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OPTOMETRY REVIEW

Animal models in myopia research Clin Exp Optom 2015; 98: 507–517 Frank Schaeffel PhD Marita Feldkaemper PhD Section of Neurobiology of the Eye, Ophthalmic Research Institute, Tuebingen, Germany E-mail: [email protected]

Submitted: 21 October 2014 Revised: 20 March 2015 Accepted for publication: 26 April 2015

DOI:10.1111/cxo.12312 Our current understanding of the development of refractive errors, in particular myopia, would be substantially limited had Wiesel and Raviola not discovered by accident that monkeys develop axial myopia as a result of deprivation of form vision. Similarly, if Josh Wallman and colleagues had not found that simple plastic goggles attached to the chicken eye generate large amounts of myopia, the chicken model would perhaps not have become such an important animal model. Contrary to previous assumptions about the mechanisms of myopia, these animal models suggested that eye growth is visually controlled locally by the retina, that an afferent connection to the brain is not essential and that emmetropisation uses more sophisticated cues than just the magnitude of retinal blur. While animal models have shown that the retina can determine the sign of defocus, the underlying mechanism is still not entirely clear. Animal models have also provided knowledge about the biochemical nature of the signal cascade converting the output of retinal image processing to changes in choroidal thickness and scleral growth; however, a critical question was, and still is, can the results from animal models be applied to myopia in children? While the basic findings from chickens appear applicable to monkeys, some fundamental questions remain. If eye growth is guided by visual feedback, why is myopic development not self-limiting? Why does undercorrection not arrest myopic progression even though positive lenses induce myopic defocus, which leads to the development of hyperopia in emmetropic animals? Why do some spectacle or contact lens designs reduce myopic progression and others not? It appears that some major differences exist between animals reared with imposed defocus and children treated with various optical corrections, although without the basic knowledge obtained from animal models, we would be lost in an abundance of untestable hypotheses concerning human myopia.

Key words: accommodation, children’s vision, myopia, retina In 1933, Sorsby1 summarised current opinions as to why school children often become myopic and quoted Johannes Kepler, who wrote 300 years earlier that ‘short sight is more common among students and others who use their eyes excessively’. He also cited Hermann Cohn,2 who stated in 1867 that ‘myopia is a result of too much close work’ and ‘good illumination was needed in order to avoid unnecessary close application’. Since there was no experimental evidence for these assertions, Sorsby1 concluded that ‘the optimism of those who regarded myopia as a product of controllable environmental conditions has not proved altogether justified’. For a number of years, most people believed that myopia was largely genetically determined; however, considering the precision by which the optical elements of the eye combine to achieve near emmetropic refraction raises doubt that the globe’s dimensions are controlled by genetic factors alone, rather than a mechanism incorporating visual feedback. Also, the significant change in the © 2015 Optometry Australia

distribution of refractive errors from birth to age six years is difficult to explain by genetics. Nevertheless, it is possible that the genetic explanation of myopia would still dominate today, if animal models had not introduced new evidence of active emmetropisation or vision-dependent ocular growth. A shift in opinion emerged following Wiesel and Raviola’s3 discovery of experimental axial myopia, an apparent accidental finding since the initial goal of their experiment was to study the effects of monocular deprivation on the response of binocular neurons in the visual cortex. Around the same time, Sherman, Norton and Casagrande4 reported that lid-sutured tree shrews also develop myopia. Another major advance was published by Wallman, Turkel and Trachtman5 that chickens developed extreme myopia ‘by modest change in early visual experience’. In chicks, 20 dioptres of myopia could be induced within two weeks, with more than two millimetres of axial elongation. These experiments

triggered sudden scientific interest in experimental myopia even though the worldwide prevalence of myopia was relatively low compared to the present day. A central question was how visual feedback influences axial eye growth. The emerging research involving animal models of myopia became extensive, and more than 1,000 publications on this topic have appeared since 1977. The selection of topics in this review has been restricted to summarising key animal models and their translation to human myopia. Important experimental findings from different animal models are shown in Table 1. THE CHICKEN MODEL The chick model was introduced by Wallman, Turkel and Trachtman5 and still remains one of the major models for myopia today, more than 35 years later. Major advantages of the chick include: 1. relatively large eyes (8 to 14 mm) 2. rapid eye growth of about 100 μm per day Clinical and Experimental Optometry 98.6 2015

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Experimental findings Induction of deprivation myopia

Chick5,12; tree shrew4; guinea pig85; mouse99,102; marmoset63; rhesus monkey3,77; fish124; rabbit131; kestrel128

Induction of lens-induced myopia

Chick11; tree shrew169; guinea pig86; mouse102; marmoset64; rhesus monkey75; fish126

