Eye Growth Regulation Research Articles

Expression of Sonic Hedgehog and Retinal Opsin Genes in Experimentally-induced Myopic Chick Eyes

The purpose of this study was to evaluate changes in the expression of different genes in chick retinal tissues after induction of experimental myopia and to evaluate the roles of these genes in the regulation of postnatal eye growth and myopia. Form-deprivation using occlusive goggles and hyperopic defocus by negative spectacle lenses were used to induce myopia in hatched chicks.Expression levels of Sonic hedgehog, its receptor complex, and other retinal cell genes were evaluated by semi-quantitative reverse transcription-polymerase chain reaction. Levels of Sonic hedgehog protein were further evaluated by Western blot analysis. The induction of myopia caused significant increase in expression of Sonic hedgehog mRNA and protein and increased expression of blue and red opsin mRNA. In contrast, the expression of mRNA for Sonic hedgehog receptor complex (Patched–Smoothened), rhodopsin,vimentin , green opsin, violet opsin, and HPC-1 were unaffected by the induction of myopia. The increase in expression of Sonic hedgehog in chick retinas in experimentally-induced myopia suggests involvement in the retina control of postnatal eye growth. Furthermore, Sonic hedgehog may influence the expression of blue andred opsins under myopic conditions.

A model of the contribution of oculomotor and optical factors to emmetropization and myopia.

The purpose of this work was to investigate quantitatively the interactions between accommodation, vergence and a mechanism of emmetropization driven by optical blur within the retinal image with a view to developing a model that provides an explanation of both normal emmetropization and near-work associated myopia. The simulations of the change in the refractive state of the eye over time that derive from this model indicate that optical regulation of eye growth can result in emmetropization, i.e. a progressive reduction in refractive errors over time leading towards emmetropia. This occurs when viewing conditions involve a preponderance of distance work. With increasing near work, the model predicts that the refraction of the eyes will converge towards myopia. In keeping with the previously reported associations of myopia with esophoria, poor accommodation function and high AC/A ratios, these conditions increase the amount of myopia produced under intensive near viewing conditions but do not lead to myopia during mainly distance viewing. This model provides quantitative validation of the hypothesis that the epidemiological association between myopia and increased nearwork may be caused by a disturbance of normal emmetropization by steady state errors of accommodation. The same model can explain normal emmetropization, increasing myopia with increasing nearwork demands and the currently recognised oculomotor associations that have been reported to precede the development of myopia.

Visual Influences on Diurnal Rhythms in Ocular Length and Choroidal Thickness in Chick Eyes

Recent investigations have raised the possibility that ocular diurnal rhythms might be involved in the regulation of eye growth. Specifically, the chick eye elongates with a daily rhythm, said to be absent in form-deprived eyes. The present study asks: (1) Which components of the eye have daily rhythms—only the overall eye size, or also choroidal thickness or anterior chamber depth? (2) Does the phase or amplitude of these rhythms differ in eyes growing either faster than normal (form-deprived eyes) or slower than normal (eyes recovering from form-deprivation myopia)?Using high-frequency A-scan ultrasonography that allowed fine (8–20 μm) resolution of anterior chamber depth, vitreous chamber depth, choroidal thickness and axial length, we measured normal eyes, form-deprived eyes and eyes recovering from form-deprivation myopia at 6 hour intervals for 5 days and 4 nights. All eyes showed daily rhythms in axial elongation and choroidal thickness. In both normal and form-deprived eyes, the axial length was greatest in the afternoon when the choroid was thinnest, and hence, these rhythms were approximately in anti-phase to one another; in addition, there is some evidence that the axial length rhythm in form-deprived eyes is phase-advanced relative to that of their fellow control eyes. The amplitude of the rhythm in choroidal thickness in form-deprived eyes was significantly larger than in normal eyes.In recovering eyes in which elongation is slowed, the rhythm in axial length was significantly phase-delayed relative to normal eyes (peak at 8 pm) and the rhythm in choroidal thickness was phase-advanced (peak at 8 pm); thus in these eyes, the two rhythms are in phase. In these eyes, the choroids were thickening by approximately 100 μm/day. In all three groups, the rhythm in anterior chamber depth appears to differ in phase from the rhythm in axial length (and hence from the rhythm at the posterior wall of the eye). We propose that the phase relationship between these choroidal and eye length rhythms influence the rate of growth of the eye, and conclude that diurnal ocular rhythms may be important in eye growth regulation.

