in brain slices and isolated retinae,” Nat. Protoc. 9(2), 323–336 (2014).
[Crossref] [PubMed]

Hebert, T.

Hendrickson, A. E.

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]

Hochheimer, B. F.

Hughes, T. E.

Y. Fei and T. E. Hughes, “Transgenic expression of the jellyfish green fluorescent protein in the cone photoreceptors of the mouse,” Vis. Neurosci. 18(4), 615–623 (2001).
[Crossref] [PubMed]

Hume, D. A.

D. A. Hume, V. H. Perry, and S. Gordon, “Immunohistochemical localization of a macrophage-specific antigen in developing mouse retina: phagocytosis of dying neurons and differentiation of microglial cells to form a regular array in the plexiform layers,” J. Cell Biol. 97(1), 253–257 (1983).
[Crossref] [PubMed]

Hunter, J. J.

Insinna, C.

L. L. Daniele, C. Insinna, R. Chance, J. Wang, S. S. Nikonov, and E. N. Pugh., “A mouse M-opsin monochromat: retinal cone photoreceptors have increased M-opsin expression when S-opsin is knocked out,” Vision Res. 51(4), 447–458 (2011).
[Crossref] [PubMed]

Izatt, J. A.

Jacob, M.

M. Jacob and M. Unser, “Design of steerable filters for feature detection using canny-like criteria,” IEEE Trans. Pattern Anal. Mach. Intell. 26(8), 1007–1019 (2004).
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Jian, Y.

Jones, S. M.

Jonnal, R. S.

R. S. Jonnal, O. P. Kocaoglu, R. J. Zawadzki, S. H. Lee, J. S. Werner, and D. T. Miller, “The cellular origins of the outer retinal bands in optical coherence tomography images,” Invest. Ophthalmol. Vis. Sci. 55(12), 7904–7918 (2014).
[Crossref] [PubMed]

Jung, S.

S. Jung, J. Aliberti, P. Graemmel, M. J. Sunshine, G. W. Kreutzberg, A. Sher, and D. R. Littman, “Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion,” Mol. Cell. Biol. 20(11), 4106–4114 (2000).
[Crossref] [PubMed]

Kage, K.

M. L. Applebury, M. P. Antoch, L. C. Baxter, L. L. Chun, J. D. Falk, F. Farhangfar, K. Kage, M. G. Krzystolik, L. A. Lyass, and J. T. Robbins, “The murine cone photoreceptor: a single cone type expresses both S and M opsins with retinal spatial patterning,” Neuron 27(3), 513–523 (2000).
[Crossref] [PubMed]

Kalina, R. E.

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]

Kholodenko, R.

S. S. Nikonov, R. Kholodenko, J. Lem, and E. N. Pugh., “Physiological features of the S- and M-cone photoreceptors of wild-type mice from single-cell recordings,” J. Gen. Physiol. 127(4), 359–374 (2006).
[Crossref] [PubMed]

Kim, D. Y.

D. M. Schwartz, J. Fingler, D. Y. Kim, R. J. Zawadzki, L. S. Morse, S. S. Park, S. E. Fraser, and J. S. Werner, “Phase-variance optical coherence tomography: a technique for noninvasive angiography,” Ophthalmology 121(1), 180–187 (2014).
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D. Y. Kim, J. Fingler, R. J. Zawadzki, S. S. Park, L. S. Morse, D. M. Schwartz, S. E. Fraser, and J. S. Werner, “Optical imaging of the chorioretinal vasculature in the living human eye,” Proc. Natl. Acad. Sci. U.S.A. 110(35), 14354–14359 (2013).
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R. J. Zawadzki, S. M. Jones, S. Pilli, S. Balderas-Mata, D. Y. Kim, S. S. Olivier, and J. S. Werner, “Integrated adaptive optics optical coherence tomography and adaptive optics scanning laser ophthalmoscope system for simultaneous cellular resolution in vivo retinal imaging,” Biomed. Opt. Express 2(6), 1674–1686 (2011).
[PubMed]

D. Y. Kim, J. Fingler, J. S. Werner, D. M. Schwartz, S. E. Fraser, and R. J. Zawadzki, “In vivo volumetric imaging of human retinal circulation with phase-variance optical coherence tomography,” Biomed. Opt. Express 2(6), 1504–1513 (2011).
[Crossref] [PubMed]

Klaunberg, B.

Y. Wang, J. P. Macke, S. L. Merbs, D. J. Zack, B. Klaunberg, J. Bennett, J. Gearhart, and J. Nathans, “A locus control region adjacent to the human red and green visual pigment genes,” Neuron 9(3), 429–440 (1992).
[Crossref] [PubMed]

Klimczak, R. R.

D. Dalkara, L. C. Byrne, R. R. Klimczak, M. Visel, L. Yin, W. H. Merigan, J. G. Flannery, and D. V. Schaffer, “In vivo-directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous,” Sci. Transl. Med. 5(189), 189ra76 (2013).
[Crossref] [PubMed]

Knox, B. E.

