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Purpose: To identify choroidal characteristics associated with susceptibility to development of naturally occurring and experimentally induced myopia., Methods: We compared choroidal properties between pigmented and albino guinea pig (GP) strains. Biometry, cycloplegic refractive error (RE), and eye wall sublayer thickness were measured from 171 GPs at postnatal day (P)6, 14, and 28. Forty-three P14 GPs underwent two-week monocular form-deprivation myopia (FDM). En face images of choroidal vasculature were obtained with a customized swept-source optical coherence tomography. Multivariate regression analyses were performed, with P28 RE as the outcome and P14 choroidal thickness (ChT) as the main predictor variable. Proteomic analysis was performed on choroidal tissue from P14 albino and pigmented GPs., Results: At P14, RE was correlated with thickness of the choroid (β = 0.06), sclera (β = 0.12), and retina (β = 0.27; all P < 0.001). P14 ChT was correlated with P28 RE both with (β = 0.06, P = 0.0007) and without FDM (β = 0.05, P = 0.008). Multivariate regression analysis, taking into account FDM (versus physiological growth) and strain, revealed that for every 10-µm greater ChT at P14, P28 RE was 0.50D more positive (P = 0.005, n = 70). En face images of choroidal sublayers showed that albino choroids were relatively underdeveloped, with frequent avascular regions. Consistent with this finding, proteomic analysis suggested abnormalities of the nitric oxide system in the albino GP choroid., Conclusions: Current results are consistent with the notion that greater ChT could protect from or delay the onset of myopia, while lower ChT is associated with greater susceptibility to myopia development. The underlying mechanism could be related to dysfunction of the choroidal vascular system.

Purpose: To investigate differences in sensitivity to myopia-inducing stimuli of two strains of pigmented guinea pigs., Methods: Eleven-day-old animals (New Zealand [NZ], n = 24 and Elm Hill strains [EH], n = 26) wore either a +2 or -2 diopter (D) lens over one eye and a plano lens over the fellow eye for 5 days; other 10-day-old EH (n = 9) and 7-day-old NZ (n = 9) animals were monocularly form-deprived (FD) for 28 days. Choroidal thickness and axial length were measured using A-scan ultrasonography at baseline and after 1 and 5 days for optical defocus treatments, and at baseline and after 28 days for the FD treatment. Refractive errors were measured by retinoscopy. Choroids of untreated animals were also evaluated using spectral-domain optical coherence tomography., Results: One day of optical defocus induced bidirectional (optical sign-dependent) choroidal responses in EH animals only (P < 0.01). Similar responses were detected in NZ animals after 5 days (P < 0.01), with concordant spherical equivalent refraction changes (P < 0.01). Compared with NZ animals, EH animals developed minimal myopia with FD after 28 days (-4.58 ± 0.97 vs. -0.69 ± 0.75 D for NZ versus EH, P < 0.001). Yet, EH animals showed paradoxical choroidal thickening, 20 ± 9 vs. -8 ± 8 μm for EH versus NZ, P < 0.001. Untreated EH animals also had significantly thicker choroids than NZ animals (147 ± 19 vs. 132 ± 16 μm, P < 0.05), with well-defined layering., Conclusions: As previously reported in chicks, guinea pigs show strain-related differences in response to myopia-inducing stimuli. The finding of a thicker, multilayered choroid in the strain showing decreased sensitivity to FD is provocative, suggesting a possible protective role of the choroid.

Purpose: To determine if myopia in albino guinea pigs is linked to altered ocular dopamine (DA) levels in both the retinal and uveal dopaminergic systems., Methods: Retina and retinal pigment epithelium (RPE)/choroid were dissected from eyes of 2-week-old albino myopic (AM) and pigmented hyperopic (PH) guinea pigs. The levels of DA, dihydroxy-phenyl acetic acid (DOPAC), and homovanillic acid (HVA) were determined. Tyrosine hydroxylase (TH) and tyrosinase activities were also measured. PH animals received daily unilateral peribulbar injections of either kojic acid (tyrosinase inhibitor) or vehicle for 2 to 4 weeks. Refractive errors and ocular axial dimensions were measured by eccentric infrared photoretinoscopy and A-scan ultrasonography., Results: Retinal DA levels were similar between the two strains, but AM eyes had higher levels of DOPAC. RPE/choroid DA and tyrosinase activity in AM eyes were lower than in PH eyes (P < 0.01); however, the DA turnover was higher (P < 0.05). After 2 weeks of kojic acid treatment, PH eyes developed significant myopia, accompanied by elongated vitreous chambers and axial lengths. Inhibition of tyrosinase activity was linearly correlated with a myopic refraction shift (R = 0.79, P < 0.01). PH animals that received 62.5 ng/mL kojic acid treatment daily for 2 weeks followed by 625 ng/mL for 2 more weeks became more myopic and had deeper anterior chambers compared to those that received the 62.5 ng/mL dose over this period (P = 0.04)., Conclusions: The uveal tyrosinase-dependent dopaminergic system is involved in the development of guinea pig refraction. Enhancing uveal tyrosinase activity might slow down the development of myopia.

