March 2010
Volume 51, Issue 3
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Anatomy and Pathology/Oncology  |   March 2010
Mouse Experimental Myopia Has Features of Primate Myopia
Author Affiliations & Notes
  • Tatiana V. Tkatchenko
    From the Departments of Anatomy and Cell Biology,
  • Yimin Shen
    Radiology, and
  • Andrei V. Tkatchenko
    From the Departments of Anatomy and Cell Biology,
    Ophthalmology, Wayne State University, Detroit, Michigan.
  • Corresponding author: Andrei V. Tkatchenko, Department of Anatomy and Cell Biology, Wayne State University, 540 E. Canfield Avenue, Detroit, MI 48201; atkatche@med.wayne.edu
Investigative Ophthalmology & Visual Science March 2010, Vol.51, 1297-1303. doi:10.1167/iovs.09-4153
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      Tatiana V. Tkatchenko, Yimin Shen, Andrei V. Tkatchenko; Mouse Experimental Myopia Has Features of Primate Myopia. Invest. Ophthalmol. Vis. Sci. 2010;51(3):1297-1303. doi: 10.1167/iovs.09-4153.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: Several recent studies have suggested that experimental myopia can be induced in mice. However, it is not clear what role the photopic visual input plays in this process and whether mouse myopia is similar to human myopia. The purpose of this study was to carry out an in vivo high-resolution analysis of changes in ocular components and refractive state of the eye upon induction of experimental myopia in mice.

Methods.: A high-resolution small animal MRI system and a high-resolution automated eccentric infrared photorefractor were used to analyze changes of the refractive state and ocular components in C57BL/6J mice associated with experimental myopia induced by diffusers and −25 D lenses under photopic conditions.

Results.: The authors found that both diffusers and −25 D lenses induce myopia in C57BL/6J mice under photopic conditions (continuous light, 200 ± 15 lux). The extent of myopic shift induced by −25 D lenses was greater than the shift induced by diffusers (−15.2 ± 0.7 D, lenses; −12.0 ± 1.4 D, diffusers). Myopia in mice is attributed to an increase in size of the postequatorial segment of the eye. Experimental myopia in mice can be induced only during the susceptible period in postnatal development, which ends around postnatal day 67.

Conclusions.: Both diffusers and spectacle lenses induce myopia in mice under photopic conditions, during the susceptible period in postnatal development. Myopia in mice is associated with elongation of the vitreous chamber of the eye, as in humans and nonhuman primates.