Induction of lens-induced hyperopia

Chick19–21; tree shrew170,171; guinea pig86; marmoset172; rhesus monkey75

Local control of eye growth in case of: Neurotoxins blocking retinal output or optic nerve cut

Chick12,13; tree shrew51

Locally imposed defocus

Chick14; tree shrew52; guinea pig89; marmoset70; rhesus monkey80,81

Compensation of imposed defocus when accommodation is eliminated (EW lesion; drugs; nerve cuts)

Chick16,17; tree shrew173

Role of accommodation

Chick15; tree shrew173

Chromatic cues are necessary for lens compensation

Mouse105; fish126

Chromatic cues are not necessary for lens compensation

Chick22–24; guinea pig174

Signaling pathways/molecules involved: Dopamine

Chick31; tree shrew176; guinea pig94; mouse119; rhesus monkey74

Egr-1/ZENK

Chick26,27; tree shrew177; mouse112,113; rhesus monkey188

Vasoactive peptide

Chick44; tree shrew177; guinea pig182; rhesus monkey73

Antimuscarinics

Chick37–39,175; tree shrew,178; guinea pig183; mouse115; rhesus monkey189

Retinoic acid

Chick41; guinea pig95; marmoset68

Nitric oxide

Chick42; tree shrew177; guinea pig184

Inhibition of myopia by high ambient illuminance: Deprivation myopia

Chick34; tree shrew53; rhesus monkey84

Lens-induced myopia

Chick35; tree shrew54; guinea pig93; rhesus monkey83

Choroidal thinning/thickening in response to imposed defocus

Chick17; tree shrew178; guinea pig85; marmoset64; rhesus monkey75

Scleral metabolism changes in the fibrous sclera of myopic eyes: Thinning of the fibrous sclera

Chick45; tree shrew176,180; guinea pig185,186; rhesus monkey190; rabbit133

Decreased proteoglycan synthesis

Chick45; tree shrew181; marmoset68,187

Table 1. Experimental findings across different species. 3. highly sensitive control of refractive state by retinal image quality and focus 4. excellent optics (diffraction-limited at 2.0 mm pupils) 5. active accommodation (about 17 D) 6. high visual acuity (7 cycles/degree) 7. easy drug delivery by intravitreal injection 8. friendly, co-operative nature and 9. inexpensive and easy to keep. Disadvantages of an avian model include the lack of a fovea, differences in scleral composition (more cartilage) and a different mechanism of accommodation (corneal and lenticular)6–8 compared to mammals. In birds, the crystalline lens is squeezed during accommodation at the equatorial ‘annular pad’ by forces exerted by the ciliary body9 rather than becoming more spherical when the zonular fibers are relaxed. The ciliary muscle in birds is composed of striated muscle, as opposed to smooth found in mammals, which may mediate the extremely fast Clinical and Experimental Optometry 98.6 2015

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and transient accommodation responses observed in birds (chicks: 80 D/second, personal observation) and some reptiles (water turtles: up to 800 D/second, personal observation). The ciliary muscle contains nicotinergic receptors, rather than by muscarinic receptors and therefore, atropine cannot be used in cycloplegia in chicks.10 Nevertheless, chicks provided fundamental information on the mechanisms of emmetropisation. It was found that the growing chick eye can compensate for defocus imposed by spectacle lenses by adjusting axial eye growth rates11 and that deprivation myopia (induced by any kind of degradation of the retinal image during post-hatching development) does not require an intact optic nerve.12,13 In addition, it was shown that deprivation myopia can be induced in parts of the globe, when deprivation is restricted to certain retinal areas.14 Initially, it was assumed that emmetropisation is guided by

the average level of accommodation;15 however, based on an experiment suggested by Josh Wallman at the Annual Association for Research in Vision and Ophthalmology (ARVO) meeting in 1987, it was found that compensation of imposed defocus still occurs when accommodation is eliminated by a lesion of the Edinger-Westphal nucleus16 or when the ciliary nerve is cut.17 A striking finding was that the choroid thickens or thins to move the retina closer to the focal plane.18 Chicken eyes can compensate for imposed defocus even when cyclopleged with a controlled viewing distance, which rules out that the sign of defocus is deciphered by comparing image contrast at different viewing distances.19,20 In fact, the retina must be able to extract the sign of defocus to either accelerate or slow down axial eye growth. Zhu and Wallman21 have shown that the sign of defocus in the retinal image can be detected in only two minutes; © 2015 Optometry Australia