J. A. Peet, A. Bragin, P. D. Calvert, S. S. Nikonov, S. Mani, X. Zhao, J. C. Besharse, E. A. Pierce, B. E. Knox, and E. N. Pugh., “Quantification of the cytoplasmic spaces of living cells with EGFP reveals arrestin-EGFP to be in disequilibrium in dark adapted rod photoreceptors,” J. Cell Sci. 117(14), 3049–3059 (2004).
[Crossref] [PubMed]

Ko, T.

Kocaoglu, O. P.

R. S. Jonnal, O. P. Kocaoglu, R. J. Zawadzki, S. H. Lee, J. S. Werner, and D. T. Miller, “The cellular origins of the outer retinal bands in optical coherence tomography images,” Invest. Ophthalmol. Vis. Sci. 55(12), 7904–7918 (2014).
[Crossref] [PubMed]

Kowalczyk, A.

Kreutzberg, G. W.

S. Jung, J. Aliberti, P. Graemmel, M. J. Sunshine, G. W. Kreutzberg, A. Sher, and D. R. Littman, “Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion,” Mol. Cell. Biol. 20(11), 4106–4114 (2000).
[Crossref] [PubMed]

Krzystolik, M. G.

M. L. Applebury, M. P. Antoch, L. C. Baxter, L. L. Chun, J. D. Falk, F. Farhangfar, K. Kage, M. G. Krzystolik, L. A. Lyass, and J. T. Robbins, “The murine cone photoreceptor: a single cone type expresses both S and M opsins with retinal spatial patterning,” Neuron 27(3), 513–523 (2000).
[Crossref] [PubMed]

Laut, S.

LaVail, M. M.

L. D. Carter-Dawson and M. M. LaVail, “Rods and cones in the mouse retina. I. Structural analysis using light and electron microscopy,” J. Comp. Neurol. 188(2), 245–262 (1979).
[Crossref] [PubMed]

Lee, S. H.

R. S. Jonnal, O. P. Kocaoglu, R. J. Zawadzki, S. H. Lee, J. S. Werner, and D. T. Miller, “The cellular origins of the outer retinal bands in optical coherence tomography images,” Invest. Ophthalmol. Vis. Sci. 55(12), 7904–7918 (2014).
[Crossref] [PubMed]

S. H. Lee, J. S. Werner, and R. J. Zawadzki, “Improved visualization of outer retinal morphology with aberration cancelling reflective optical design for adaptive optics - optical coherence tomography,” Biomed. Opt. Express 4(11), 2508–2517 (2013).
[Crossref] [PubMed]

Lem, J.

S. S. Nikonov, R. Kholodenko, J. Lem, and E. N. Pugh., “Physiological features of the S- and M-cone photoreceptors of wild-type mice from single-cell recordings,” J. Gen. Physiol. 127(4), 359–374 (2006).
[Crossref] [PubMed]

Levine, E. S.

E. S. Levine, A. Zam, P. Zhang, A. Pechko, X. Wang, P. FitzGerald, E. N. Pugh, R. J. Zawadzki, and M. E. Burns, “Rapid light-induced activation of retinal microglia in mice lacking Arrestin-1,” Vision Res. 102, 71–79 (2014).
[Crossref] [PubMed]

Libby, R. T.

Lin, C. P.

C. Alt, J. M. Runnels, L. J. Mortensen, W. Zaher, and C. P. Lin, “In vivo imaging of microglia turnover in the mouse retina after ionizing radiation and dexamethasone treatment,” Invest. Ophthalmol. Vis. Sci. 55(8), 5314–5319 (2014).
[Crossref] [PubMed]

D. P. Biss, D. Sumorok, S. A. Burns, R. H. Webb, Y. Zhou, T. G. Bifano, D. Côté, I. Veilleux, P. Zamiri, and C. P. Lin, “In vivo fluorescent imaging of the mouse retina using adaptive optics,” Opt. Lett. 32(6), 659–661 (2007).
[Crossref] [PubMed]

Littman, D. R.

S. Jung, J. Aliberti, P. Graemmel, M. J. Sunshine, G. W. Kreutzberg, A. Sher, and D. R. Littman, “Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion,” Mol. Cell. Biol. 20(11), 4106–4114 (2000).
[Crossref] [PubMed]

Lutty, G. A.

Lyass, L. A.

M. L. Applebury, M. P. Antoch, L. C. Baxter, L. L. Chun, J. D. Falk, F. Farhangfar, K. Kage, M. G. Krzystolik, L. A. Lyass, and J. T. Robbins, “The murine cone photoreceptor: a single cone type expresses both S and M opsins with retinal spatial patterning,” Neuron 27(3), 513–523 (2000).
[Crossref] [PubMed]

Macke, J. P.

Y. Wang, J. P. Macke, S. L. Merbs, D. J. Zack, B. Klaunberg, J. Bennett, J. Gearhart, and J. Nathans, “A locus control region adjacent to the human red and green visual pigment genes,” Neuron 9(3), 429–440 (1992).
[Crossref] [PubMed]

Mani, S.

J. A. Peet, A. Bragin, P. D. Calvert, S. S. Nikonov, S. Mani, X. Zhao, J. C. Besharse, E. A. Pierce, B. E. Knox, and E. N. Pugh., “Quantification of the cytoplasmic spaces of living cells with EGFP reveals arrestin-EGFP to be in disequilibrium in dark adapted rod photoreceptors,” J. Cell Sci. 117(14), 3049–3059 (2004).
[Crossref] [PubMed]

Martin, J. A.