Postnatal eye development is a tightly coordinated process whereby visual input regulates growth of the eye in a process called emmetropization. 1 Emmetropization is a result of the eye's capacity to adjust its growth during early postnatal development according to the quality of the image received by the retina. The failure of emmetropization often leads to the development of myopia. Myopia affects 33% of the adult population in the United States 2 and up to 80% of population in some parts of Asia, 3,4 and it represents the seventh leading cause of blindness. 5  
Degradation of the visual input during the early postnatal period was shown to lead to the development of myopia in children 6,7 and to abnormal enlargement of the postequatorial segment of the eye and the development of myopia in several vertebrate species, including nonhuman primates, 8,9 the tree shrew, 10 and the chicken. 11 Visual deprivation during the early postnatal period of development leads to reduction in visual acuity in mice, 12 as in other vertebrates. 1315 Several recent reports suggest that myopia can also be induced experimentally in mice. 1618 However, current protocols for the induction of experimental myopia did not produce substantial myopia in mice, and it is unclear to what extent the ocular changes associated with experimental myopia in mice are similar to those observed in primate myopia. It is also unclear what role the photopic visual input plays in the development of myopia in mice, which is important given that mice are nocturnal animals. 
In the present study, we used high-resolution small animal MRI and high-resolution automated eccentric infrared photorefractometry to analyze ocular changes upon induction of form- deprivation and defocus-induced myopia in C57BL/6J mice in photopic conditions. We showed that visual form deprivation and lens-imposed defocus in photopic conditions can induce substantial myopia in mice. We demonstrated that ocular changes associated with experimental myopia in mice have some features of primate myopia. We also demonstrated that experimental myopia in mice can be induced only during a susceptible period in early postnatal development, and we established the limits of this period. 
Methods
Animals and Experimental Design
C57BL/6J mice were obtained from the Jackson Laboratory (Bar Harbor, ME) and were maintained as an in-house breeding colony at the Wayne State University School of Medicine. Sixty-nine animals were analyzed, including 34 that were used for pilot experiments to optimize anesthesia, MRI, and photorefraction procedures and 11 that were lost because of problems with MRI. The remaining 24 animals, which were analyzed in the experiments reported here, represented six litters; we used groups of four animals from the same litter to minimize the impact of individual variations within the mouse population. C57BL/6J mice are known to have a relatively high incidence of microphthalmia, which affects from 4.4% to 10% of animals. 19,20 Therefore, animals were screened for the presence of microphthalmia and other ophthalmic abnormalities, such as corneal opacities and anterior polar cataracts, often associated with this condition. 21 Animals found to have microphthalmia, corneal opacities, or cataract were removed from the study (∼10% in our colony). All procedures adhered to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and were approved by the Wayne State University Institutional Animal Care and Use Committee. 
Visual Form Deprivation and Lens-Imposed Defocus
Frosted hemispherical plastic diffusers were handmade using caps from 0.2-mL PCR tubes (Molecular BioProducts, San Diego, CA) and rings made of medical tape (inner diameter, 6 mm; outer diameter, 8 mm). A cap was frosted with fine sandpaper and was attached to a ring with cyanoacrylate adhesive (Loctite Super Glue; Henkel Consumer Adhesives, Avon, OH). Mouse spectacle lenses (diameter, 6 mm; base curve radius, 7 mm; optical zone, 5.4 mm) were custom manufactured by Art Optical Contact Lens, Inc. (Grand Rapids, MI) and were attached to a ring made of medical tape using epoxy glue. On the day of the experiment (postnatal day [P] 24), animals were anesthetized by intraperitoneal injection of ketamine (90 mg/kg) and xylazine (10 mg/kg), and diffusers or spectacle lenses were attached to the skin surrounding the right eye with three stitches and were reinforced with glue (Vetbond; 3M Animal Care Products, St. Paul, MN); the left eye served as a control. Toenails were clipped to prevent mice from removing the diffusers or lenses (goggles). Animals recovered on a warming pad and were monitored until fully mobile. A collar made of transparent plastic foil was fitted around the neck of each mouse on day 6 to protect the goggles further, as described by Schaeffel et al. 17 Treated animals were housed in transparent plastic cages under constant light conditions (24 hours light, 200 ± 15 lux horizontal illuminance, n = 10) for 21 days. 
High-Resolution MRI