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however, the underlying image processing is still not understood. Chromatic cues do not seem to be necessary since compensation of lenses occurs similarly in white light and in monochromatic light.22–24 However, an elegant experiment by Rucker and Wallman showed a small input from chromaticity.25 It is also clear that the eye takes longitudinal chromatic aberration into account, when only monochromatic light is available, since chicks raised in red light become more myopic than chicks raised in blue light.22 Based on a suggestion by Professor William K Stell in 1998, the expression of the transcription factor ZENK was studied and it was found that glucagon amacrine cells express ZENK in correlation with the sign of imposed defocus, upregulation with myopic defocus and downregulation with hyperopic defocus.26,27 Therefore, the immediate early gene product ZENK which controls the transcription of a large number of other genes, acts as an axial eye growth inhibitor. Glucagon, produced in the amacrine cells that express ZENK in a sign-of-defocus dependent fashion, also serves as an inhibitor of myopia in chicks.28 Conversely, glucagon antagonists suppress the development of hyperopia.29,30 A number of other transmitter systems have been studied in chicks. Stone and colleagues31 were the first to show that retinal dopamine content drops during the development of deprivation myopia and that dopamine agonists may inhibit myopia. Dopamine has been studied over many years and it became clear that its release from the retina is controlled by both retinal image brightness and by the contrast in the retinal image.32 There is little evidence that dopamine release can change bi-directionally in correlation with the sign of defocus; in most cases, its release was reduced only when the image was in poor focus, irrespective of whether the defocus was myopic or hyperopic.33 More recently, dopamine regained interest following the finding that form deprivation myopia and lens-induced myopia can be partially suppressed by bright light.34,35 Since the beneficial effect of bright light on development of myopia disappears after intravitreal application of a dopamine antagonist and because long-lasting exposure to bright light causes higher retinal dopamine levels in chicks,36 it was proposed that the inhibitory effect of bright light on myopia is mediated, in part, by dopamine. Another transmitter system of interest is the cholinergic system. Cholinergic antagonists (both muscarinic and nicotinic) are potent © 2015 Optometry Australia

inhibitors of experimentally induced myopia37–39 and deprivation myopia can be suppressed even when the drugs used have no effect on accommodation. This lead McBrien and colleagues40 to conclude that inhibition of myopia by atropine is not mediated by accommodation. The chick is an ideal model for studying visual function following various drug regimes that may affect eye growth. Other transmitters include retinoic acid, also regulated in the choroid in a defocus-dependent fashion,41 nitric oxide,42 transforming growth factor beta (TGF-ß),43 fibroblast growth factor (FGF)43 and vasoactive polypeptide.44 During the progression of myopia, the cartilaginous layer becomes thicker45 and proteoglycan synthesis increases,46 while the fibrous layer thins, as it does in mammals. The chicken is also a great model for studying visual function after the intravitreal application of drugs. Diether and Schaeffel19 discovered that intravitreal atropine increased contrast sensitivity, suggesting that contrast adaptation may be ‘an error signal for emmetropisation’, as first proposed by Josh Wallman at the ARVO meeting in 1999. There are many more interesting findings from the chicken model; however, only two more are mentioned here. It was found that interruption of deprivation or negative lens wear of only 30 minutes reduces myopic development by half or more, which led Winawer and Wallman47 to suggest that ‘if children were like chicks, reading should be interrupted at regular intervals’. The other was the suggestion that astigmatism can be compensated for during development by visual feedback. Current data suggest ‘yes’ (Geoffrey Chu, unpublished PhD thesis, PolyU Hong Kong) and this leaves the fascinating question of how retinal ‘signals’ can control the sphericity of the cornea or lens in a radially non-symmetric fashion. Other authors have found that the development of corneal astigmatism in response to imposed astigmatic defocus is typically not compensatory in magnitude or orientation.48 Furthermore, it was found that astigmatic lenses do not induce astigmatic accommodation in chicks even though astigmatic accommodation would have been a plausible precursor for astigmatic corneal growth.49 THE TREE SHREW MODEL Tree shrews were introduced into myopic research as early as the chick model.5 The majority of the work in tree shrews was performed in two laboratories by Professor