Retinal dopamine in the recovery from experimental myopia

PURPOSE. To address further a possible role for retinal dopamine in postnatal eye growth, we studied the response of retinal dopamine in eyes of chicks recovering from myopia. METHODS. Newborn chicks either received a unilateral translucent goggle to induce form deprivation myopia or were reared with unimpaired visual input. The goggle was removed from half of the chicks on day 7. Myopic, recovering and control never-goggled chicks were studied on days 7, 9 and 14. Eyes were enucleated postmortem and measured in axial and equatorial dimensions with calipers. Retinal levels of dopamine and its principal metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were assayed by high performance liquid chromatography with electrochemical detection. RESULTS. Compared to contralateral and control eyes, retinas of goggled eyes at each time point had reduced levels of dopamine and DOPAC and a lowered calculated DOPAC/dopamine ratio, an index of dopamine metabolism. In eyes recovering from myopia, all biochemical parameters showed prominent increases by 2 days after goggle removal and had reached the level of both contralateral eyes and control eyes by one week after goggle removal. As evidence of a contralateral effect, the retinas of open eyes of chicks wearing a unilateral goggle demonstrated equal dopamine levels but reduced DOPAC compared to eyes of never-goggled chicks. CONCLUSION. An early rise and eventual normalization of retinal dopamine, DOPAC and the DOPAC/dopamine ratio correlate with recovery from myopia. Combined with recent results from lens rearing experiments, these findings suggest that dopaminergic amacrine cells may participate in visually guided eye growth regulation and not just in the myopia response to visual form deprivation. The retinal biochemical alteration in eyes contralateral to a goggle indentifies a previously unappreciated binocular interaction in the chick.

Traumatic cycloplegia and myopic anisometropia.

The pathogenesis of myopia and the mechanism of atropine in preventing myopic progression have long been widely discussed. Recent studies with animals have pointed to the possible role of the muscarinic receptor of the retina itself in regulating eye growth. This paper stresses that, for myopia in humans, the importance of accommodation still holds. Twenty-five recovered cases of previous traumatic hyphema, occurring under age 16, were collected. For four or more years, the patients were examined for ocular refraction, axial length, intraocular pressure, gonioscopy and accommodation time; the latter was measured with an accommodo-polyrecorder. Data from injured eyes and fellow eyes were compared and analyzed. The results indicated that, in the injured eyes the refractive status was invariably less myopic than in the fellow eye, and was not related to intraocular pressure. In injured eyes the accommodation time was highly correlated with the extent of angle recess. And the difference of anisometropia was also related to the extent of angle recess. These observations showed that there was a significant correlation between the degree of myopic anisometropia and the impairment of accommodation.

Photoperiod, early post-natal eye growth, and visual deprivation

(1) We studied the influence of photoperiod and unilateral lid suture on post-natal ocular growth in two types of White Leghorn chicks previously reported to respond differently to visual deprivation, Truslow and Cornell K chicks. We analyzed the chicks after 2 weeks of rearing, a time period commonly used in neuropharmacological studies of eye growth but much shorter than in most prior studies of photoperiod effects on the chick eye. (2) Altering the photoperiod length significantly influenced the refraction and growth of both open and sutured eyes even at this early time, with differences between the two types of chicks. (3) The most prominent effect on the open eyes was the development of hyperopia with rearing under constant light, a response especially prominent in the Cornell K chicks. In the open eyes under this condition, the anterior chamber shallowed and the vitreous chamber elongated in the axial dimension only, reciprocal changes that resulted in no net alteration of axial length at 2 weeks. A high variability in refraction of open eyes reared with constant illumination suggests the need for a dark period in the regulation of eye growth. (4) Compared to contralateral open eyes, the lid-sutured eyes of both types of chicks developed longer total axial lengths and enlarged vitreous chambers in both axial and equatorial dimensions under each photoperiod. The effects on anterior chamber depth and refraction were complex and differed between the two types of chicks. (5) The responses in open eyes support the notion that growth of the vitrious chamber of the chick eye is differentially regulated in the axial and equatorial dimensions, previously indicated by pharmacological studies. The responses in both open and sutured eyes indicate different control mechanisms for anterior chamber and vitreous cavity growth.

