Experiments in several species have shown that the axial elongation rate of the developing eye can be increased or decreased by manipulating the visual environment, indicating that a visually guided emmetropization mechanism controls the enlargement of the vertebrate eye during postnatal development. Previous studies in tree shrews (Tupaia glis belangeri) suggest that regulation of the mechanical properties of the sclera may be an important part of the mechanism that controls the axial elongation rate in this mammal. To learn whether the mechanical properties of the sclera change when the axial elongation rate is increased or decreased under visual control, uniaxial mechanical tests were performed on 3-mm wide strips of tree shrew sclera. The creep rate was measured under 1, 3, and 5 g of tension, maintained for 30 min at each level. The modulus of elasticity was calculated from the elastic extension that occurred when the force was increased from 0 to 1 g, 1 to 3 g, and 3 to 5 g. Both were measured in the sclera of both eyes from animals exposed to four experimental conditions: (1) Normal development, at intervals from the day of natural eyelid opening (day 1 of visual experience [VE]) to greater than 5 years of age; (2) Monocular form deprivation (MD), for varying lengths of time; (3) Recovery from MD; (4) Monocular -5 D lens treatment. The creep rate was low in normal animals (1-2% elongation/h), did not change significantly between day 1 and day 75 of VE, and was not significantly different between the two eyes. Four days of MD produced a 200-300% increase in creep rate in the sclera from deprived eyes. Creep rate remained similarly elevated after 11 and 21 days of MD. After 2 days of recovery, which followed 11 days of MD, the creep rate of sclera from the recovering eyes was below normal levels. In animals that wore a monocular -5 D lens for up to 21 days, creep rate increased, and then decreased, in concert with the increase, and decrease, in axial elongation rate as the eyes compensated for the lens. The modulus of elasticity of the sclera was not significantly affected by any manipulation. The temporal correspondence between changes in axial elongation rate and changes in creep rate support the hypothesis that regulation of the time-dependent mechanical properties of fibrous mammalian sclera plays a role in controlling axial elongation rate during both normal emmetropization and the development of refractive errors.
Recent epidemiological evidence in children indicates that time spent outdoors is protective against myopia. Studies in animal models (chick, macaque, tree shrew) have found that light levels (similar to being in the shade outdoors) that are mildly elevated compared to indoor levels, slow form-deprivation myopia and (in chick and tree shrew) lens-induced myopia. Normal chicks raised in low light levels (50 lux) with a circadian light on/off cycle often develop spontaneous myopia. We propose a model in which the ambient illuminance levels produce a continuum of effects on normal refractive development and the response to myopiagenic stimuli such that low light levels favor myopia development and elevated levels are protective. Among possible mechanisms, elevation of retinal dopamine activity seems the most likely. Inputs from intrinsically-photosensitive retinal ganglion cells (ipRGCs) at elevated light levels may be involved, providing additional activation of retinal dopaminergic pathways.
When viewing distance was limited to objects >1 m away, viewing through a plano lens for 45 minutes (minimal defocus) consistently prevented the development of axial elongation and myopia in response to a myopiagenic -5-D lens. Myopic defocus prevented compensation in some but not all animals. Thus, myopic defocus is encoded by at least some tree shrew retinas as being different from hyperopic defocus, and myopic defocus can sometimes counteract the myopiagenic effect of the -5-D lens (hyperopic defocus). However, it appears that minimal defocus is a more consistent, strong antidote to a myopiagenic stimulus in this mammal closely related to primates.
Shortly after birth, the eyes of most animals (including humans) are hyperopic because the short axial length places the retina in front of the focal plane. During postnatal development, an emmetropization mechanism uses cues related to refractive error to modulate the growth of the eye, moving the retina toward the focal plane. One possible cue may be longitudinal chromatic aberration (LCA), to signal if eyes are getting too long (long [red] wavelengths in better focus than short [blue]) or too short (short wavelengths in better focus). It could be difficult for the short-wavelength sensitive (SWS, “blue”) cones, which are scarce and widely spaced across the retina, to detect and signal defocus of short wavelengths. We hypothesized that the SWS cone retinal pathway could instead utilize temporal (flicker) information. We thus tested if exposure solely to long-wavelength light would cause developing eyes to slow their axial growth and remain refractively hyperopic, and if flickering short-wavelength light would cause eyes to accelerate their axial growth and become myopic. Four groups of infant northern tree shrews (Tupaia glis belangeri, dichromatic mammals closely related to primates) began 13 days of wavelength treatment starting at 11 days of visual experience (DVE). Ambient lighting was provided by an array of either long-wavelength (red, 626±10 nm) or short-wavelength (blue, 464±10 nm) light-emitting diodes placed atop the cage. The lights were either steady, or flickering in a pseudo-random step pattern. The approximate mean illuminance (in human lux) on the cage floor was red (steady, 527 lux; flickering, 329 lux), and blue (steady, 601 lux; flickering, 252 lux). Refractive state and ocular component dimensions were measured and compared with a group of age-matched normal animals (n=15 for refraction (first and last days); 7 for ocular components) raised in broad spectrum white fluorescent colony lighting (100-300 lux). During the 13 day period, the refraction of the normal animals decreased from (mean±SEM) 5.8±0.7 diopters (D) to 1.5±0.2 D as their vitreous chamber depth increased from 2.77±0.01mm to 2.80±0.03 mm. Animals exposed to red light (both steady and flickering) remained hyperopic throughout the treatment period so that the eyes at the end of wavelength treatment were significantly hyperopic (7.0±0.7 D, steady; 4.7±0.8 D, flickering) compared with the normal animals (p<0.01). The vitreous chamber of the steady red group (2.65±0.03 mm) was significantly shorter than normal (p<0.01). On average, steady blue light had little effect; the refractions paralleled the normal refractive decrease. In contrast, animals housed in flickering blue light increased the rate of refractive decrease so that the eyes became significantly myopic (−2.9±1.3 D) compared with the normal eyes and had longer vitreous chambers (2.93±0.04 mm). Upon return to colony lighting, refractions in all groups gradually returned toward emmetropia. These data are consistent both with the hypothesis that LCA can be an important visual...