Thomas T Norton in Birmingham, Alabama, together with his post-doctoral fellow, Neville McBrien, who later moved to Melbourne and continued work on myopia in tree shrews in Australia. While eye size (7.8 mm)50 and visual acuity in tree shrews (2.0 cycles/degree; Norton, personal communication, 1999) are less than in chickens, they present a number of advantages. 1. Tree shrews are mammals and closely related to primates and therefore, much more closely related to humans; after some problems, it became possible to induce deprivation myopia consistently with implanted holders to secure occluders in front of the eye. 2. Their eye growth is modulated to compensate for defocus, similar to the chicken, although the time point for the experiments has to be carefully selected to match their sensitive period to detect the effects of positive lenses. 3. They offer the opportunity to study the signalling cascades from retinal processing to scleral growth biochemically and with techniques of molecular genetics, again with the benefit that they are more closely related to humans. 4. Unlike the double-layered sclera in chicks, the tree shrew sclera is single layered, similar to humans. Disadvantages include the lack of a fovea, no clear indication of accommodation and more complex handling and breeding. Nevertheless, many important results have been obtained using the tree shrew model. Similar to the chick, which showed that the signal to control axial eye growth is generated in the amacrine cells (or even earlier), the blockade of ganglion cell action potentials by tetrodotoxin (TTX) in tree shrews did not prevent the development of deprivation myopia.51 It was also demonstrated in tree shrews, as in chickens, that deprivation myopia could be induced in only a half of the globe,52 that bright light reduces both deprivation myopia and lens-induced myopia, and that bright light enhances the anti-myopia effect of positive lenses.53,54 Perhaps the most important advances in this animal model were extremely elaborate proteomic studies by Frost and Norton55,56 and the more recent attempts to generate a ‘gene expression signature’ for the development of lensinduced myopia.57,58 Other important studies in tree shrews were the descriptions of scleral metabolism during development of myopia by McBrien and Gentle59 and McBrien, Clinical and Experimental Optometry 98.6 2015

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Jobling and Gentle60 and a number of pharmacological studies to elucidate the mechanisms of suppression of myopia by muscarinic antagonists (including atropine, pirenzepine and himbacine), focusing on muscarinic receptor subtypes possibly involved in the development of myopia. These authors59,60 also performed extensive comparative studies in chick and tree shrew, examining the changes in cellular structure and receptors of the sclera during the induction of myopia (reviewed by Beuerman61). PRIMATES - MARMOSET The marmoset was introduced into myopic research by Professors David Troilo and Stuart Judge,62 when Troilo came to Oxford as a post-doctoral researcher. They described normal ocular development in the marmoset and showed that deprivation myopia can be induced by lid suture. They also found that recovery from deprivation myopia is limited as no slowing of axial elongation was observed after the lids were re-opened. Graham and Judge63 extended the initial studies by providing detailed descriptions of ocular growth curves in marmosets. The same authors also showed that lens-induced defocus triggered compensatory changes in axial eye growth and refraction but observed no evidence of interocular yoking of the growth changes.64 Two fundamental findings in marmosets were that the choroidal thickness changes observed in chicks in response to imposed retinal defocus were also present in primates (Troilo, Nickla, Wildsoet65) and that deprivation myopia can also be induced in young adult animals (Troilo, Nickla and Wildsoet66). Whatham and Judge67 improved the lens treatment procedures in marmosets, showing that soft contact lenses were as effective as spectacle lenses in inducing refractive errors. Troilo and colleagues68 showed that changes occur in the rates of synthesis of ocular retinoic acid and scleral glycosaminoglycans during the induction of deprivation myopia. More recently, Troilo, Quinn and Baker69 studied the role of accommodation in the development of myopia in marmosets as well as the role of peripheral refractive error in emmetropisation70 and how the eye compensates for simultaneously imposed positive and negative defocus.71 Marmosets are not trivial to maintain and breed but they are nevertheless becoming a more common animal model in vision research. Their advantages are that they are primates, with a fovea and very active accommodation (more than 20 D) and that Clinical and Experimental Optometry 98.6 2015

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they can be trained to perform visual tasks. Their visual acuity is much better than in tree shrews,62 namely 30 versus two cycles/degree (see above). PRIMATES - RHESUS MONKEY The rhesus monkey is most closely related to humans and generates interest on its own. Findings from chick studies are considered applicable to humans when they can be verified in rhesus monkeys. Rhesus monkeys have a fovea, large amplitudes of accommodation, excellent visual acuity (30 cycles/degree or more) and very good optics. Raviola and Wiesel72 showed in 1978 that deprivation myopia induced by lid suture or corneal opacification requires visual input myopia is not induced during dark rearing. In 1988, Stone and colleagues73 found the first retinal marker that changed in response to myopia. In 1991, Iuvone and colleagues74 showed that a dopamine receptor agonist, apomorphine, could be used to reduce the development of deprivation myopia. A break-through finding was that spectacle lenses are compensated for in monkey eyes, similar to chick.75 Interestingly, in this study, each eye of an animal was treated with a different lens (that is, a different sign of defocus), like in the first chick experiments by Schaeffel, Glasser and Howland11 in 1988 but with the critical difference that accommodation is yoked in monkeys. Therefore, the interpretation of the results was more complicated. It was found that the more hyperopic eye (treated with a negative lens) controlled accommodation, causing more myopic refractions in the positive lens-treated eye. Similar to the marmoset, choroidal thickness changes occur with imposed defocus76 and that deprivation myopia could also be induced also in adult monkeys.77 Similar to data from the chicken model, it was shown that deprivation myopia is a graded phenomenon - the more image degradation, the more resultant induced myopia and that short interruptions of deprivation have strong inhibitory effects on the development of deprivation myopia.78 Perhaps among the most striking findings from rhesus monkeys were observations that eyes can recover from deprivation myopia, after the fovea was ablated by laser coagulation, suggesting that the fovea is not needed for emmetropisation.79 This was further supported by the observation that diffusers with a hole in the centre, permitting unobstructed vision for the fovea, could still induce

