Special Issue IMI – Report on Experimental Models of Emmetropization and Myopia David Troilo,1 Earl L. Smith III,2 Debora L. Nickla,3 Regan Ashby,4 Andrei V. Tkatchenko,5 Lisa A. Ostrin,2 Timothy J. Gawne,6 Machelle T. Pardue,7 Jody A. Summers,8 Chea-su Kee,9 Falk Schroedl,10 Siegfried Wahl,11 and Lyndon Jones12 1SUNY College of Optometry, State University of New York, New York, New York, United States 2College of Optometry, University of Houston, Houston, Texas, United States 3Biomedical Sciences and Disease, New England College of Optometry, Boston, Massachusetts, United States 4Health Research Institute, University of Canberra, Canberra, Australia 5Department of Ophthalmology, Department of Pathology and Cell Biology, Columbia University, New York, New York, United States 6School of Optometry, University of Alabama Birmingham, Birmingham, Alabama, United States 7Biomedical Engineering, Georgia Tech College of Engineering, Atlanta, Georgia, United States31 8College of Medicine, University of Oklahoma, Oklahoma City, Oklahoma, United States 9School of Optometry, The Hong Kong Polytechnic University, Hong Kong, SAR, China 10Departments of Ophthalmology and Anatomy, Paracelsus Medical University, Salzburg, Austria 11Institute for Ophthalmic Research, University of Tuebingen, Zeiss Vision Science Laboratory, Tuebingen, Germany 12CORE, School of Optometry and Vision Science, University of Waterloo, Ontario, Canada Correspondence: David Troilo, The results of many studies in a variety of species have significantly advanced our SUNY College of Optometry, State understanding of the role of visual experience and the mechanisms of postnatal eye growth, University of New York, 33 West and the development of myopia. This paper surveys and reviews the major contributions 42nd Street, New York, NY 10036, that experimental studies using animal models have made to our thinking about USA; [email protected]. emmetropization and development of myopia. These studies established important concepts informing our knowledge of the visual regulation of eye growth and refractive Submitted: October 14, 2018 development and have transformed treatment strategies for myopia. Several major findings Accepted: October 20, 2018 have come from studies of experimental animal models. These include the eye’s ability to Citation: Troilo D, Smith EL III, Nickla detect the sign of retinal defocus and undergo compensatory growth, the local retinal DL, et al. IMI – Report on Experi- control of eye growth, regulatory changes in choroidal thickness, and the identification of mental Models of Emmetropization components in the biochemistry of eye growth leading to the characterization of signal and Myopia. Invest Ophthalmol Vis cascades regulating eye growth and refractive state. Several of these findings provided the Sci. 2019;60:M31–M88. https:// doi.org/10.1167/iovs.18-25967 proofs of concepts that form the scientific basis of new and effective clinical treatments for controlling myopia progression in humans. Experimental animal models continue to provide new insights into the cellular and molecular mechanisms of eye growth control, including the identification of potential new targets for drug development and future treatments needed to stem the increasing prevalence of myopia and the vision-threatening conditions associated with this disease. Keywords: myopia, emmetropization, animal models, visual regulation, eye growth signal changes in the retinal pigment epithelium (RPE), 1. INTRODUCTION choroid, and eventually sclera, leading to altered eye growth mmetropization refers to the developmental process that and changes in refractive state. These studies provide a E matches the eye’s optical power to its axial length so that framework for the development of optical and pharmacologic the unaccommodated eye is focused at distance. Investigations treatments that can be used to effectively reduce the using animal models have informed our understanding of the prevalence and progression of myopia, which has become a role of vision in postnatal eye growth, the mechanisms and major public health concern.1 operating characteristics of emmetropization, and the develop- In this paper, the findings of investigations using experi- ment of refractive errors (myopia, where the eye is typically too long for its optical power; and hyperopia, where the eye is too mental animal models to study emmetropization and myopia short for its optical power). Animal models have established the development are reviewed. The contributions that studies with existence of visual regulation of eye growth and refractive experimental animal models have made to understanding the development as well as local retinal control of eye growth. mechanisms of