MRI was performed as previously described. 22,23 On the day of the examination, animals were anesthetized by intraperitoneal injection of ketamine (90 mg/kg) and xylazine (10 mg/kg). A contrast agent, gadopentetate dimeglumine (117 mg/mL, Magnevist; Berlex Laboratories, Wayne, NJ), was used as eyedrops to highlight the anterior chamber of the eye (see Fig. 1S for an MRI image of the mouse eye without this contrast agent). Each mouse was then gently positioned on an MRI-compatible homemade holder. Animals were allowed to breathe spontaneously during the experiment. Rectal temperature was continuously monitored while the animal was inside the magnet. MRI data were acquired on an MRI system (4.7T Avance; Bruker BioSpin MRI GmbH, Ettlingen, Germany) using a two-turn transmit/receive surface coil (0.8-cm diameter) placed over the eye. A preliminary low-resolution scan, in the horizontal plane of the eye, was used to position the high-resolution scan in the sagittal plane of the eye. The plane for the high-resolution scan was positioned to go through the center of the lens, the center of the cornea, and the optic nerve, thus ensuring its proximity to the optical axis of the eye. Five serial low-resolution slices were collected using an adiabatic spin-echo imaging sequence (repetition time, 0.45 seconds; echo time, 13.6 ms; number of acquisitions, 1; matrix size, 256 × 128; slice thickness, 1 mm; field of view, 32 × 32 mm2; 57 seconds for five slices). This resulted in an in-plane resolution of 125 μm2. High-resolution images were collected using an adiabatic spin-echo imaging sequence (repetition time, 1 second; echo time, 13.6 ms; number of acquisitions, 4; matrix size, 512 × 512; slice thickness, 0.62 mm; field of view, 12 × 12 mm2; 35 minutes/image). This resulted in an in-plane resolution of 23.4 μm2. Virtual sagittal slices through the optical axis of the eye were obtained for each eye, and axial length, equatorial diameter, anterior chamber depth, anterior chamber width, lens thickness, vitreous chamber depth, and circumference of the eye were measured with imaging software (Image; Scion, Frederick, MD) and derived macros, as previously described. 23 Five independent measurements were taken for each parameter, and the mean and SD were calculated for each eye. Axial length was measured as a distance from the posterior surface of the cornea to the anterior surface of the sclera. Equatorial diameter was measured as a distance between the inner surfaces of the sclera at the equator. Anterior chamber depth (ACD) was measured as a distance from the posterior surface of the cornea to the anterior pole of the lens. Anterior chamber width (ACW) was measured as a distance between the inner surfaces of the cornea in the iridocorneal angle, at the level of the anterior pole of the lens. Corneal radius of curvature (CRC) was calculated as CRC = ACD/2 + ACW2/8ACD. Lens thickness was determined as a distance between the anterior and posterior poles of the lens. Vitreous chamber depth was measured as a distance from the posterior pole of the lens to the anterior surface of the sclera. 
Photorefraction
The refractive state of both left and right eyes was determined on alert animals using a high-resolution automated eccentric infrared photorefractor. 17,23 The animal to undergo refraction was immobilized on a restraining platform, and each eye was refracted along the optical axis in dim room light (<1 lux) 5 to 7 minutes after the instillation of 1% tropicamide ophthalmic solution (Alcon Laboratories, Inc.) to ensure mydriasis and cycloplegia. Five independent measurements (5- to 10-second duration each) were taken for each eye. Each successful measurement was marked by a green light-emitting diode (LED) flash, which was registered by the photorefractor software. Sixty points (automatically acquired by the system every 16 ms) from each measurement immediately preceding the green LED flash were combined; 300 points were used to calculate the mean and SD. 
Statistical Analysis
Data modeling and statistical analysis were performed using commercially available software packages (SigmaPlot; Systat Software, San Jose, CA; and STATISTICA; StatSoft, Tulsa, OK). All data are presented as mean ± SD. 
Results
Analysis of Form-Deprivation Myopia in Mice
We have analyzed changes in the dimensions of ocular components induced by visual form deprivation in C57BL/6J mice (Fig. 1; Table 1; Supplementary Table S1). After 21 days of deprivation in photopic conditions (continuous light, 200 ± 15 lux; n = 10), we detected a myopic shift in refraction in the deprived eyes (−11.9 ± 0.9 D) relative to that in the control eyes (+0.1 ± 0.6 D) (Fig. 1B); the interocular difference (−12.0 ± 1.4 D) was highly significant (P = 0.0004). At the end of the deprivation period (P45), high-resolution images of both right (deprived) and left (control) eyes were acquired, and the interocular differences in derived diameter (DD), ACD, CRC, lens thickness (LT), and vitreous chamber depth (VCD) revealed statistically significant enlargement of the eye and the vitreous chamber in the deprived eyes. The DD of deprived eyes was, on average, 54 ± 9 μm larger (P < 0.0001; Fig. 1C), and the VCD in the deprived eyes was 45 ± 5 μm longer (P < 0.0001; Fig. 1D) than in the control fellow eyes. In contrast, no significant interocular differences were observed in ACD, CRC, or LT (Fig. 1D), suggesting that both the myopic shift in refraction and the ocular enlargement observed in mouse form-deprivation myopia were due primarily to the increase in the size of the postequatorial segment of the eye. 
Figure 1.
 
