[1] London, A., Benhar, I. & Schwartz, M. The retina as a window to the brain—from eye research to CNS disorders. Nat. Rev. Neurol. 9, 44–53 (2013). doi: 10.1038/nrneurol.2012.227
[2] Ramirez, A. I. et al. The role of microglia in retinal Neurodegeneration: Alzheimer's disease, Parkinson, and Glaucoma. Front. Aging Neurosci. 9, 214 (2017). doi: 10.3389/fnagi.2017.00214
[3] Johnson, T. V. & Tomarev, S. I. Rodent models of glaucoma. Brain Res. Bull. 81, 349–358 (2010). doi: 10.1016/j.brainresbull.2009.04.004
[4] McNally, N. et al. Murine model of autosomal dominant retinitis pigmentosa generated by targeted deletion at codon 307 of the rds-peripherin gene. Hum. Mol. Genet. 11, 1005–1016 (2002). doi: 10.1093/hmg/11.9.1005
[5] Redmond, T. M. et al. Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle. Nat. Genet. 20, 344–351 (1998). doi: 10.1038/3813
[6] Geng, Y. et al. Adaptive optics retinal imaging in the living mouse eye. Biomed. Opt. Express 3, 715–734 (2012). doi: 10.1364/BOE.3.000715
[7] Geng, Y. et al. Optical properties of the mouse eye. Biomed. Opt. Express 2, 717–738 (2011). doi: 10.1364/BOE.2.000717
[8] Godara, P. et al. Adaptive optics retinal imaging: emerging clinical applications. Optom. Vis. Sci. 87, 930–941 (2010). doi: 10.1097/OPX.0b013e3181ff9a8b
[9] Sharma, R. et al. Two-photon autofluorescence imaging reveals cellular structures throughout the retina of the living primate eye. Invest. Ophthalmol. Vis. Sci. 57, 632–646 (2016). doi: 10.1167/iovs.15-17961
[10] Sharma, R. et al. In vivo two-photon fluorescence kinetics of primate rods and cones. Invest. Ophthalmol. Vis. Sci. 57, 647–657 (2016). doi: 10.1167/iovs.15-17946
[11] Hunter, J. J. et al. Images of photoreceptors in living primate eyes using adaptive optics two-photon ophthalmoscopy. Biomed. Opt. Express 2, 139–148 (2011). doi: 10.1364/BOE.2.000139
[12] Sharma, R. et al. In vivo two-photon imaging of the mouse retina. Biomed. Opt. Express 4, 1285–1293 (2013). doi: 10.1364/BOE.4.001285
[13] Sharma, R. et al. Formation and clearance of all-trans-retinol in rods investigated in the living primate eye with two-photon ophthalmoscopy. Investigative Ophthalmol. Vis. Sci. 58, 604–613 (2017). doi: 10.1167/iovs.16-20061
[14] Wahl, D. J. et al. Non-invasive cellular-resolution retinal imaging with two-photon excited fluorescence. Biomed. Opt. Express 10, 4859–4873 (2019). doi: 10.1364/BOE.10.004859
[15] Palczewska, G. et al. Noninvasive two-photon microscopy imaging of mouse retina and retinal pigment epithelium through the pupil of the eye. Nat. Med. 20, 785–789 (2014). doi: 10.1038/nm.3590
[16] Wahl, D. J. et al. Wavefront sensorless adaptive optics fluorescence biomicroscope for in vivo retinal imaging in mice. Biomed. Opt. Express 7, 1–12 (2016). doi: 10.1364/BOE.7.000001
[17] Zhou, X. L. et al. Contrast-based sensorless adaptive optics for retinal imaging. Biomed. Opt. Express 6, 3577–3595 (2015). doi: 10.1364/BOE.6.003577
[18] Wahl, D. J. et al. Adaptive optics in the mouse eye: wavefront sensing based vs. image-guided aberration correction. Biomed. Opt. Express 10, 4757–4774 (2019). doi: 10.1364/BOE.10.004757
[19] Aviles-Espinosa, R. et al. Measurement and correction of in vivo sample aberrations employing a nonlinear guide-star in two-photon excited fluorescence microscopy. Biomed. Opt. Express 2, 3135–3149 (2011). doi: 10.1364/BOE.2.003135
[20] Tao, X. D. et al. Adaptive optical two-photon microscopy using autofluorescent guide stars. Opt. Lett. 38, 5075–5078 (2013). doi: 10.1364/OL.38.005075
[21] Wang, K. et al. Rapid adaptive optical recovery of optimal resolution over large volumes. Nat. Methods 11, 625–628 (2014). doi: 10.1038/nmeth.2925
[22] Ikeda, W., Nakatani, T. & Uemura, A. Cataract-preventing contact lens for in vivo imaging of mouse retina. BioTechniques 65, 101–104 (2018). doi: 10.2144/btn-2018-0040