J. Tam, J. A. Martin, and A. Roorda, “Noninvasive visualization and analysis of parafoveal capillaries in humans,” Invest. Ophthalmol. Vis. Sci. 51(3), 1691–1698 (2010).
[Crossref] [PubMed]

Merbs, S. L.

Y. Wang, J. P. Macke, S. L. Merbs, D. J. Zack, B. Klaunberg, J. Bennett, J. Gearhart, and J. Nathans, “A locus control region adjacent to the human red and green visual pigment genes,” Neuron 9(3), 429–440 (1992).
[Crossref] [PubMed]

Merigan, W. H.

L. Yin, Y. Geng, F. Osakada, R. Sharma, A. H. Cetin, E. M. Callaway, D. R. Williams, and W. H. Merigan, “Imaging light responses of retinal ganglion cells in the living mouse eye,” J. Neurophysiol. 109(9), 2415–2421 (2013).
[Crossref] [PubMed]

R. Sharma, L. Yin, Y. Geng, W. H. Merigan, G. Palczewska, K. Palczewski, D. R. Williams, and J. J. Hunter, “In vivo two-photon imaging of the mouse retina,” Biomed. Opt. Express 4(8), 1285–1293 (2013).
[Crossref] [PubMed]

D. Dalkara, L. C. Byrne, R. R. Klimczak, M. Visel, L. Yin, W. H. Merigan, J. G. Flannery, and D. V. Schaffer, “In vivo-directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous,” Sci. Transl. Med. 5(189), 189ra76 (2013).
[Crossref] [PubMed]

Y. Geng, A. Dubra, L. Yin, W. H. Merigan, R. Sharma, R. T. Libby, and D. R. Williams, “Adaptive optics retinal imaging in the living mouse eye,” Biomed. Opt. Express 3(4), 715–734 (2012).
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Miller, D. T.

R. S. Jonnal, O. P. Kocaoglu, R. J. Zawadzki, S. H. Lee, J. S. Werner, and D. T. Miller, “The cellular origins of the outer retinal bands in optical coherence tomography images,” Invest. Ophthalmol. Vis. Sci. 55(12), 7904–7918 (2014).
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A. Mishra, F. M. O’Farrell, C. Reynell, N. B. Hamilton, C. N. Hall, and D. Attwell, “Imaging pericytes and capillary diameter in brain slices and isolated retinae,” Nat. Protoc. 9(2), 323–336 (2014).
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D. M. Schwartz, J. Fingler, D. Y. Kim, R. J. Zawadzki, L. S. Morse, S. S. Park, S. E. Fraser, and J. S. Werner, “Phase-variance optical coherence tomography: a technique for noninvasive angiography,” Ophthalmology 121(1), 180–187 (2014).
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C. Alt, J. M. Runnels, L. J. Mortensen, W. Zaher, and C. P. Lin, “In vivo imaging of microglia turnover in the mouse retina after ionizing radiation and dexamethasone treatment,” Invest. Ophthalmol. Vis. Sci. 55(8), 5314–5319 (2014).
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Y. Wang, J. P. Macke, S. L. Merbs, D. J. Zack, B. Klaunberg, J. Bennett, J. Gearhart, and J. Nathans, “A locus control region adjacent to the human red and green visual pigment genes,” Neuron 9(3), 429–440 (1992).
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J. Schallek, Y. Geng, H. Nguyen, and D. R. Williams, “Morphology and topography of retinal pericytes in the living mouse retina using in vivo adaptive optics imaging and ex vivo characterization,” Invest. Ophthalmol. Vis. Sci. 54(13), 8237–8250 (2013).
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J. B. Schallek, H. N. Nguyen, C. Schwarz, and D. R. Williams, “Non-invasive Adaptive Optics Imaging of Retinal Pericytes and Capillary Blood Velocity in Mice,” J. Vis. 12(14), 50 (2012).
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L. L. Daniele, C. Insinna, R. Chance, J. Wang, S. S. Nikonov, and E. N. Pugh., “A mouse M-opsin monochromat: retinal cone photoreceptors have increased M-opsin expression when S-opsin is knocked out,” Vision Res. 51(4), 447–458 (2011).
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A. Mishra, F. M. O’Farrell, C. Reynell, N. B. Hamilton, C. N. Hall, and D. Attwell, “Imaging pericytes and capillary diameter in brain slices and isolated retinae,” Nat. Protoc. 9(2), 323–336 (2014).
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Osakada, F.

L. Yin, Y. Geng, F. Osakada, R. Sharma, A. H. Cetin, E. M. Callaway, D. R. Williams, and W. H. Merigan, “Imaging light responses of retinal ganglion cells in the living mouse eye,” J. Neurophysiol. 109(9), 2415–2421 (2013).
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Palczewski, K.

Park, S. S.