Form deprivation significantly accelerated eye growth and caused myopia in C57BL/6J mice. (A) Photograph of C57BL/6J mouse (P24) wearing a diffuser. (B) Statistically significant myopic shift in refraction in deprived eyes. (C) Statistically significant enlargement of the form-deprived mouse eye. (D) Statistically significant increase in VCD in form-deprived mouse eyes. ACD, anterior chamber depth; CRC, corneal radius of curvature; DD, derived diameter; LT, lens thickness; MOD, monocular deprivation; VCD, vitreous chamber depth. Vertical error bars, SD. P, significance value; n = 4.
Figure 1.
 
Form deprivation significantly accelerated eye growth and caused myopia in C57BL/6J mice. (A) Photograph of C57BL/6J mouse (P24) wearing a diffuser. (B) Statistically significant myopic shift in refraction in deprived eyes. (C) Statistically significant enlargement of the form-deprived mouse eye. (D) Statistically significant increase in VCD in form-deprived mouse eyes. ACD, anterior chamber depth; CRC, corneal radius of curvature; DD, derived diameter; LT, lens thickness; MOD, monocular deprivation; VCD, vitreous chamber depth. Vertical error bars, SD. P, significance value; n = 4.
Table 1.
 
Ocular Changes Associated with Form-Deprivation Myopia in C57BL/6J Mice
Table 1.
 
Ocular Changes Associated with Form-Deprivation Myopia in C57BL/6J Mice
Mouse Refractive Error (D) Interocular Difference (OD − OS, μm)
OD OS OD − OS DD* ACD CRC† LT VCD
D1 −11.2 ± 1.4 −0.7 ± 2.1 −10.5 45 ± 4 2 ± 0 1 ± 17 −4 ± 3 38 ± 12
D2 −11.1 ± 1.7 +0.4 ± 1.0 −11.5 53 ± 5 12 ± 0 7 ± 29 −13 ± 3 44 ± 13
D3 −12.9 ± 1.6 +0.6 ± 0.7 −13.5 66 ± 4 14 ± 12 −6 ± 44 −6 ± 8 50 ± 21
D4 −12.4 ± 1.5 +0.3 ± 1.2 −12.7 51 ± 9 4 ± 3 14 ± 36 −7 ± 10 46 ± 19
Analysis of Lens-Induced Myopia in Mice
We also analyzed the effects of −25 D lenses on the eye in C57BL/6J mice (Fig. 2; Table 2; Supplementary Table S2). After 21 days of lens treatment under photopic conditions, we detected a myopic shift in refraction in the lens-treated eyes (−14.6 ± 0.3 D) relative to that in the control eyes (+0.6 ± 0.6 D) (Fig. 2B); as with form deprivation, the interocular difference (−15.2 ± 0.7 D) was highly significant (P < 0.0001). High-resolution MRI again revealed enlargement of the eye and the vitreous chamber in the treated eyes. The DD of lens-treated eyes was, on average, 65 ± 8 μm larger (P < 0.0001; Fig. 2C), and the VCD in the lens-treated eyes was 61 ± 4 μm longer (P < 0.0001; Fig. 2D) than in the control fellow eyes. No significant interocular differences were observed in ACD, CRC, or LT (Fig. 2D), suggesting that changes induced in mouse eyes by treatment with negative lenses, like those induced by form deprivation (Fig. 1), are largely confined to the postequatorial segment of the eye. 
Figure 2.
 
Minus-lens treatment significantly accelerated eye growth and caused myopia in C57BL/6J mice. (A) Photograph of C57BL/6J mouse (P24) wearing a −25 D lens. (B) Statistically significant myopic shift in refraction in lens-treated mouse eyes. (C) Statistically significant enlargement in lens-treated mouse eyes. (D) Statistically significant increase in VCD in lens-treated mouse eyes. ACD, anterior chamber depth; CRC, corneal radius of curvature; DD, derived diameter; LT, lens thickness; MOD, monocular deprivation; VCD, vitreous chamber depth. Vertical error bars, SD. P, significance value; n = 4.
Figure 2.
 
Minus-lens treatment significantly accelerated eye growth and caused myopia in C57BL/6J mice. (A) Photograph of C57BL/6J mouse (P24) wearing a −25 D lens. (B) Statistically significant myopic shift in refraction in lens-treated mouse eyes. (C) Statistically significant enlargement in lens-treated mouse eyes. (D) Statistically significant increase in VCD in lens-treated mouse eyes. ACD, anterior chamber depth; CRC, corneal radius of curvature; DD, derived diameter; LT, lens thickness; MOD, monocular deprivation; VCD, vitreous chamber depth. Vertical error bars, SD. P, significance value; n = 4.
Table 2.
 