[23] Antonini, A., Liberale, C. & Fellin, T. Fluorescent layers for characterization of sectioning microscopy with coverslip-uncorrected and water immersion objectives. Opt. Express 22, 14293–14304 (2014). doi: 10.1364/OE.22.014293
[24] Zipfel, W. R., Williams, R. M. & Webb, W. W. Nonlinear magic: multiphoton microscopy in the biosciences. Nat. Biotechnol. 21, 1369–1377 (2003). doi: 10.1038/nbt899
[25] Haverkamp, S. & Wässle, H. Immunocytochemical analysis of the mouse retina. J. Comp. Neurol. 424, 1–23 (2000). doi: 10.1002/1096-9861(20000814)424:1<1::AID-CNE1>3.0.CO;2-V
[26] Zhang, L. et al. Volumetric fluorescence retinal imaging in vivo over a 30-degree field of view by oblique scanning laser ophthalmoscopy (oSLO). Biomed. Opt. Express 9, 25–40 (2018). doi: 10.1364/BOE.9.000025
[27] Wanek, J. et al. Inner retinal oxygen delivery and metabolism under normoxia and hypoxia in rat. Invest. Ophthalmol. Vis. Sci. 54, 5012–5019 (2013). doi: 10.1167/iovs.13-11887
[28] Fortune, B. et al. Structural and functional abnormalities of retinal ganglion cells measured in vivo at the onset of optic nerve head surface change in experimental glaucoma. Investigative Ophthalmol. Vis. Sci. 53, 3939–3950 (2012). doi: 10.1167/iovs.12-9979
[29] Sekirnjak, C. et al. Changes in physiological properties of rat ganglion cells during retinal degeneration. J. Neurophysiol. 105, 2560–2571 (2011). doi: 10.1152/jn.01061.2010
[30] Yin, L. et al. Imaging light responses of retinal ganglion cells in the living mouse eye. J. Neurophysiol. 109, 2415–2421 (2013). doi: 10.1152/jn.01043.2012
[31] Yin, L. et al. Imaging light responses of foveal ganglion cells in the living macaque eye. J. Neurosci. 34, 6596–6605 (2014). doi: 10.1523/JNEUROSCI.4438-13.2014
[32] Margolis, D. J. et al. Dendritic calcium signaling in ON and OFF mouse retinal ganglion cells. J. Neurosci. 30, 7127–7138 (2010). doi: 10.1523/JNEUROSCI.5694-09.2010
[33] Bar-Noam, A. S., Farah, N. & Shoham, S. Correction-free remotely scanned two-photon in vivo mouse retinal imaging. Light.: Sci. Appl. 5, e16007 (2016). doi: 10.1038/lsa.2016.7
[34] Borghuis, B. G. et al. Imaging light responses of targeted neuron populations in the rodent retina. J. Neurosci. 31, 2855–2867 (2011). doi: 10.1523/JNEUROSCI.6064-10.2011
[35] Cheong, S. K. et al. All-optical recording and stimulation of retinal neurons in vivo in retinal degeneration mice. PLoS ONE 13, e0194947 (2018). doi: 10.1371/journal.pone.0194947
[36] Della Santina, L. et al. Differential progression of structural and functional alterations in distinct retinal ganglion cell types in a mouse model of glaucoma. J. Neurosci. 33, 17444–17457 (2013). doi: 10.1523/JNEUROSCI.5461-12.2013
[37] Rashid, K., Akhtar-Schaefer, I. & Langmann, T. Microglia in retinal degeneration. Front. Immunol. 10, 1975 (2019). doi: 10.3389/fimmu.2019.01975
[38] Miller, E. B. et al. In vivo imaging reveals transient microglia recruitment and functional recovery of photoreceptor signaling after injury. Proc. Natl Acad. Sci. USA 116, 16603–16612 (2019). doi: 10.1073/pnas.1903336116
[39] Bremer, D. et al. Longitudinal intravital imaging of the retina reveals long-term dynamics of immune infiltration and its effects on the glial network in experimental autoimmune uveoretinitis, without evident signs of neuronal dysfunction in the ganglion cell layer. Front. Immunol. 7, 642 (2016). doi: 10.3389/fimmu.2016.00642
[40] Silverman, S. M. & Wong, W. T. Microglia in the retina: roles in development, maturity, and disease. Annu. Rev. Vis. Sci. 4, 45–77 (2018). doi: 10.1146/annurev-vision-091517-034425
[41] Dreyer, E. B. & Lipton, S. A. New perspectives on glaucoma. JAMA 281, 306–308 (1999). doi: 10.1001/jama.281.4.306