Purpose: Disruption of dopaminergic signaling has been implicated in the abnormalities of ocular development in albinism, and many experiments have shown that retinal dopamine is a major regulator of postnatal eye growth and myopia in animal models. Therefore, in the present study we investigated whether progressive myopia, which can occur in albino guinea pigs without experimental manipulation of visual conditions, is affected by dopaminergic agents., Methods: Two-week-old albino guinea pigs, selected for being myopic (range refractive error [RE], -2 to -10 diopters [D]), received unilateral peribulbar injections of apomorphine (nonselective dopamine receptor agonist; 0, 7.5, 25, 75, 250, 750, and 2500 ng; n = 112), SKF38393 (D1-like agonist; 0, 10, 100, 1000 ng; n = 63), SCH23390 (D1-like antagonist; 0, 2500 ng; n = 27), quinpirole (D2-like agonist; 0, 10, 100, 1000 ng; n = 58), or sulpiride (D2-like antagonist; 0, 2500 ng; n = 24) once a day for four weeks. One noninjected group (n = 19) served as untreated control. Refractive states and axial dimensions of the eyes were measured without cycloplegia or general anesthetic, using eccentric infrared photoretinoscopy and A-scan ultrasonography, respectively, before treatment, and after 2 and 4 weeks of treatment. The main drug effects were analyzed by paired t-test or 2-way repeated measures ANOVA, as required., Results: The naturally occurring progression of myopic RE was inhibited by apomorphine at relatively high doses (250 and 750 ng), SKF38393 at 100 ng (D1-like agonist), and sulpiride at 2500 ng (D2-like antagonist), but promoted by apomorphine at a lower dose (25 ng), quinpirole at 100 ng (D2-like agonist), and SCH23390 at 2500 ng (D1-like antagonist). All drugs affected primarily vitreous chamber depth, rather than anterior segment dimensions., Conclusions: Our data suggest that the activation of D1-like receptors inhibits, whereas activation of D2-like receptors promotes, progressive myopia in this animal model. The robust effects of antagonists suggest that ocular dopamine receptors in these albinos may be in a chronic state of partial excitation. The precise location and identity of the receptors responsible for these effects remain to be determined., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Purpose: To compare emmetropization in albino and pigmented guinea pigs., Methods: Distributions of refractive state were examined in 214 albino and 234 pigmented guinea pigs. Albino (A) and pigmented (P) guinea pigs were divided into two groups, hyperopic (H) and myopic (M). Eye development was separately followed in 10 randomly selected animals from each group (AH, AM, PH, PM) from 2 to 10 weeks of age. In addition, deprivation myopia was induced in 36 age-matched albino (18 AH and 18 AM) and 36 pigmented (18 PH and 18 PM) guinea pigs by diffusers that were worn from 2 to 6 weeks of age. Finally, sclera fibril diameters were measured using transmission electron microscopy., Results: Strikingly, the distributions of refractive errors were bimodal at 2 weeks of age, both in albino and pigmented animals, with clearly different averages (-2.86 ± 5.60 diopters [D] vs. 2.13 ± 5.27 D respectively; t = 9.712; P < 0.001). Spontaneous myopia was more common in albino animals: 70.1% were myopic (AM) and 29.9% hyperopic (AH), whereas only 28.6% were myopic (PM) and 71.4% hyperopic (PH) in pigmented guinea pigs. Different from PM and AM did not show any recovery from myopia. With diffusers, AH became more myopic (-7.61 ± 2.71 D and -11.17 ± 2.55 D) than PH (-4.48 ± 1.46 D and -8.28 ± 2.13 D) after 2 and 4 weeks, respectively. Deprivation myopia could still be induced in PM (-1.64 ± 1.44 D and -5.17 ± 1.88 D after 2 and 4 weeks, respectively; P < 0.01) but not in AM. Scleral fibril diameters were smaller in myopic animals, both albino and pigmented., Conclusions: Deprivation myopia could not be induced in spontaneously myopic but only in hyperopic albino guinea pigs, where it was even higher than in pigmented animals. The distinct effects of albinism on emmetropization will help to elucidate the mechanisms underlying the emmetropization.