D. M. Schwartz, J. Fingler, D. Y. Kim, R. J. Zawadzki, L. S. Morse, S. S. Park, S. E. Fraser, and J. S. Werner, “Phase-variance optical coherence tomography: a technique for noninvasive angiography,” Ophthalmology 121(1), 180–187 (2014).
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D. Y. Kim, J. Fingler, R. J. Zawadzki, S. S. Park, L. S. Morse, D. M. Schwartz, S. E. Fraser, and J. S. Werner, “Optical imaging of the chorioretinal vasculature in the living human eye,” Proc. Natl. Acad. Sci. U.S.A. 110(35), 14354–14359 (2013).
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E. S. Levine, A. Zam, P. Zhang, A. Pechko, X. Wang, P. FitzGerald, E. N. Pugh, R. J. Zawadzki, and M. E. Burns, “Rapid light-induced activation of retinal microglia in mice lacking Arrestin-1,” Vision Res. 102, 71–79 (2014).
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Z. Zhong, H. Song, T. Y. Chui, B. L. Petrig, and S. A. Burns, “Noninvasive measurements and analysis of blood velocity profiles in human retinal vessels,” Invest. Ophthalmol. Vis. Sci. 52(7), 4151–4157 (2011).
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J. A. Peet, A. Bragin, P. D. Calvert, S. S. Nikonov, S. Mani, X. Zhao, J. C. Besharse, E. A. Pierce, B. E. Knox, and E. N. Pugh., “Quantification of the cytoplasmic spaces of living cells with EGFP reveals arrestin-EGFP to be in disequilibrium in dark adapted rod photoreceptors,” J. Cell Sci. 117(14), 3049–3059 (2004).
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Pugh, E. N.

E. S. Levine, A. Zam, P. Zhang, A. Pechko, X. Wang, P. FitzGerald, E. N. Pugh, R. J. Zawadzki, and M. E. Burns, “Rapid light-induced activation of retinal microglia in mice lacking Arrestin-1,” Vision Res. 102, 71–79 (2014).
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A. Z. Zam, E. N. Pugh, and R. J. Zawadzki, “Evaluation of OCT for quantitative in vivo measurements of changes in neural tissue scattering in longitudinal studies of retinal degeneration in mice,” Proceedings of SPIE BiOS: Optical Coherence Tomography and Coherence Domain Optical Methods in Biomedicine 8934, 6 (2014).

L. L. Daniele, C. Insinna, R. Chance, J. Wang, S. S. Nikonov, and E. N. Pugh., “A mouse M-opsin monochromat: retinal cone photoreceptors have increased M-opsin expression when S-opsin is knocked out,” Vision Res. 51(4), 447–458 (2011).
[Crossref] [PubMed]

F. Naarendorp, T. M. Esdaille, S. M. Banden, J. Andrews-Labenski, O. P. Gross, and E. N. Pugh., “Dark light, rod saturation, and the absolute and incremental sensitivity of mouse cone vision,” J. Neurosci. 30(37), 12495–12507 (2010).
[Crossref] [PubMed]

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J. A. Peet, A. Bragin, P. D. Calvert, S. S. Nikonov, S. Mani, X. Zhao, J. C. Besharse, E. A. Pierce, B. E. Knox, and E. N. Pugh., “Quantification of the cytoplasmic spaces of living cells with EGFP reveals arrestin-EGFP to be in disequilibrium in dark adapted rod photoreceptors,” J. Cell Sci. 117(14), 3049–3059 (2004).
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Reynell, C.

A. Mishra, F. M. O’Farrell, C. Reynell, N. B. Hamilton, C. N. Hall, and D. Attwell, “Imaging pericytes and capillary diameter in brain slices and isolated retinae,” Nat. Protoc. 9(2), 323–336 (2014).
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M. L. Applebury, M. P. Antoch, L. C. Baxter, L. L. Chun, J. D. Falk, F. Farhangfar, K. Kage, M. G. Krzystolik, L. A. Lyass, and J. T. Robbins, “The murine cone photoreceptor: a single cone type expresses both S and M opsins with retinal spatial patterning,” Neuron 27(3), 513–523 (2000).
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J. Tam, J. A. Martin, and A. Roorda, “Noninvasive visualization and analysis of parafoveal capillaries in humans,” Invest. Ophthalmol. Vis. Sci. 51(3), 1691–1698 (2010).
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C. Alt, J. M. Runnels, L. J. Mortensen, W. Zaher, and C. P. Lin, “In vivo imaging of microglia turnover in the mouse retina after ionizing radiation and dexamethasone treatment,” Invest. Ophthalmol. Vis. Sci. 55(8), 5314–5319 (2014).
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Schaffer, D. V.

D. Dalkara, L. C. Byrne, R. R. Klimczak, M. Visel, L. Yin, W. H. Merigan, J. G. Flannery, and D. V. Schaffer, “In vivo-directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous,” Sci. Transl. Med. 5(189), 189ra76 (2013).
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J. Schallek, Y. Geng, H. Nguyen, and D. R. Williams, “Morphology and topography of retinal pericytes in the living mouse retina using in vivo adaptive optics imaging and ex vivo characterization,” Invest. Ophthalmol. Vis. Sci. 54(13), 8237–8250 (2013).
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J. B. Schallek, H. N. Nguyen, C. Schwarz, and D. R. Williams, “Non-invasive Adaptive Optics Imaging of Retinal Pericytes and Capillary Blood Velocity in Mice,” J. Vis. 12(14), 50 (2012).
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Schwartz, D.