[42] Ito, A. et al. Assessing retinal ganglion cell death and neuroprotective agents using real time imaging. Brain Res. 1714, 65–72 (2019). doi: 10.1016/j.brainres.2019.02.008
[43] Nakazawa, T. et al. Pitavastatin prevents NMDA-induced retinal ganglion cell death by suppressing leukocyte recruitment. J. Neurochemistry 100, 1018–1031 (2007). doi: 10.1111/j.1471-4159.2006.04274.x
[44] Madry, C. et al. Microglial ramification, surveillance, and interleukin-1β release are regulated by the two-pore domain K+ channel THIK-1. Neuron 97, 299–312.e6 (2018). doi: 10.1016/j.neuron.2017.12.002
[45] Heindl, S. et al. Automated morphological analysis of microglia after stroke. Front. Cell. Neurosci. 12, 106 (2018). doi: 10.3389/fncel.2018.00106
[46] Kreutzberg, G. W. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 19, 312–318 (1996). doi: 10.1016/0166-2236(96)10049-7
[47] Fechtner, R. D. & Weinreb, R. N. Mechanisms of optic nerve damage in primary open angle glaucoma. Surv. Ophthalmol. 39, 23–42 (1994). doi: 10.1016/S0039-6257(05)80042-6
[48] Nickells, R. W. The cell and molecular biology of glaucoma: mechanisms of retinal ganglion cell death. Invest. Ophthalmol. Vis. Sci. 53, 2476–2481 (2012). doi: 10.1167/iovs.12-9483h
[49] Munemasa, Y. & Kitaoka, Y. Molecular mechanisms of retinal ganglion cell degeneration in glaucoma and future prospects for cell body and axonal protection. Front. Cell. Neurosci. 6, 60 (2013). doi: 10.3389/fncel.2012.00060
[50] Munemasa, Y. & Kitaoka, Y. Autophagy in axonal degeneration in glaucomatous optic neuropathy. Prog. Retinal Eye Res. 47, 1–18 (2015). doi: 10.1016/j.preteyeres.2015.03.002
[51] Sun, Q. Q. et al. In vivo imaging-guided microsurgery based on femtosecond laser produced new fluorescent compounds in biological tissues. Biomed. Opt. Express 9, 581–590 (2018). doi: 10.1364/BOE.9.000581
[52] Qin, Z. Y. et al. New fluorescent compounds produced by femtosecond laser surgery in biological tissues: the mechanisms. Biomed. Opt. Express 9, 3373–3390 (2018). doi: 10.1364/BOE.9.003373
[53] Kalesnykas, G. et al. Retinal ganglion cell morphology after optic nerve crush and experimental glaucoma. Invest. Ophthalmol. Vis. Sci. 53, 3847–3857 (2012). doi: 10.1167/iovs.12-9712
[54] Pernet, V. & Schwab, M. E. Lost in the jungle: new hurdles for optic nerve axon regeneration. Trends Neurosci. 37, 381–387 (2014). doi: 10.1016/j.tins.2014.05.002
[55] Trost, A. et al. Time-dependent retinal ganglion cell loss, microglial activation and blood-retina-barrier tightness in an acute model of ocular hypertension. Exp. Eye Res. 136, 59–71 (2015). doi: 10.1016/j.exer.2015.05.010
[56] Zhou, X. L., Bedggood, P. & Metha, A. Limitations to adaptive optics image quality in rodent eyes. Biomed. Opt. Express 3, 1811–1824 (2012). doi: 10.1364/BOE.3.001811
[57] Dubra, A. & Sulai, Y. Reflective afocal broadband adaptive optics scanning ophthalmoscope. Biomed. Opt. Express 2, 1757–1768 (2011). doi: 10.1364/BOE.2.001757
[58] Zawadzki, R. J. et al. Adaptive-optics SLO imaging combined with widefield OCT and SLO enables precise 3D localization of fluorescent cells in the mouse retina. Biomed. Opt. Express 6, 2191–2210 (2015). doi: 10.1364/BOE.6.002191
[59] Geng, Y. et al. In vivo imaging of microscopic structures in the rat retina. Invest. Ophthalmol. Vis. Sci. 50, 5872–5879 (2009). doi: 10.1167/iovs.09-3675
[60] Gray, D. C. et al. In vivo fluorescence imaging of primate retinal ganglion cells and retinal pigment epithelial cells. Opt. Express 14, 7144–7158 (2006). doi: 10.1364/OE.14.007144
[61] Rossi, E. A. et al. Imaging individual neurons in the retinal ganglion cell layer of the living eye. Proc. Natl Acad. Sci. USA 114, 586–591 (2017). doi: 10.1073/pnas.1613445114