Ocular Changes Associated with Negative-Lens–Induced Myopia in C57BL/6J Mice
Table 2.
 
Ocular Changes Associated with Negative-Lens–Induced Myopia in C57BL/6J Mice
Mouse Refractive Error (D) Interocular Difference (OD − OS, μm)
OD OS OD − OS DD* ACD CRC† LT VCD
L1 −14.3 ± 2.0 +1.0 ± 2.4 −15.3 71 ± 4 1 ± 12 −1 ± 47 −1 ± 11 60 ± 12
L2 −15.1 ± 1.7 +0.8 ± 1.3 −15.9 71 ± 5 4 ± 12 3 ± 17 5 ± 7 66 ± 16
L3 −14.4 ± 2.4 −0.3 ± 2.3 −14.1 54 ± 8 −2 ± 13 1 ± 41 0 ± 9 58 ± 13
L4 −14.6 ± 3.6 +0.8 ± 1.4 −15.4 64 ± 7 4 ± 4 −3 ± 26 9 ± 11 60 ± 8
Susceptible Period for Experimental Myopia in Mice
Given that the magnitude of experimentally induced myopia is reduced with age in other warm-blooded vertebrates, 9,2426 we sought to determine whether the same is true in mice (Fig. 3). We found a sharp decline in response to form deprivation between P24 and P40 and a lesser decline from then to P67, after which 3 weeks of form deprivation did not produce any detectable change in eye growth. Thus, the period during which form deprivation induces significant ocular enlargement and myopia in mice ends around P67. 
Figure 3.
 
Susceptibility to experimentally induced myopia declined with age and leveled off around 67 days of age. Mice were monocularly deprived of form vision at specified ages (n = 4 animals per group). Vertical error bars, SD.
Figure 3.
 