Purpose: To critically evaluate whether the adenosine A2A receptor (A2AR) plays a role in postnatal refractive development in mice., Methods: Custom-built biometric systems specifically designed for mice were used to assess the development of relative myopia by examining refraction and biometrics in A2AR knockout (KO) mice and wild-type (WT) littermates between postnatal days (P)28 and P56. Ocular dimensions were measured by customized optical coherence tomography (OCT), refractive state by eccentric infrared photorefraction (EIR), and corneal radius of curvature by modified keratometry. Scleral collagen diameter and density were examined by electron microscopy on P35. The effect of A2AR activation on collagen mRNA expression and on soluble collagen production was examined in cultured human scleral fibroblasts by real-time RT-PCR and a collagen assay kit., Results: Compared with WT littermates, the A2AR KO mice displayed relative myopia (average difference, 5.1 D between P28 and P35) and associated increases in VC depth and axial length from P28 to P56. Furthermore, the myopic shift in A2AR KO mice was associated with ultrastructural changes in the sclera: Electron microscopy revealed denser collagen fibrils with reduced diameter in A2AR KO compared with WT. Last, A2AR activation induced expression of mRNAs for collagens I, III, and V and increased production of soluble collagen in cultured human scleral fibroblasts., Conclusions: Genetic deletion of the A2AR promotes development of relative myopia with increased axial length and altered scleral collagen fiber structure during postnatal development in mice. Thus, the A2AR may be important in normal refractive development.

Purpose: To describe a wild-type guinea pig strain with an incidence of spontaneous axial myopia, minimal pupil responses, lack of accommodation, and apparently normal spatial vision. Such a strain is of interest because it may permit the exploration of defective emmetropization and mapping of the underlying quantitative trait loci., Methods: Twenty-eight guinea pigs were selected from 220 animals based on binocular myopia (exceeding -1.50 diopter [D]) or anisometropia (difference between both eyes exceeding 10 D) at 4 weeks of age. Refractions and pupil responses were measured with eccentric infrared photoretinoscopy, corneal curvature by modified conventional keratometer, and axial lengths by A-scan ultrasonography once a week. Twenty-one guinea pigs were raised under a normal 12-hour light/12-hour dark cycle. From a sample of 18 anisometropic guinea pigs, 11 were raised under normal light cycle and 7 were raised in the dark to determine the extent to which visual input guides emmetropization. Spatial vision was tested in an automated optomotor drum., Results: In 10 guinea pigs with myopia in both eyes, refractive errors ranged from -15.67 D to -1.50 D at 3 weeks with a high interocular correlation (R = 0.82); axial length and corneal curvature grew almost linearly over time. Strikingly, two patterns of recovery were observed in anisometropic guinea pigs: in 12 (67%) anisometropia persisted, and in 6 (33%) it declined over time. These ratios remained similar in dark-reared guinea pigs. Unlike published strains, all guinea pigs of this strain showed weak pupil responses and no signs of accommodation but up to 3 cyc/deg of spatial resolution., Conclusions: This strain of guinea pigs has spontaneous axial refractive errors that may be genetically or epigenetically determined. Interestingly, it differs from other published strains that show no refractive errors, vivid accommodation, or pupil responses.

Purpose: To investigate refraction, corneal curvature, axial components, and the correlations between the refraction and ocular growth during the emmetropization in the C57BL/6 mouse., Methods: Ten groups of 10 mice underwent ocular measurements at 22 to 102 days after birth. Refraction was measured by photoretinoscopy and corneal radius of curvature (CRC) was measured by keratometry. Corneal thickness (CT), anterior chamber depth (ACD), lens thickness (LT), vitreous chamber depth (VCD), retinal thickness (RT), and axial length (AL) were measured by optical coherence tomography (OCT) with focal plane advancement., Results: Refraction was -1.49 +/- 3.17 diopters (D; mean +/- SD) at day 22 and the highest myopia was at day 25 (-4.61 +/- 2.96 D). The refractive error then increased and reached a hyperopic peak (+9.43 +/- 3.33 D) on day 47. The overall change in refraction was significant from 22 to 102 days (P < 0.05). All measured ocular components changed significantly during the study period except for CT and RT (P > 0.05 for CT and RT; P < 0.05 for others). The CRC, ACD, LT, and AL increased from 22 to 47 days. The increase in ACD, LT, and AL continued after 47 days; however, the CRC increased slowly after this age. The ACD became stable around 67 days and LT and AL at 81 days., Conclusions: In C57BL/6 mouse eyes, myopia developed early and then the refractive error increased rapidly in the hyperopic direction to reach a peak at around 47 days with the major contributing changes being in axial length and corneal curvature.