[62] Morgan, J. I. W. et al. In vivo autofluorescence imaging of the human and macaque retinal pigment epithelial cell mosaic. Invest. Ophthalmol. Vis. Sci. 50, 1350–1359 (2009). doi: 10.1167/iovs.08-2618
[63] Yu, Y. X. et al. High-speed adaptive optics for imaging of the living human eye. Opt. Express 23, 23035–23052 (2015). doi: 10.1364/OE.23.023035
[64] Burns, S. A. et al. Adaptive optics imaging of the human retina. Prog. Retinal Eye Res. 68, 1–30 (2019). doi: 10.1016/j.preteyeres.2018.08.002
[65] Zhang, J. et al. An adaptive optics imaging system designed for clinical use. Biomed. Opt. Express 6, 2120–2137 (2015). doi: 10.1364/BOE.6.002120
[66] Alexander, N. S. et al. Image registration and averaging of low laser power two-photon fluorescence images of mouse retina. Biomed. Opt. Express 7, 2671–2691 (2016). doi: 10.1364/BOE.7.002671
[67] Palczewska, G. et al. Two-photon imaging of the mammalian retina with ultrafast pulsing laser. JCI Insight 3, e121555 (2018). doi: 10.1172/jci.insight.121555
[68] Stremplewski, P. et al. Periscope for noninvasive two-photon imaging of murine retina in vivo. Biomed. Opt. Express 6, 3352–3361 (2015). doi: 10.1364/BOE.6.003352
[69] Schwarz, C. et al. Safety assessment in macaques of light exposures for functional two-photon ophthalmoscopy in humans. Biomed. Opt. Express 7, 5148–5169 (2016). doi: 10.1364/BOE.7.005148
[70] Schwarz, C. et al. Selective s cone damage and retinal remodeling following intense ultrashort pulse laser exposures in the near-infrared. Investigat. Ophthalmol. Vis. Sci. 59, 5973–5984 (2018). doi: 10.1167/iovs.18-25383
[71] Jayabalan, G. S. et al. Retinal safety evaluation of two-photon laser scanning in rats. Biomed. Opt. Express 10, 3217–3231 (2019). doi: 10.1364/BOE.10.003217
[72] Feeks, J. A. & Hunter, J. J. Adaptive optics two-photon excited fluorescence lifetime imaging ophthalmoscopy of exogenous fluorophores in mice. Biomed. Opt. Express 8, 2483–2495 (2017). doi: 10.1364/BOE.8.002483
[73] Murashova, G. A. et al. Multimodal nonlinear optical imaging of unstained retinas in the epi-direction with a sub-40 fs Yb-fiber laser. Biomed. Opt. Express 8, 5228–5242 (2017). doi: 10.1364/BOE.8.005228
[74] He, S. C. et al. Label-free nonlinear optical imaging of mouse retina. Biomed. Opt. Express 6, 1055–1066 (2015). doi: 10.1364/BOE.6.001055
[75] Wang, K. et al. Direct wavefront sensing for high-resolution in vivo imaging in scattering tissue. Nat. Commun. 6, 7276 (2015). doi: 10.1038/ncomms8276
[76] Park, J. H. et al. Large-field-of-view imaging by multi-pupil adaptive optics. Nat. Methods 14, 581–583 (2017). doi: 10.1038/nmeth.4290
[77] Kaspar, B. K. et al. Adeno-associated virus effectively mediates conditional gene modification in the brain. Proc. Natl Acad. Sci. USA 99, 2320–2325 (2002). doi: 10.1073/pnas.042678699
[78] Chen, T. W. et al. Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature 499, 295–300 (2013). doi: 10.1038/nature12354
[79] Zhang, P. F. et al. Effect of a contact lens on mouse retinal in vivo imaging: effective focal length changes and monochromatic aberrations. Exp. Eye Res. 172, 86–93 (2018). doi: 10.1016/j.exer.2018.03.027
[80] Zhong, Z. Y. et al. In vivo measurement of erythrocyte velocity and retinal blood flow using adaptive optics scanning laser ophthalmoscopy. Opt. Express 16, 12746–12756 (2008). doi: 10.1364/OE.16.012746
[81] Drew, P. J. et al. Rapid determination of particle velocity from space-time images using the Radon transform. J. Comput. Neurosci. 29, 5–11 (2010). doi: 10.1007/s10827-009-0159-1
[82] Remtulla, S. & Hallett, P. E. A schematic eye for the mouse, and comparisons with the rat. Vis. Res. 25, 21–31 (1985). doi: 10.1016/0042-6989(85)90076-8
[83] Thevenaz, P., Ruttimann, U. E. & Unser, M. A pyramid approach to subpixel registration based on intensity. IEEE Trans. Image Process. 7, 27–41 (1998). doi: 10.1109/83.650848