Susceptibility to experimentally induced myopia declined with age and leveled off around 67 days of age. Mice were monocularly deprived of form vision at specified ages (n = 4 animals per group). Vertical error bars, SD.
Discussion
The mouse, recently introduced as a model for myopia research, 16 has a number of important advantages compared to other species traditionally used for studies of myopia. The mouse genome is completely sequenced, is 85% homologous to the human genome, 27 and can be readily manipulated, making it a popular model for studies of visual system plasticity, 12,2830 glaucoma, 3133 retinal degeneration, 3436 and behavioral studies of vision. 12,3742 For the same reasons, the mouse could be a powerful model for studying refractive eye development and myopia. 
Mouse Vision
It is widely believed that mice have poor vision because of their small eyes, paucity of cone photoreceptors, lack of a central fovea, and adaptation to dim-light habitat. Nevertheless, the density of retinal ganglion cells is increased in a small area just temporal to the optic disc, which is anatomically and functionally analogous to an area centralis. 43 Mice also follow a visual stimulus and use a specific fixation axis during Hartmann-Shack aberrometry, 44 and they show robust photopic optokinetic reflexes. 45,46 The peak retinal ganglion cell (RGC) density in the mouse is approximately 8000 cells/mm2. 43 Based on the peak RGC density, visual acuity of the mouse is estimated at 1.4 cyc/deg. 47 Although estimates of visual acuity based on the optomotor response and visual evoked potentials (VEPs) point to a visual acuity of approximately 0.5 to 0.6 cyc/deg, 37,4850 this may be an underestimate because inherent optical aberrations can significantly reduce visual acuity in the mouse. 44 Therefore, mouse visual acuity may be, in fact, close to the estimated value of 1.4 cyc/deg, which is similar to the visual acuity of 1- to 2-month-old human infants. 5158 Recent detailed analysis of the optical characteristics of the mouse eye revealed that depth-of-focus for this spatial frequency is 6 D, 44 which is much lower than previously thought. 59 Schmucker and Schaeffel 60 have demonstrated that mice have sufficient spatial vision to respond to treatment with spectacle lenses and diffusers under photopic conditions, and behavioral studies on anophthalmic mice suggest that vision is critical for accurate spatial navigation in mice. 39,40 Taken together, these data indicate that the mouse has sufficient visual acuity to discriminate and process the detailed visual stimuli. Our experimental data further support this notion. 
Experimental Myopia in Mice
Visual deprivation in mice during the early postnatal period leads to a reduction in visual acuity 12 similar to that reported in other vertebrates. 1315 Tejedor and de la Villa 16 have reported that lid fusion causes enlargement of the eyeball and a myopic shift in refraction in C57BL mice (−2 D shift after 14 days of eyelid fusion, or ∼0.14 D/d). Although these authors found a correlation between the interocular differences in refraction and in axial length after monocular form deprivation, there was a discrepancy between the extent of the myopic shift and the increase in the axial length; the observed shift of ∼1 D/45.8 μm is approximately 10 times less than one would anticipate based on the schematic mouse eye. 59,61 Schaeffel et al. 17 have described a statistically significant myopic shift induced by frosted diffusers in a group of C57BL mice (−4 D shift after 14 days of form deprivation, or ∼0.29 D/d); however, the change in axial length that is expected to accompany the myopic shift could not be documented because the video technique used to measure axial length in freshly enucleated eyes did not have sufficient resolution. The same laboratory subsequently reported that a statistically significant increase in axial length (∼38 μm) could be measured in C57BL mice using OLCI after 14 days of form deprivation 62 ; however, the modest myopic shift in refraction (∼2 D) did not reach statistical significance. Recently, Barathi et al. 18 reported significant myopic shifts in refraction in Balb/cJ mice induced by eyelid fusion and −10 D lenses (−6 D for eyelid fusion, −14 D for lenses) after 46 days of treatment (∼0.13 D/d and ∼0.3 D/d, respectively) and suggested that the myopia was due to enlargement of the posterior portion of the eye. However, these findings are somewhat ambiguous because albino mice in general, and Balb/cJ mice in particular, have seriously impaired visual function that may make them unsuitable for myopia research. 50,6366 The extent of the myopic shift reported by Barathi et al. 18 (1 D/38 μm of axial length for diffusers; 1 D/27 μm of axial length for lenses) is 10 times and 7 times, respectively, less than predicted by the “schematic mouse eye” 59,61 Barathi et al. 18 and Tejedor and de la Villa 16 measured axial length on enucleated eyes after death. Eye enucleation introduces large errors that would make it difficult to measure extremely small changes in axial length induced in experimental mouse myopia. 17,61,67  
