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already after one to two days, but two to three weeks are necessary in the mouse. Furthermore, treatment of mice with diffusers or lenses is demanding, compared to chicks, and experiments often fail because the mice had removed their eye occluders or lenses. Finally, the small size of the eye of the mouse (little more than 3 mm in diameter in adult mice7; and Fig. 1) requires new technology to measure ocular dimensions and optical properties with sufficient precision.
Despite these obstacles, the number of publications on myopia in the mouse model increases continuously, and the results were surprisingly clear in some cases.
This chapter will review: (1) the spatial visual performance of the mouse and the optical features of its eye; (2) the techniques that are now available for myopia studies in the mouse, both for induction and its measurement; and (3) examples of results that were recently obtained using the mouse model. This review extends and updates a previous analysis of the mouse as a model of myopia,8 but will still not cover all studies that were published on this topic.
Spatial Visual Performance and Optical Features of the Eye
The mouse eye, scaled to body weight, is five times larger than the human eye and therefore cannot be considered vestigial. A basic question is whether it also provides “scaled visual acuity.” In a human eye, one degree of the visual field maps on 0.29 mm linear distance on the retina. In a 28-day-old mouse, the image magnification is only a tenth (0.03 mm/deg). Accordingly, even with the best possible optics, a mouse eye can achieve only a tenth in angular resolution — about 5 cyc/deg — since the “pixels” of the image, the photoreceptors, cannot be made much smaller. Behavioral (see detailed descriptions below) and electrophysiological studies9 show, however, that the spatial resolution of the mouse eye is considerably lower by another factor of 10 — only about 0.5 cyc/deg.
Although the optics of the mouse eye are far from diffraction-limited,10 it does not seem to be the final limiting factor in visual acuity. Also, cone photoreceptor diameters do not vary much between human and mouse (mouse >2–3 m; humans 2–8 m),11,12 and it remains to be explained why the mouse has such poor spatial resolution. Unexpectedly, there is also no clear evidence for a higher level of convergence of photoreceptor
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signals in the mouse retina. The ratio of optic nerve fibers in human and mouse (about 1,100,000 in human versus 66,000 in mouse)13 is about 16:1, and matches roughly the ratio of the retinal areas (14:1) — definitely different, for instance, from the cat (fiber number for human to cat is about 13:1 vs retinal area ratio 1.4:1), suggesting that a much higher level of photoreceptor convergence exists in the cat retina, compared to mouse or human. These findings suggest that mouse spatial vision is not optimized for low illuminances, unlike in the cat. In fact, Schmucker et al.14 found that the spatial resolution of mice in an optomotor task increased with increasing illuminances (up to 400 lux), but was very poor at 4 lux. Given poor visual acuity, depth of focus should be large and it is possible that emmetropization (the developmental matching of axial eye length to the focal length of the eye optics) may not be as precise as in some birds or primates. To focus an image of the environment onto the retina of a mouse eye, a refractive power of cornea and lens of more than 500 diopters [D] is necessary in air (a third of the power is lost because the vitreous cavity is, like in all vertebrate eyes, filled with water-like fluid). Relative to the 500 diopters of optical power, refractive errors of a few diopters may be negligible, and imperfections in the optics of the mouse eye may have less impact on vision than in humans. However, regarding emmetropization, one should keep in mind that a change in axial length of only about 5 m in the mouse changes the refractive state already by about one diopter.15 Even if the depth of focus of the mouse eye is as large as 10 diopters (see below), the absolute axial growth, determined by the growth of the scleral tissue, needs to be regulated with a precision of 50 m in axial direction, which is similar to that in the chicken, where this value converts to about one diopter.16
Remtulla and Hallett7 were the first to present a schematic eye model for the adult C57B1/6J mouse, based on frozen sections of 14 eyes of 20–23-week-old animals. Later, Schmucker and Schaeffel15 developed a paraxial schematic eye model for C57BL/6J mice at different ages, also based on frozen sections. Although frozen sections have limited resolution due to distortions that may occur during freezing and sectioning, it is always possible to take averages from several eyes, and to fit the biometrical data from different ages by polynomials. The averaging procedure reduces the impact of measurement variability, and a few general statements could be made about the optics of the mouse eye, which are now compared to more recent measurements with other techniques.