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D. M. Schwartz, J. Fingler, D. Y. Kim, R. J. Zawadzki, L. S. Morse, S. S. Park, S. E. Fraser, and J. S. Werner, “Phase-variance optical coherence tomography: a technique for noninvasive angiography,” Ophthalmology 121(1), 180–187 (2014).
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D. Y. Kim, J. Fingler, J. S. Werner, D. M. Schwartz, S. E. Fraser, and R. J. Zawadzki, “In vivo volumetric imaging of human retinal circulation with phase-variance optical coherence tomography,” Biomed. Opt. Express 2(6), 1504–1513 (2011).
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J. B. Schallek, H. N. Nguyen, C. Schwarz, and D. R. Williams, “Non-invasive Adaptive Optics Imaging of Retinal Pericytes and Capillary Blood Velocity in Mice,” J. Vis. 12(14), 50 (2012).
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Z. Zhong, H. Song, T. Y. Chui, B. L. Petrig, and S. A. Burns, “Noninvasive measurements and analysis of blood velocity profiles in human retinal vessels,” Invest. Ophthalmol. Vis. Sci. 52(7), 4151–4157 (2011).
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Sumorok, D.

Sunshine, M. J.

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J. Tam, J. A. Martin, and A. Roorda, “Noninvasive visualization and analysis of parafoveal capillaries in humans,” Invest. Ophthalmol. Vis. Sci. 51(3), 1691–1698 (2010).
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L. L. Daniele, C. Insinna, R. Chance, J. Wang, S. S. Nikonov, and E. N. Pugh., “A mouse M-opsin monochromat: retinal cone photoreceptors have increased M-opsin expression when S-opsin is knocked out,” Vision Res. 51(4), 447–458 (2011).
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Werner, J. S.

D. M. Schwartz, J. Fingler, D. Y. Kim, R. J. Zawadzki, L. S. Morse, S. S. Park, S. E. Fraser, and J. S. Werner, “Phase-variance optical coherence tomography: a technique for noninvasive angiography,” Ophthalmology 121(1), 180–187 (2014).
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D. Y. Kim, J. Fingler, R. J. Zawadzki, S. S. Park, L. S. Morse, D. M. Schwartz, S. E. Fraser, and J. S. Werner, “Optical imaging of the chorioretinal vasculature in the living human eye,” Proc. Natl. Acad. Sci. U.S.A. 110(35), 14354–14359 (2013).
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S. H. Lee, J. S. Werner, and R. J. Zawadzki, “Improved visualization of outer retinal morphology with aberration cancelling reflective optical design for adaptive optics - optical coherence tomography,” Biomed. Opt. Express 4(11), 2508–2517 (2013).
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J. Schallek, Y. Geng, H. Nguyen, and D. R. Williams, “Morphology and topography of retinal pericytes in the living mouse retina using in vivo adaptive optics imaging and ex vivo characterization,” Invest. Ophthalmol. Vis. Sci. 54(13), 8237–8250 (2013).
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R. Sharma, L. Yin, Y. Geng, W. H. Merigan, G. Palczewska, K. Palczewski, D. R. Williams, and J. J. Hunter, “In vivo two-photon imaging of the mouse retina,” Biomed. Opt. Express 4(8), 1285–1293 (2013).
[Crossref] [PubMed]

L. Yin, Y. Geng, F. Osakada, R. Sharma, A. H. Cetin, E. M. Callaway, D. R. Williams, and W. H. Merigan, “Imaging light responses of retinal ganglion cells in the living mouse eye,” J. Neurophysiol. 109(9), 2415–2421 (2013).
[Crossref] [PubMed]

Y. Geng, A. Dubra, L. Yin, W. H. Merigan, R. Sharma, R. T. Libby, and D. R. Williams, “Adaptive optics retinal imaging in the living mouse eye,” Biomed. Opt. Express 3(4), 715–734 (2012).
[Crossref] [PubMed]

J. B. Schallek, H. N. Nguyen, C. Schwarz, and D. R. Williams, “Non-invasive Adaptive Optics Imaging of Retinal Pericytes and Capillary Blood Velocity in Mice,” J. Vis. 12(14), 50 (2012).
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Y. Geng, L. A. Schery, R. Sharma, A. Dubra, K. Ahmad, R. T. Libby, and D. R. Williams, “Optical properties of the mouse eye,” Biomed. Opt. Express 2(4), 717–738 (2011).
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D. R. Williams, “Imaging single cells in the living retina,” Vision Res. 51(13), 1379–1396 (2011).
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Yang, C.

Yin, L.