deprivation myopia. In addition, lens-induced hyperopic defocus imposed only in the periphery could induce myopia as well.80 Hemiretinal deprivation of sharp vision generates local myopia in only half of the globe, as in the other animal models described above. These findings confirm local control of eye growth and refractive development in infant monkeys.81 The authors concluded that ‘effects of optical defocus on refractive development in monkeys provide evidence for local, regionally selective mechanisms’. The conclusion that is currently considered most relevant was that emmetropisation appears largely controlled by the retina in the periphery, while accommodation is largely controlled by the fovea. The spatial separation of the two input sites needs to be taken into account when attempting to explain the effects of defocus on emmetropisation in children (see the human model below). Different from recent observations in chickens, no active compensation of imposed astigmatism has been observed in monkeys.82 More recently, the effects of bright light on the development of myopia have been studied in rhesus monkeys, similar to the previous experiments in the chicken model by Ashby, Ohlendorf and Schaeffel.34 While myopia induced by negative lenses was not suppressed,83 deprivation myopia was inhibited by bright light as previously observed in chickens and tree shrews.84 While the lack of an effect of bright light on lens-induced myopia could trace back to experimental parameters (which need to be identified and controlled for in the future), it could also be a special case for foveate primates. If so, it would certainly have an impact on the interpretation of the effects of bright light on myopia in children. THE GUINEA PIG MODEL The guinea pig model was first presented by McFadden and Wallman at ARVO in 1995.85 They showed that guinea pigs develop deprivation myopia in a reasonably short period of time (a few days) and also respond to lens-induced blur similar to chicks and tree shrews.86 The guinea pig has a number of advantages: 1. it is easy to maintain and breed, it is ‘friendly’ and co-operative 2. it has large pupils and reasonably large eyes (axial length 8.0 mm86) and 3. measurements of refraction and ocular biometry are easy to perform. © 2015 Optometry Australia

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Visual acuity is in the same range as the tree shrew87 but less than in the chicken. Natural accommodation in the guinea pig has not yet been demonstrated, and the only evidence for its existence is based on pharmacological studies.88 The guinea pig model is currently on the rise and is the most common animal model for myopia in Asian laboratories. In guinea pigs, myopia can be induced in local retinal areas.89 Different from chicks, compensation of positive lenses requires an intact optic nerve; however, it is difficult to prove that the brain is involved in eye growth regulation. Cutting the optic nerve eliminates retinal ganglion cells, which may change the internal retinal wiring and perhaps the processing necessary to detect myopic defocus. It is known that retinal activity measured by pattern electroretinogram (PERGs) persists in pigeons after optic nerve section but disappears soon after optic nerve section in mammalian models.90 A striking finding was that guinea pigs may be born with spontaneous myopia that recovers slowly or not at all.91 Albino guinea pigs are generally more myopic and show no recovery from induced deprivation myopia, compared to tricolour wildtype animals.92 Recent guinea pig studies also tackled the question of the role of spectral composition of light in emmetropisation.93 Guinea pigs have also been used to elucidate the role of dopamine in naturally occurring myopia. A more complex picture emerged compared to the chicken model, since there is evidence of biphasic response curves of dopamine agonists and antagonists when peribulbar injections were used to interfere with the development of natural myopia.94 The role of retinoic acid in lensinduced myopia was studied in both the chicken and the guinea pig by Mertz and Wallman41 and McFadden, Howlett and Mertz,95 respectively and it was found that retinoic acid in retina and choroid are regulated in correlation with the sign of imposed refractive errors. THE MOUSE MODEL A major advantage of the mouse is that it is a well-established animal model for a range of human diseases with a wealth of knowledge on its biochemistry and genetics. There is no other mammalian disease model that is available in so many transgenic versions, in which genes have been intentionally altered or inactivated. Further advantages are that the mouse can be easily obtained and bred. © 2015 Optometry Australia