In the present study, we systematically evaluated form-deprivation and lens-imposed defocus models for myopia in postnatal C57BL/6J mice. To reduce the impact of individual variations, animals in each experimental group came from the same litter. According to the schematic mouse eye, a 4-μm increase in axial elongation should cause a −1 D (myopic) shift in refraction. 59,61 Therefore, the 45-μm increase in VCD that we observed in form-deprived eyes was predicted to cause a myopic shift of approximately −11.3 D, which is in good agreement with the myopic shift that we measured (−12.0 D). Similarly, the 61-μm increase in VCD that we observed in eyes treated with −25 D lenses was predicted to cause a myopic shift of approximately −15.3 D, which is in good agreement with the measured value (−15.2 D). Considering that primate (including human) myopia is mostly caused by axial elongation of the vitreous chamber of the eye, 8,68 we have also analyzed changes in dimensions of various components of the eye and found that the same is true of experimental myopia in the mouse. 
In cold-blooded vertebrates, such as amphibians and teleosts, myopia can be induced experimentally throughout the lifetime, 69,70 but in warm-blooded vertebrates it can be induced only at relatively early ages. 9,2426 Human population studies also show that the incidence and rate of progression of myopia decline with age. 71 In addition, we have found that experimental myopia in mice can only be induced during a susceptible period in postnatal development, ending around P67. 
Role of Lighting Conditions in Refractive Eye Development
We found that the extent of myopia induced in mice under a continuous light regimen is greater than that induced under a 12-hour light/12-hour dark cycle. This is different from chicks, in which constant light exposure causes suppression of the effects of visual form deprivation or lens-imposed defocus on the eye 7275 (or both) and ocular changes, 7679 including enlargement of the eye accompanied by reductions in anterior chamber depth and increases in corneal radius of curvature and vitreous chamber depth. 73,76,80,81 However, these effects of constant light have been reported only in chickens and appear to be unique to this species because rearing of infant rhesus monkeys (Macaca mulatta) in constant light did not cause significant deviations from normal refractive development. 82,83 These interspecies differences may result from important differences between avian and mammalian circadian systems. 8487 The most important difference is that the pineal gland in birds can function autonomously because it contains light-sensitive photoreceptors and an endogenous circadian clock 85 and, therefore, can control the production of melatonin independently of retinal input. 8890 Thus, in chickens, anterior chamber depth and corneal radius of curvature are controlled by pineal-derived melatonin (Li T, et al. IOVS 2000;41:ARVO Abstract 690; Li T, et al. IOVS 1999;40:ARVO Abstract 4463). The effects of constant light on the eye persist even after complete elimination of all neural signals from the retina, 9193 but they are eliminated by hoods used to shield the pineal gland from extraocular light (Li T, et al. IOVS 2000;41:ARVO Abstract 690). 94 Conversely, extraocular light does not influence plasma melatonin levels or entrain the circadian clock in mammals. 86,87,95  
Mice are nocturnal animals and, therefore, are usually assumed not to use vision in their natural habitat and to rely primarily on other senses. However, mice have good vision under photopic conditions. 37,42,46 Visual input (i.e., a photopically illuminated environment) is a prerequisite for the development of experimental myopia. 9699 Therefore, we conducted both diffuser and lens treatments under continuous 24-hour, low-intensity light (∼200 lux). Because extraocular light does not influence plasma melatonin levels or entrain the circadian clock in mammals 86,87,95 and because continuous illumination does not disrupt normal circadian rhythms in mice, 100102 we expected that mice under continuous illumination would be most active during subjective night under photopic conditions. Therefore, the effects of both diffusers and lenses on the mouse eye were expected to be proportional to the amount of visual stimulation and to be maximal in the animals maintained in continuous light. Continuous exposure to light intensities up to 5000 lux has been shown not to cause retinal degeneration in pigmented mice (Takase H, et al. IOVS 2008;49:ARVO E-Abstract 4417), and young rodents were shown to be more resistant to light-induced retinal damage than adult rodents. 103 Consistent with the previous observations, 100102 we did not detect significant changes in the activity pattern of our animals for at least 3 weeks after they had been moved to constant light. As expected, we found that visual form deprivation under continuous (24-hour) low-intensity photopic illumination induced a myopic shift in refraction approximately 2.3 times greater than under a 12-hour light/12-hour dark cycle (0.7 D/d in the present study compared with 0.3 D/d in previous studies). 1618  
Thus, visual form-deprivation and lens-imposed defocus in photopic conditions induced substantial myopia in young C57BL/6J mice during a susceptible period in postnatal development. We also found that ocular changes associated with experimental myopia in mice resembled closely those in human and nonhuman primate myopia. 
Supplementary Materials
Footnotes
 Supported by National Eye Institute Grant 1R21EY018902, National Eye Institute Core Grant for Vision Research P30EY004068, a research grant from Midwest Eye-Banks, and a grant from Research to Prevent Blindness.
Footnotes
 Disclosure: T.V. Tkatchenko, None; Y. Shen, None; A.V. Tkatchenko, None
The authors thank Frank Schaeffel for help with the mouse photorefractor setup and for generously providing the mouse pupillography and photorefraction software, Bill Stell for help with the manuscript, and the staff of the Wayne State University MR Research Facility for assistance with small animal MRI. 
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Figure 1.
 