The observed changes in MT1-MMP, MMP-2, TIMP-2, and TIMP-3 mRNA are consistent with visually modulated MT1-MMP activation of MMP-2 and with MT1-MMP degradation of scleral extracellular matrix components. These data constitute further evidence that visual signals modulate gene expression of selected MMPs and TIMPs to control scleral remodeling, the mechanical properties of the sclera, axial elongation, and refractive state.
To examine the susceptible period for deprivation-induced myopia, six groups of tree shrew pups (Tupaia glis belangeri) were monocularly deprived for 12 days with an opaque occluder starting 7, 15, 21, 33, 48, or 63 days after natural eyelid opening. Compared to the untreated fellow control eye, significant myopia and vitreous chamber elongation were produced by the deprivation in all six groups. The effect was greater in the middle three groups in comparison with the youngest and the two oldest groups and the amount of induced myopia and axial elongation was not proportional to the normal rate of axial growth. The peak period of susceptibility was between approximately 15 and 45 days after eye opening during the juvenile, slow-elongation phase of ocular development when the eye is within 7% of its adult axial length. Significant myopia and axial elongation were also induced in adult animals by 70 days of monocular deprivation. To examine recovery from deprivation-induced myopia, the occluder was removed at the end of the 12 day deprivation period. After an additional 48 days of binocular visual experience, no significant myopia was present in the previously deprived eyes in any experimental group. During the recovery period, the elongation rate of the previously deprived eyes was reduced in comparison with the control eyes while normal corneal flattening and lens development continued, thus reducing the myopia. No difference in corneal curvature, relative to the untreated control eyes, was found after deprivation or after the recovery period. Data are presented which suggests that changes in the thickness of the choroid may occur in this mammal during deprivation and recovery that are in the same direction, but of smaller magnitude, than those reported in the chicken. The results of this study provide evidence that visually guided emmetropization occurs in this mammalian species during a period of ocular development analogous to the juvenile period in humans.
We examined in tree shrews the effect of age on the development of, and recovery from, myopia induced with a negative lens. Starting at 11, 16, 24, 35 or 48 days after natural eye-opening (days of visual experience [VE]), juvenile tree shrews (n = 5 per group) wore a monocular −5 D lens for 11 days. A long-term lens-wear group (n=6) began treatment at 16 days of VE and wore the lens for 30 days. A young adult group (n = 5) began to wear a −5 D lens between 93 and 107 days of VE (mean ± SD, 100 ± 6 days of VE) and wore the lens for 29 to 54 days (mean ± SD, 41.8 ± 9.8 days). The recovery phase in all groups was started by discontinuing −5 D lens wear. Contralateral control eyes in the three youngest groups were compared with a group of age-matched normal eyes and showed a small (<1 D), transient myopic shift. The amount of myopia that developed during lens wear was measured as the difference between the treated and control eye refractions. After 11 days of lens wear, the induced myopia was similar for the four younger groups (near full compensation: 11 day, −5.1 ± 0.4 D; 16 day, −4.7 ± 0.3 D, 24 day, −4.9 ± 0.4 D; 35 day, −4.0 ± 0.02) and slightly less in the oldest juvenile group (48 day, −3.3 ± 0.5 D). The young adult animals developed −4.8 ± 0.3 D of myopia after a longer lens-wear period. The rate of compensation (D/day) was high in the 4 youngest groups and decreased in the 48-day and young adult groups. The refractions of the long-term lens-wear juvenile group remained stable after compensating for the −5 D lens. During recovery, all animals in the youngest group recovered fully (< 1 D residual myopia) within seven days. Examples of both rapid (< 10 days) and slow recovery (> 12 days) occurred in all age groups except the youngest. Every animal showed more rapid recovery (higher recovery slope) in the first 4 days than afterward. One animal showed extremely slow recovery. Based on the time-course of myopia development observed in the youngest age groups, the start of the susceptible period for negative lens wear is around 11 to 15 days after eye opening; the rate of compensation remains high until approximately 35 days of VE and then gradually declines. Compensation is stable with continued lens wear. The emmetropization mechanism, both for negative lens compensation and recovery, remains active into young adulthood. The time-course of recovery is more variable than that of compensation and seems to vary with age, with the amount of myopia (weakly) and with the individual animal.
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