Disadvantages of the mouse model include small eye size (around 3.3 mm axial length) and it is demanding to measure axial length96–98 and refraction99 with sufficient resolution to reliably determine the effects of altered visual environments. Furthermore, mouse eyes have poor optics, no accommodation and no fovea. Experimental manipulations of their visual experience with diffusers or spectacle lenses are demanding and the induced changes in refraction and ocular growth are slow to develop in comparison to chickens and guinea pigs.99–104 Finally, in contrast to guinea pigs, alert mice are not easy to handle and most researchers have experienced their sharp teeth. The importance of vision may have been underestimated in mice, since it was assumed that they are ‘nocturnal’; however, direct observations of their diurnal activity, both of laboratory mice and mice in the wild, show that they are not truly nocturnal.105,106 Mouse spatial vision is relatively poor (0.5 to 0.6 cycles/degree, at least 60 times worse than that of humans) but this is not due to the size of the eye alone. If one compares the spatial performance of the mouse eye to a camera in a smart phone, it becomes clear what level of resolution is possible with such an eye size, even with only a 2.0 mm pupil. It must be the low optical performance107,108 together with large ‘pixels’ (photoreceptors, 95 per cent of them rods82) that limits their visual acuity. A number of interesting findings have been made using the mouse model. The mice carrying a mutation that blocks the ON channel (the Nob -/- mouse) develop deprivation myopia more rapidly and to higher levels than wildtype mice.109 This is in line with the findings of Crewther and Crewther110 in the chicken model that ON activity tends to inhibit myopia and OFF activity tends to inhibit development of hyperopia, although reasons remain unclear. Like guinea pigs, mice have no glucagon in the retina,111 which is unfortunate as ZENK expression in glucagon amacrine cells was a reliable indicator for future enhanced or reduced axial eye growth in chicks. Nevertheless, a ZENK knock-out mouse was found temporarily more myopic, in line with the assumption that genes controlled by the ZENK protein serve as axial eye growth inhibitors.112 Retinal genes that may be regulated by image contrast were studied by microarrays.113 The transgenic mice with high levels of TGF-ß had thicker scleras.114 Pharmacological studies may be easier to perform in mice than in chickens since drugs

applied as topical eye drops penetrate easily into the globe and, due to the small eye, reach their targets in the retina at sufficient concentrations. High doses of atropine (one per cent, daily) severely reduce axial eye growth115 and knock-down of the adenosine A2A receptor causes temporarily enhanced axial eye growth, similar to the deletion of the Egr-1 gene.116 Flicker light, known to suppress deprivation myopia in chicks117 downregulates the content of crystalline proteins in deprived C57BL/6 mouse retina.118 Tkatchenko and colleagues105 showed that emmetropisation in mice is dependent on photopic visual exposure. An interesting finding was that mice with retinal degenerations tended to be more hyperopic but, upon deprivation, became more myopic than wildtypes.119 The same authors also studied release of retinal dopamine in mice and found that low dopamine levels predispose animals to become more myopic in a variety of different experiments - a finding that is in line with studies in chickens. Most recently, it was shown that mice lacking rods by functional knockout due to a mutation in the rod transducin alpha do not develop deprivation myopia.120 This could indicate that rods are implicated in the emmetropisation process, which may not be too surprising, given that emmetropisation in primates appears to be largely driven by the peripheral retina,121 where rods are predominant. The wide range of different findings on myopia in the mouse model were thoroughly summarized by Pardue, Stone and Iuvone.122 A surprising issue in mice is that the effects on refraction are generally quite small. With a total power of the optics of the mouse eye above 500 D, the changes are typically only five dioptres or less, which is only one per cent of the total power, while in the chicken with a power of 140 D, 20 D of myopia can easily be induced, which is around 15 per cent of the power of the eye. It is not fully clear what this means. OTHER MYOPIA MODELS - TILAPIA, ZEBRAFISH, KESTREL, RABBIT Some fish eyes also have the ability to emmetropise. In 1996, Kroger and Wagner123 demonstrated that the eye of the blue acara (Aequidens pulcher, Cichlidae) grows to compensate for defocus due to longitudinal chromatic aberration. Shen, Vijayan and Sivak124 also showed that fish (Tilapia) can develop deprivation myopia and that the crystalline lens grows largely independently of visual Clinical and Experimental Optometry 98.6 2015