R. Sharma, L. Yin, Y. Geng, W. H. Merigan, G. Palczewska, K. Palczewski, D. R. Williams, and J. J. Hunter, “In vivo two-photon imaging of the mouse retina,” Biomed. Opt. Express 4(8), 1285–1293 (2013).
[Crossref] [PubMed]

L. Yin, Y. Geng, F. Osakada, R. Sharma, A. H. Cetin, E. M. Callaway, D. R. Williams, and W. H. Merigan, “Imaging light responses of retinal ganglion cells in the living mouse eye,” J. Neurophysiol. 109(9), 2415–2421 (2013).
[Crossref] [PubMed]

D. Dalkara, L. C. Byrne, R. R. Klimczak, M. Visel, L. Yin, W. H. Merigan, J. G. Flannery, and D. V. Schaffer, “In vivo-directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous,” Sci. Transl. Med. 5(189), 189ra76 (2013).
[Crossref] [PubMed]

Y. Geng, A. Dubra, L. Yin, W. H. Merigan, R. Sharma, R. T. Libby, and D. R. Williams, “Adaptive optics retinal imaging in the living mouse eye,” Biomed. Opt. Express 3(4), 715–734 (2012).
[Crossref] [PubMed]

Zack, D. J.

Y. Wang, J. P. Macke, S. L. Merbs, D. J. Zack, B. Klaunberg, J. Bennett, J. Gearhart, and J. Nathans, “A locus control region adjacent to the human red and green visual pigment genes,” Neuron 9(3), 429–440 (1992).
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Zaher, W.

C. Alt, J. M. Runnels, L. J. Mortensen, W. Zaher, and C. P. Lin, “In vivo imaging of microglia turnover in the mouse retina after ionizing radiation and dexamethasone treatment,” Invest. Ophthalmol. Vis. Sci. 55(8), 5314–5319 (2014).
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E. S. Levine, A. Zam, P. Zhang, A. Pechko, X. Wang, P. FitzGerald, E. N. Pugh, R. J. Zawadzki, and M. E. Burns, “Rapid light-induced activation of retinal microglia in mice lacking Arrestin-1,” Vision Res. 102, 71–79 (2014).
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A. Z. Zam, E. N. Pugh, and R. J. Zawadzki, “Evaluation of OCT for quantitative in vivo measurements of changes in neural tissue scattering in longitudinal studies of retinal degeneration in mice,” Proceedings of SPIE BiOS: Optical Coherence Tomography and Coherence Domain Optical Methods in Biomedicine 8934, 6 (2014).

Zamiri, P.

Zawadzki, R. J.

D. M. Schwartz, J. Fingler, D. Y. Kim, R. J. Zawadzki, L. S. Morse, S. S. Park, S. E. Fraser, and J. S. Werner, “Phase-variance optical coherence tomography: a technique for noninvasive angiography,” Ophthalmology 121(1), 180–187 (2014).
[Crossref] [PubMed]

R. S. Jonnal, O. P. Kocaoglu, R. J. Zawadzki, S. H. Lee, J. S. Werner, and D. T. Miller, “The cellular origins of the outer retinal bands in optical coherence tomography images,” Invest. Ophthalmol. Vis. Sci. 55(12), 7904–7918 (2014).
[Crossref] [PubMed]

A. Z. Zam, E. N. Pugh, and R. J. Zawadzki, “Evaluation of OCT for quantitative in vivo measurements of changes in neural tissue scattering in longitudinal studies of retinal degeneration in mice,” Proceedings of SPIE BiOS: Optical Coherence Tomography and Coherence Domain Optical Methods in Biomedicine 8934, 6 (2014).

E. S. Levine, A. Zam, P. Zhang, A. Pechko, X. Wang, P. FitzGerald, E. N. Pugh, R. J. Zawadzki, and M. E. Burns, “Rapid light-induced activation of retinal microglia in mice lacking Arrestin-1,” Vision Res. 102, 71–79 (2014).
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S. H. Lee, J. S. Werner, and R. J. Zawadzki, “Improved visualization of outer retinal morphology with aberration cancelling reflective optical design for adaptive optics - optical coherence tomography,” Biomed. Opt. Express 4(11), 2508–2517 (2013).
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Supplementary Material (8)

» Media 1: AVI (41477 KB)     
» Media 2: AVI (24307 KB)     
» Media 3: AVI (138248 KB)     
» Media 4: AVI (31584 KB)     
» Media 5: AVI (3954 KB)     
» Media 6: AVI (3198 KB)     
» Media 7: AVI (9340 KB)     
» Media 8: AVI (41477 KB)     

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Figures (9)

Fig. 1
Fig. 1

Optical layout of the AO-SLO system. The layout is presented in a scale drawing, and the precise x-, y- and z- locations of each element are presented in Table 1. Abbreviations: L#, lens; M, mirror; SM, spherical mirror; DM, deformable mirror; D#, dichroic mirror; OBJ, focusing objective lens; Hsc, horizontal resonant scanner; Vsc, vertical scanner; PMT, photomultiplier tube; P (circled in blue) optical planes conjugate with the pupil; SLD, superluminescent diode. Collimated beams are marked as dashed lines and focusing beams are marked as solid lines. The on-axis beams are represented by red lines and scanned beams by green and blue.