Form deprivation significantly accelerated eye growth and caused myopia in C57BL/6J mice. (A) Photograph of C57BL/6J mouse (P24) wearing a diffuser. (B) Statistically significant myopic shift in refraction in deprived eyes. (C) Statistically significant enlargement of the form-deprived mouse eye. (D) Statistically significant increase in VCD in form-deprived mouse eyes. ACD, anterior chamber depth; CRC, corneal radius of curvature; DD, derived diameter; LT, lens thickness; MOD, monocular deprivation; VCD, vitreous chamber depth. Vertical error bars, SD. P, significance value; n = 4.
Figure 1.
 
Form deprivation significantly accelerated eye growth and caused myopia in C57BL/6J mice. (A) Photograph of C57BL/6J mouse (P24) wearing a diffuser. (B) Statistically significant myopic shift in refraction in deprived eyes. (C) Statistically significant enlargement of the form-deprived mouse eye. (D) Statistically significant increase in VCD in form-deprived mouse eyes. ACD, anterior chamber depth; CRC, corneal radius of curvature; DD, derived diameter; LT, lens thickness; MOD, monocular deprivation; VCD, vitreous chamber depth. Vertical error bars, SD. P, significance value; n = 4.
Figure 2.
 
Minus-lens treatment significantly accelerated eye growth and caused myopia in C57BL/6J mice. (A) Photograph of C57BL/6J mouse (P24) wearing a −25 D lens. (B) Statistically significant myopic shift in refraction in lens-treated mouse eyes. (C) Statistically significant enlargement in lens-treated mouse eyes. (D) Statistically significant increase in VCD in lens-treated mouse eyes. ACD, anterior chamber depth; CRC, corneal radius of curvature; DD, derived diameter; LT, lens thickness; MOD, monocular deprivation; VCD, vitreous chamber depth. Vertical error bars, SD. P, significance value; n = 4.
Figure 2.
 
Minus-lens treatment significantly accelerated eye growth and caused myopia in C57BL/6J mice. (A) Photograph of C57BL/6J mouse (P24) wearing a −25 D lens. (B) Statistically significant myopic shift in refraction in lens-treated mouse eyes. (C) Statistically significant enlargement in lens-treated mouse eyes. (D) Statistically significant increase in VCD in lens-treated mouse eyes. ACD, anterior chamber depth; CRC, corneal radius of curvature; DD, derived diameter; LT, lens thickness; MOD, monocular deprivation; VCD, vitreous chamber depth. Vertical error bars, SD. P, significance value; n = 4.
Figure 3.
 
Susceptibility to experimentally induced myopia declined with age and leveled off around 67 days of age. Mice were monocularly deprived of form vision at specified ages (n = 4 animals per group). Vertical error bars, SD.
Figure 3.
 
Susceptibility to experimentally induced myopia declined with age and leveled off around 67 days of age. Mice were monocularly deprived of form vision at specified ages (n = 4 animals per group). Vertical error bars, SD.
Table 1.
 
Ocular Changes Associated with Form-Deprivation Myopia in C57BL/6J Mice
Table 1.
 
Ocular Changes Associated with Form-Deprivation Myopia in C57BL/6J Mice
Mouse Refractive Error (D) Interocular Difference (OD − OS, μm)
OD OS OD − OS DD* ACD CRC† LT VCD
D1 −11.2 ± 1.4 −0.7 ± 2.1 −10.5 45 ± 4 2 ± 0 1 ± 17 −4 ± 3 38 ± 12
D2 −11.1 ± 1.7 +0.4 ± 1.0 −11.5 53 ± 5 12 ± 0 7 ± 29 −13 ± 3 44 ± 13
D3 −12.9 ± 1.6 +0.6 ± 0.7 −13.5 66 ± 4 14 ± 12 −6 ± 44 −6 ± 8 50 ± 21
D4 −12.4 ± 1.5 +0.3 ± 1.2 −12.7 51 ± 9 4 ± 3 14 ± 36 −7 ± 10 46 ± 19
Table 2.
 
Ocular Changes Associated with Negative-Lens–Induced Myopia in C57BL/6J Mice
Table 2.
 
Ocular Changes Associated with Negative-Lens–Induced Myopia in C57BL/6J Mice
Mouse Refractive Error (D) Interocular Difference (OD − OS, μm)
OD OS OD − OS DD* ACD CRC† LT VCD
L1 −14.3 ± 2.0 +1.0 ± 2.4 −15.3 71 ± 4 1 ± 12 −1 ± 47 −1 ± 11 60 ± 12
L2 −15.1 ± 1.7 +0.8 ± 1.3 −15.9 71 ± 5 4 ± 12 3 ± 17 5 ± 7 66 ± 16
L3 −14.4 ± 2.4 −0.3 ± 2.3 −14.1 54 ± 8 −2 ± 13 1 ± 41 0 ± 9 58 ± 13
L4 −14.6 ± 3.6 +0.8 ± 1.4 −15.4 64 ± 7 4 ± 4 −3 ± 26 9 ± 11 60 ± 8
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