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manipulations. As for other animal models, the question as to whether the crystalline lens makes a significant contribution to compensatory changes in refraction in response to imposed defocus, is unclear.125 Like other animal models, fish (Tilapia) eyes can also compensate for both myopic and hyperopic defocus.126 Elements of the signalling cascade have also been studied in zebrafish. The knockdown of the zebrafish lumican gene (zlum) causes scleral thinning and an increase in the diameter of the scleral coats.127 High amounts of deprivation myopia can also be induced in kestrels.128 Interestingly, these raptors are highly myopic when they hatch and emmetropise toward zero refractive error, different from most other animal models and humans, which all tend to be hyperopic at birth and approach emmetropia from the other side. Even though the authors proposed kestrels as a new model for myopia, these birds cannot be easily obtained and the chicken may remain a more approachable model. Spontaneous myopia was also found in barn owls who open their eyes 13 days after hatching and may actually develop natural deprivation myopia.129 Rabbits have also been used as an animal model for research into myopia. Tokoro130 was the first to show that myopia can be induced experimentally in rabbits by increasing intraocular pressure and temperature using atropine. Verolino131 demonstrated that rabbits can also develop deprivation myopia. The myopic shift and vitreous chamber/axial elongation in lid-sutured rabbit eyes can be reduced by intravitreal injection of dopamine.132 Like in other mammals, deprived eyes have markedly reduced scleral thickness and smaller diameters of the scleral collagen fibrils.133 The non-selective antagonist of the adenosine receptor, 7-methylxanthine, has been found to prevent development of myopia and axial elongation of the eye in visually deprived rabbits by remodeling of the posterior scleral tissue.134 THE HUMAN ‘MODEL’ If results from research on animal models are applied to humans, the fundamental assumption needs to be made that the biological mechanisms of emmetropisation are similar. This assumption is not far-fetched as long as observations made in the chicken model can be reproduced in mammalian models, including monkeys. Examples include that the responses of growing eyes to defocus imposed Clinical and Experimental Optometry 98.6 2015

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by lenses are similar, that the growth changes can be induced in only half of the globe and that the expression of the transcription factor ZENK in the retina (Egr-1 in mammals) is correlated with the sign of imposed defocus (Table 1). The observations leave little doubt that imposed defocus should also change eye growth in children. Also, other findings from animal models appear applicable to humans, such as the effects of light and atropine on myopia development. Children were treated with progressive addition lenses (COMET135 and STAMP study136). While the observed changes in refraction were in the expected direction, they were by far too small to compensate for the imposed refractive errors (that is, additions 1.50 D, changes 0.2 D).134 The changes were much smaller than in animal experiments. Executive bifocals appeared more effective.137,138 Also, neither undercorrection139 nor omission of any correction140 had any clear inhibitory effect on myopic development. So what happened? We offer a few possible explanations. 1. Children treated with progressive addition lenses are assumed to accommodate more accurately, with a lower lag of accommodation. It was hypothesised that this would reduce residual hyperopic retinal defocus that could stimulate axial eye growth. However, since children have ample accommodation, it is possible that they did not consistently use the lower segment of the spectacles with the reading addition. In this case, the superior retina was theoretically exposed to myopic defocus, with the fovea optimally corrected. It is possible that eye growth was restricted regionally (in the superior retina) but no off-axis measurements were taken to confirm this assumption; only the foveal refraction was recorded over time and became only slightly less myopic (COMET study135). 2. For the same reason, perhaps executive bifocals were more effective141 because they may have defocused a larger retinal area, resulting in more consistent inhibition of axial eye growth. This study also used base-out prisms in the addition but they had only small effects compared to the plus addition. 3. Philips142 has shown in 18 myopic children that unilateral undercorrection by up to 2.00 D of the non-dominant eye has consistent inhibitory effects on the growth of the undercorrected eye. He also showed that the fully corrected dominant eye controlled accommodation. It is likely that

the consistent myopic defocus in the undercorrected eye generated the clear effect on eye growth. The author states that ‘after refitting with conventional spectacles, the resultant anisometropia returned to baseline levels after 9 to 18 months’. 4. In the case of binocular undercorrection or no correction of myopia at all, it is likely that accommodation relaxes to the amount that the focal plane remains on the photoreceptor plane at least for close viewing distances, so that the retina does not receive an error signal and no inhibition of eye growth occurs. To confirm this hypothesis, it would be necessary to carefully measure accommodation. Like in the studies with progressive addition lenses, a big unknown is accommodative behaviour. Another factor that has not been studied in detail is the role of the peripheral refraction profile at the time when the treatment started. These two unknowns may partially explain the unexpected observation that undercorrection of myopia actually exacerbated myopic progression in two studies.139,143 5. Why do emmetropic animals develop refractive errors when they wear lenses? At least in chickens, lenses elicit only temporary changes in accommodation. Chicks have rapid and transient accommodative responses. Most of the time, the retinal image is out of focus due to the power of the spectacle lenses. This assumption is supported by the observation that chicks show profound contrast adaptation with both positive and negative lenses.144 For this reason the retina receives a consistent error signal, which is compensated by subsequent changes in ocular growth. Furthermore, at least chickens have very similar refractions in the centre and the periphery of the visual field,145 so that a focal error signal is generated by the lenses all across the visual field. Another factor might be differences in the ‘scaled’ ages. It may be difficult to compare precocial species like chickens with slowly developing species like monkey and humans. A few more findings have emerged from research in animal models that need to be compared to observations in humans:

The mechanism of deprivation myopia After deprivation myopia was first described in monkeys,3 several studies were published © 2015 Optometry Australia

Animal models in myopia research Schaeffel and Feldkaemper

to demonstrate its presence in humans. It was found that any condition that degrades the retinal image in the first years after birth causes deprivation myopia,146 early cataract,147 keratitis,148 blepharospasm149 or even persistent myelinisation of retinal ganglion cell axons.150 Even though it is likely that the mechanism of deprivation myopia is present in all vertebrate eyes, it is less clear what its biological function might be. Why should an eye become longer when the retinal image is degraded? It would have been a useful mechanism in hyperopic eyes but these eyes often show little emmetropisation at all.151,152 It seems obvious that there is no beneficial effect of the mechanism in eyes that are already myopic.

Short-term changes in choroidal thickness in human subjects Rapid changes in choroidal thickness following imposed retinal defocus were observed in several animal models (chicks, tree shrews, guinea pigs, marmosets, rhesus monkeys). Read, Collins and Sander153 were the first to study the role of the choroid in refractive error in humans, showing that only 60 minutes of positive defocus imposed by trial lenses caused choroidal thickening, just like in animal models. Conversely, negative defocus induced choroidal thinning. These results are most intriguing and suggest that the development of refractive state is partially controlled by the sign of defocus detected in the human eye. On the other hand, the effects were very small (range 10 ± 5 μm, which is equivalent to only about 0.03 D) and could be measured only due to the extreme axial resolution of the low coherence interferometer that was used in those studies (the Haag-Streit Lenstar LS 900). Using the same device, Bernard and colleagues154 obtained different results; the choroid actually thinned (rather than thickening), when positive defocus was imposed. However, even though the directions of the changes in the choroidal thickness did not match in both studies, it remains striking that they were significant already after one hour. It was also shown that imposed defocus interferes with diurnal cycling of choroidal thickness and axial length,155,156 a finding that was first described for deprivation myopia in chickens.157

Association between bright light and myopia in children In this case, the idea that the inhibitory effect of outdoor activity on myopia is mediated by © 2015 Optometry Australia

bright light did not emerge from studies in animal models but rather from studies in children.158,159 These studies reported an association between outdoor activities and myopic progression using questionnaires and speculated that the cause may be either light exposure or physical activities. A recent study by Read, Collins and Vincent160 was the first to differentiate between measured physical activity and light exposure and its association with refractive error in children. Animal models helped to specify the light conditions that were most effective. Lan, Feldkaemper and Schaeffel161 found in chickens that 10 hours of bright light were not more effective than five but that intermittent periods of bright light were more effective than continuous light. Karouta and Ashby162 found that inhibition of deprivation myopia in chicks increases with ambient illuminance according the function: amount of myopia ¼ -3:59  log ðilluminance in luxÞ þ 17:52

The baseline myopia induced by diffusers at 500 lux was about -8.00 D. According to their function, 80 per cent inhibition was achieved at 15,000 lux. A gain of only 20 per cent occurred after increasing illuminance further to 40,000 lux. Therefore, a reasonable illuminance, comparable to a cloudy day outside at noon, is already effective. Further studies in animal models will help to optimise to light regimes to reduce myopic development and progression in children.

The effect of atropine That atropine can inhibit the development of myopia is an old finding,163 which was later confirmed in many animal studies37 and more recent studies in children.164,165 A once daily eye drop of a one per cent solution can even reduce the axial length of the eye in the first three months but with severe side effects including complete paralysis of accommodation, photophobia, dry eyes and corneal ulcers. The interest in atropine waned after it was learned that atropine lost its effect after two to three years of treatment. Even worse, after its application was discontinued, myopia rapidly progressed to original baseline levels within one year, so that the treatment appeared useless following cessation. Low-dose atropine can also be effective against myopia, even though it takes initially longer to see an effect (more than three months). Most

encouraging is that after a treatment period of two years with eye drops of 0.01 per cent atropine and a subsequent three-year washout phase, myopia was still only about half of the one in the vehicle-treated group.166 This is supported by Chia (unpublished data) with a three-year wash-out phase. It is likely that the interest in atropine will rise in the future although the mechanism of its action remains still largely unknown.39,167 A recent study168 speculated on possible underlying mechanisms, including stimulation of dopamine release, enhancement of retinal contrast sensitivity, processing of the defocus error signal or direct inhibition of growth of scleral tissue.

ACKNOWLEDGEMENTS

We thank our two reviewers for all their most helpful suggestions. We also appreciate the extensive editorial work invested by the Associate Editor and one of the two reviewers who both improved our writing style fundamentally and provided a long list of suggestions for stylistic improvements.

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