Fig. 2
Fig. 2

Optical performance of our AO-SLO system as a function of imaging beam position in x- and y-axis (mechanical angle of HSC and VSC) on the mouse retina over 6 deg x 6 deg (200 µm x 200 µm). A. RMS wavefront error. B. Pupil wander. C. RMS wavefront error of the AO-SLO system after correction for defocus at the entrance pupil by the Deformable Mirror (one DM shape for one Defocus value), evaluated on axis and at the four extremes of the full scanning range of 3 deg ( ± 1.5 deg) and 6 deg ( ± 3.0 deg). Dashed horizontal lines represent diffraction limited RMS (λ/13.4) for 469 nm (blue) and 663 nm (red) wavelength (35 nm and 49.5 nm respectively). Note, that these simulations do not take into account the optical aberrations of the mouse eye, which necessarily reduces system performance.

Fig. 3
Fig. 3

OCT imaging and phase-variance (pv-) analysis reveals the mouse retinal vascular bed. A. B-scan centered on the optic nerve corresponding to the red dashed arrow in B (note 1:1 x-y scaling). The retinal layer and boundary identifications are: NFL neurofibrillary layer); IPL (inner plexiform layer); INL (inner nuclear layer); OPL (outer plexiform layer); ONL (outer nuclear layer); ELM (external limiting membrane); IS/OS (photoreceptors’ inner segment/outer segment junctions); RPE (retinal pigment epithelium). B. En face projection of the OCT volume (41 deg visual angle, 1400 µm diameter) centered on the optic nerve and illustrating the major blood vessels (Media 1 presents a rendering of the full volume). C. En face projection of the phase variance analysis of the OCT volume of panel B. D. High resolution pv-OCT image of the region in the red box in C; the vessel depth has been color coded as indicated in panel A (Media 2 presents a 3D rendering of the image in D). Blue box in C represents the location of the AO-SLO scan that is discussed in detail in Fig. 4.

Fig. 4
Fig. 4

Fluorescein angiography used to examine AO-SLO resolution and illustrate z-stack acquisition. A-C. Selected images from a z-stack of 350 images spanning retinal depth from the large superficial vessels to the capillaries of the outer plexiform layer (cf Fig. 3(C), blue box). The images correspond to stack positions z = 1 (A), z = 148 (B), z = 323 (C), corresponding to the NFL (A), the IPL (B), and OPL (C), respectively, as determined from the corresponding OCT volume (Fig. 3(C), 3(D)). D. Fluorescence intensity profiles (n = 17) along lines perpendicular to the smallest capillaries, illustrated in part by the red lines in panels B and C. E. Relationship between nominal position in the z-stack (abscissa) and depth in the retina measured in the corresponding pv-OCT image. The smooth parabolic curve fitted through the points was used to interpolate an image stack spaced in micrometers, shown as a “zoom-through” in Media 3. F. Depth color-coded projection of the fluorescein angiography images in Media 3; also see Media 4; the same color coding scheme was used as in Fig. 3(D).

Fig. 5
Fig. 5

AO-SLO imaging of microvasculature and depth localization via corresponding pv-OCT imaging. A. Digital zoom-in view of lower left quadrant of widefield pv-OCT image (grayscale), with three higher resolution images (color) aligned with and superimposed upon the pv-OCT map. The pv-OCT data acquired during mouse breathing was noisy in this experiment (increasing the pv-OCT signal magnitude), and for presentation clarity was masked (dark black horizontal lines) in the en face projection of panel A. The superimposed images are shown with 50% transparency to allow the underlying grayscale image to be seen: the two superimposed RGB-colorized images (yellow boxes) are projections of high resolution pv-OCT volumes, with color indicating depth, while the third image, shown in the red box, is an AO-SLO image, which is also shown in grayscale in the lowermost image (red box) of panel D. B. OCT B-scan taken at the dashed red line of panel A. C. pv-OCT image corresponding to the B-scan in B. D. AO-SLO red reflectance images (663 nm) taken at three focus levels. The layers are identified as the NFL, IPL and OPL respectively (top to bottom) based on the presence of axon bundles, and the progression of changes in the pattern of capillaries. The AO-SLO image identified as OPL was precisely aligned with the OPL layer vessels in 3D in the lower resolution pv-OCT map (red box in panel A). The high resolution pv-OCT images from the immediately adjacent retinal locations (yellow boxes) illustrate the detail available for identifying the 3D location of the AO-SLO image. The pv-OCT image (A) spanned 41 deg (1400 μm); the AO-SLO images span 200 μm x 200 μm. Note that pv-OCT shadow artifacts, marked by yellow arrows in panel C, are present below large retinal vessels in panel C. There is no vasculature in the photoreceptor layers; the phase variance detected there arises from pathlength fluctuations for light passing through fast flowing blood in the large inner retinal vessels.

Fig. 6
Fig. 6

AO-SLO reflectance imaging of OPL microvasculature. A. Average of 20 successive frames taken with 663 nm reflected light at a focus plane in the OPL. Red blood cell (RBC) motion in the lighter “looping” regions is visualized in Media 5, which plays a series of 147 successive frames. B. Map of the standard deviation of the ensemble of 147 frames shown in pseudocolor, ranging from blue (low s.d.) to red (high s.d.). The red “hotspot” near the center of the image corresponds to a site where the OPL capillary bed connects to that in the IPL: thus in Media 5 RBC’s are seen to appear at this location before traversing one of the two OPL capillaries connecting branching from the point. The images in A, B are 200 μm x 200 μm. C. Magnified view of the standard deviation image of B. D. DIC image from preparation of live mouse retina showing capillaries with red blood cells (from [37] with permission).