emmetropization, the development of myopia, They have also revealed biochemical signaling cascades that and new treatments to reduce myopia progression are transduce visual stimuli related to the sign of defocus into summarized. Current models of eye growth control, areas of cellular and biochemical changes in the retina, which, in turn, investigation and major findings, and frameworks for the Copyright 2019 The Authors iovs.arvojournals.org j ISSN: 1552-5783 M31 This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from iovs.arvojournals.org on 03/01/2019 IMI – Experimental Models of Emmetropization and Myopia IOVS j Special Issue j Vol. 60 j No. 3 j M32 TABLE 1. Retinal Differences in Species Used for Myopia Models Inner Retinal High Cell Photoreceptor Types Central Retinal Optic Nerve Head Species Blood Supply Density Region and Peak Sensitivities Thickness and Lamina Cribrosa Chick Avascular (Pecten) Area centralis (24,000 Rods, S1 (415 nm, S2 (455 295–350 lmat Sparse glial and ganglion cells/mm2)83 nm), M (508 nm), L (571 area centralis84,782 connective tissue19,783 nm)781 Zebrafish Vascular Area centralis (37,000 Rods (503 nm), UV (361 nm), 191 lm785 Glial120 ganglion cells/mm2)112 S (411 nm), M (482 nm), L (565 nm) cones784 Mouse Vascular Visual streak (6000 Rods, UV (370 nm) and M 202 lm787 Glial788 ganglion cells/mm2)786 (505 nm) cones63 Guinea pig Avascular Visual streak (2272 cells/ Rods, S (429 nm) and M (529 150 lm789 Collagenous41 mm2)39 nm) cones475 Tree shrew Vascular Area centralis27 Rods, S (428 nm) and L (555 213 lm790 Collagenous33 nm) cones32 Marmoset Vascular Fovea12 Rods, M/L (543, 556, 563 nm) 230 lm12 Collagenous19 cones791 Rhesus Vascular Fovea (33,000 ganglion Rods, S 440 nm, M (536 nm), 207 lm794 Collagenous795 cells/mm2)792 L (565 nm) cones16,793 Human Vascular Fovea (38,000 ganglion Rods, S (419 nm), M (531 nm), 182 lm at fovea798 Collagenous799 cells/mm2)796 L (558 nm) cones797 S, short wavelength; M, medium wavelength; L, long wavelength. development of new and effective treatments for myopia are structural similarities and differences between the retinas of described. the most commonly used experimental species. There are also significant species differences in the mechanisms and amount of accommodation, which regulates 2. ANIMAL MODELS COMMONLY USED IN STUDIES OF the dioptric power of the eye and may be indirectly involved in myopia development through its effects on retinal defocus. In MMETROPIZATION AND YOPIA E M many species, including human, accommodation is achieved Experimental models of myopia and the visual regulation of by changing the power of the crystalline lens by contraction of eye growth have been demonstrated in a wide variety of the ciliary muscle, whereas in other species it is achieved by 5 species from primates to invertebrates, including macaque and moving the lens. Changes in corneal power have also been 6–8 marmoset monkeys, tree shrews, guinea pigs, mice, chickens, observed in some species. fish, and squid. All of these species (with the exception of For another recent review of different species used for experimental studies of emmetropization and myopia, see squid) have been shown to develop myopia in response to 9 visual form deprivation (see Section 3.2), compensate for Schaeffel and Feldkaemper. optically imposed myopic or hyperopic defocus by regulating axial length (see Section 3.4), and recover from the induced 2.1 Comparative Ocular Anatomy and Visual refractive error when form deprivation or optical defocus is Physiology of Animal Models removed (see Section 3.3). Even though the squid model is the least well-characterized, squid eye growth responds to improve 2.1.1 Nonhuman Primates. Macaque monkeys were used 2 in the original studies showing form-deprivation myopia (FDM) focus under imposed visual conditions. Considering that all 10,11 these varied species possess visually guided eye growth despite and visual influences on eye growth. Since then, both Old differences in ecology, ocular anatomy, visual function, and World (rhesus macaque – Macaca mulatta) and New World (common marmoset – ) monkeys have been visual acuity, these results suggest that visual regulation of eye Callithrix jacchus used for myopia research. Both species have foveal retinas, growth is a fundamental property of the camera-type eye, that eyes that are optically scaled down versions of human eyes, it may have evolved more than once, and the mechanisms in and visual physiology which is essentially identical to that of vertebrates are evolutionarily conserved. From an experimen- humans.12–15 The rhesus monkey retina is most similar to the tal perspective, each species provides unique advantages to human. It is rod-dominated (rod to cone ratio ~20:1)