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Axial eye growth and development of refractive state
In line with an observation by Zhou and Williams,17 Schmucker and Schaeffel15 observed that the eyes grew about linearly in C57BL/6 mice over the first 100 days with no signs of saturation. Axial length grew from 3.0 mm at P22 by 4.4 m per day. Zhou et al.18 used a custom-built low coherence interferometer with focal plane advancement (described in detail in Zhou et al.)19 to measure axial eye growth in another strain of C57BL/6 mice. They found that axial eye growth was most rapid between P22 and P35 (about 17 m per day) and slowed down to about 3 m per
day between P53 and P100. The average growth rate over the whole period was similar, however (5.9 m/day).
Another developmental study in C57BL/6 mice was recently conducted using high resolution small animal MRI20. These authors also found nonlinear growth functions, with a fast growth phase followed by a slower phase. Axial length increased rapidly from P22 to P40, from 2.95 mm to 3.17 mm, followed by a slower increase to about 3.3 mm until P90.
Barathi et al.,21 who studied axial eye growth Balb/cJ albino mice in excised eyes with digital calipers, also observed the most rapid axial eye
growth between P1 and P56 (about 21 m per day), and a slower growth rate of only 1.8 m thereafter (average: 9.6 m/day). No saturation of
axial eye growth was obvious even beyond 100 days of age in any of these studies.
It is interesting that the growth rates were variable in the two studies using C57BL/6 mice, in particular between P22 and P35, but frozen sections and low coherence interferometry may give slightly different results in small and soft eyes. Axial eye growth, as measured in these studies, is shown in Fig. 1A, and development of refractive states in Fig. 1B. While axial eye growth was similar in all studies, there were large differences in refractive development, even though the refractions were determined with copies of the original infrared photorefractor,22 at least in the four studies on black mice. It is a question to be answered in the future, why different C57BL/6 strains show different refractive development, and whether this is genetically determined or due to environmental differences in the animal facilities. Large difference in refractive development were recently also found in guinea pigs: a Chinese tricolor guinea pig strain had a significant proportion of spontaneously myopic animals23 — a condition that was not found in other guinea pig studies (e.g. Ref. 24).
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Figure 1. (A) Axial eye growth in mice with normal visual experience as measured in four studies, using either C57BL/6 mice (Zhou et al.18 — using a custom-built low coherence interferometer; Schmucker and Schaeffel15 — using frozen sections, Tkatchenko et al.20 — using high resolution small animal MRI) or Balb/cJ albino mice (Barathi et al.21 — using digital calipers in freshly excised eyes). (B) Development of refractive states in these four studies (same symbols denote same study) with data added from the study by Pardue et al.25 Infrared photorefraction was used in the studies on black mice and streak retinoscopy in the albino mice (Barathi et al.).21 Note that axial eye growth was similar in all studies, but that there were considerable differences in refractive development.
Lens thickness and vitreous chamber depth
Because the lens grew in thickness from 1.74 mm at P22 by 5.5 m per day, vitreous chamber depth declined from 0.83 mm at 22 days, by 3.2 m per day15 (illustrated in Fig. 2). In the study by Zhou et al.,18 lens thickness was
1.47 mm at P22 and increased daily by about 7.9 m until P53, and grew slower (about 1.8 m/day) thereafter. Again, vitreous chamber depth
declined with age by 1.4 m per day between P22 to P102.
Corneal radius of curvature
A recent study, using video photokeratometry in Egr1 –/– mice and their wild type littermates27 showed that corneal radius of curvature grows from 1.35 mm to 1.53 mm from day 22 to 100 — an average daily growth rate of 2.3 m. Zhou et al.18 observed a rapid increase in corneal radius of curvature by 9 m per day between P22 and P35, and a slower phase with a
daily increase of 0.8 m thereafter (average growth rate over the whole period: 2.8 m/day, similar to Ref. 27).