Fig. 7
Fig. 7

Measurement of blood flow in mouse retinal vasculature with 663 nm AO-SLO line-scanning. A, F: widefield (50 deg) 469 nm reflectance SLO images of two different mice approximately centered on the optic disc. Superimposed are averaged 663 nm AO-SLO reflectance images taken at the locations indicated by the cyan boxes. B, G: averaged AO-SLO x-y scans of the cyan-boxed regions in A, F (presented in the “Physics” colormap of ImageJ). The vessels are situated slightly above the neurofibrillary layer, some of whose fibers are seen as pale blue streaks in the background; the AO-SLO focus was set to be approximately in the middle of the vessels. (C) and (H) show individual frames in a series of linescans (x-t) taken at the midposition of x-y scans, as identified by the white dashed lines in B, G. (D) and (I) illustrate the automated processing used to extract the particle tracks (see Methods) with the left of each pair of panels showing extracted tracks (white dots) and the right showing an overlay of the tracks (red dots) on the original ROI selected for analysis. (E) and (J) show histograms of the velocities extracted from the 100- and 81 x-t scans, respectively. The image frames in panels A, B, F, H were 200 μm × 200 μm, and each frame took 0.0366 s to capture. Successive line scans in panels C and H were taken 71 μs apart, at the frequency (14,000 Hz) of the resonant scanner. Media 6 and Media 7 show the entire set of frames in each case, along with the automated extraction of the particle tracks, velocities and histograms.

Fig. 8
Fig. 8

AO-SLO images of microglia in different retinal layers. A. Widefield SLO reflectance image (469 nm) of the same mouse and retina as shown in Fig. 5; the pv-OCT map of Fig. 5(A) (but colorized for depth) has been superimposed upon and aligned with the SLO image, and the location of the AO-SLO imaging region overlaid (red box at 7 o’clock). B. Fluorescence image corresponding to panel A, acquired simultaneously with the SLO in a second channel, showing the distribution of microglia across this 50 deg FOV. C. AO-SLO reflectance images taken at the NFL, IPL and OPL layers; the OPL image (red box) was taken at the location of the red box in panel A (see also Fig. 5); note that, while less distinct than in the 663 nm reflectance images, the same capillaries are seen in the 469 nm images. D. AO-SLO fluorescence images taken with 469 nm excitation at the identical focus position as the 469 nm reflectance images in the corresponding panels in C. Note that the microglia exhibit a distinct pattern in each layer. Images in C, D, F are all from the same 6 deg, 200 μm x 200 μm FOV. E. Left: fluorescence image of a single microglia cell located in the OPL imaged in small FOV (3 deg, 100 μm x 100 μm). Right: depth color-coded image of the z-stack from which the fluorescence image at left was obtained, with NFL blue, IPL green, OPL red. F. Depth color-coded image of the fluorescence images in panel D; also see Media 8. The color coding scheme is the same as in previous figures, and is represented discretely by the color borders around the images in panel D.

Fig. 9
Fig. 9

AO-SLO imaging of mouse cone photoreceptors expressing EGFP. A. Confocal image of a live retinal slice of a mouse two months after an intravitreal injection of a capsid-modified AAV vector (AAV-7M8) carrying the coding sequence for EGFP driven by the human L/M-cone promoter (hlm-EGFP). Imaging was performed with a 60X objective; the retina was stained with Alexa555-labeled PNA, which specifically labels cone outer segment sheaths (red). Note that the regions of highest EGFP expression (green) are the cone cell bodies and inner segments (which sit astride the ELM), and the synaptic pedicles, which are in the OPL. B, C. Simultaneously acquired widefield SLO reflectance (B) and fluorescence (C) images of another mouse eye transduced with 7m8-hlm-EGFP. A widefield pv-OCT vasculature map color-coded for depth has been overlaid on the reflectance image, and a higher resolution pv-OCT (yellow box) upon it. The white box identifies the region subjected to AO-SLO imaging. D. Images segmented from a high resolution pv-OCT volume subtending most of the region that underwent AO-SLO imaging; the region corresponding to the ELM had negligible contrast, arising from the absence of blood vessels. E. AO-SLO 663 nm reflectance images, with depth focus corresponding to the adjacent (panel D) pv-OCT images. F. Upper panel: Emission spectrum (blue trace) obtained by scanning the region shown in the cyan box in C with 469 nm light. An autofluorescence spectrum (black trace) was obtained from a region with negligible green fluorescence. The observed emission spectrum (blue trace) was predicted (green trace) by summing a scaled EGFP emission spectrum [10] with the autofluorescence spectrum. Lower panels: AO-SLO fluorescence images with focus at same retinal depth as the corresponding adjacent red reflectance channel images.

Tables (1)

Tables Icon

Table 1 Design parameters of optical system (Focal length, x, y and z position, pupil size)

Equations (2)

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V x (θ) =V( 45 )/tan(θ)
V axial = V x (θ)/cos(α)

Metrics