Regulation of eye growth in the African cichlid fish Haplochromis burtoni

Fish were reared in 6 conditions: broad spectrum white light, total darkness, scotopic illumination, and 3 monochromatic colors matched to the absorption spectra of the three cone types to study the influence of the light regime on the regulation of eye growth in the African cichlid fish Haplochromis burtoni. Fish reared in total darkness showed high variability in naso-temporal diameter and axial length of the eye. Animals reared in darkness and in scotopic illumination had significantly larger eyes relative to lens size in comparison to fish reared in white light. Eye size and shape was nearly identical in fish reared in monochromatic and in white light. Because of overlap in the absorption spectra of the three cone types of H. burtoni it could not be resolved whether the regulatory mechanism receives input from all three cone types or only from the green (523 nm) sensitive cones. It is clear from our results, however, that neither the blue (455 nm) nor the yellow sensitive (562 nm) cones alone are responsible for eye size regulation. It seems equally unlikely that all three cone types have to act in concert for normal growth of the eye.

Some visual and neurochemical correlates of refractive development

Increasing evidence indicates that the retina takes part in the postnatal regulation of eye growth, functioning in this respect to minimize refractive error. The evidence derives both from clinical observations in man and from experiments in animals. The discovery that visual form deprivation leads to an axial overgrowth of the eye and to myopia has opened the way to many current research initiatives. Neurochemical and immunocytochemical experiments in chick and monkey suggest that definable retinal neurons participate in the regulatory pathway controlling eye growth. The most comprehensive data presently implicate dopaminergic amacrine cells. Other important issues to be addressed include the relevance of an intact connection to the central nervous system and the precise retinal mechanism by which eye growth is regulated.

The regulation of eye growth and refractive state: An experimental study of emmetropization

During growth the vertebrate eye achieves a close match between the power of its optics and its axial length with the result that images are focused on the retina without accommodative effort (emmetropia). The possibility that vision is required for the regulation of eye growth was studied experimentally in chicks made myopic or hyperopic by different visual manipulations. After discontinuing these visual manipulations, the eyes returned quickly to emmetropia mainly by adjusting the growth of their vitreous chambers; growth stopped in eyes recovering from myopia and continued in eyes recovering from hyperopia. Because both hyperopic and myopic eyes were already larger than normal controls, the difference in growth indicates that refractive error, rather than eye size per se, guides the eye toward emmetropia. Evidence is also presented for nonvisual shape-related control of eye growth, but this is slow-acting and cannot explain the emmetropization from induced refractive errors. Both the visually guided and shape-related mechanisms work even in eyes with the optic nerve cut, indicating that the two mechanisms are local to the eye. Although the optic-nerve-sectioned eye can sense the sign of a refractive error and initially adjust growth accordingly, it eventually overshoots emmetropia and reverses the sign of the initial refractive error. Whether this is due to loss of feedback from the central nervous system or retinal ganglion cells is unclear.

Mathematical model of emmetropization in the chicken.

Recently a number of observations were made on refractive development in chickens and monkeys under various experimental treatments. Degradation of the retinal image by use of occluders produces myopia, although with a high variability in the individual refractions. This kind of image degradation myopia can be induced in the absence of accommodation and with the optic nerve sectioned. In chickens, recovery occurs both in normal birds and in operated birds in which accommodation has been eliminated by lesions in the Edinger Westphal nucleus. In addition, it was shown that, in the chicken eye, growth compensates for an imposed refractive error induced by spectacle lenses. A compensatory change in growth can also be induced in the absence of accommodation. Thus the role of accommodation in the refractive development must be explained. Here we develop a minimal model for regulation of eye growth that provides a possible explanation for all the above observations. A major conclusion is that the presence of two independent feedback loops must be assumed, one dependent on accommodation and one on a local mechanism detecting blur in the retina.

Accommodation, refractive error and eye growth in chickens

We raised chickens with defocusing lenses of differing powers in front of their eyes. For this purpose, small hoods made from soft, thin leather were carefully fitted to their heads. Lenses were attached to the hoods by velcro fasteners and could be easily removed for cleaning. The powers of the lenses were such that their optical effects could be compensated for by accommodation. It was verified by infrared (IR) photoretinoscopy that the chickens could keep their retinal images in focus. Wearing a lens resulted in a consistent shift of the non cycloplegic refractive state (measured without the lens) which was in the direction to compensate for the lens. We used a sensitive technique ( precision= ± 50 μm as estimated from the variability of repeated measurements) to measure the posterior nodal distance (PND) in excised eyes of birds grown with lenses. The PND, in turn, was used to compare eyes treated with different lenses. It was found that the PND was increased in eyes which were treated with negative lenses compared to those treated with positive lenses. This effect occurs independently in both eyes and it is not due to changes in corneal curvature. We discuss our result in terms of a closed-loop feedback system for the regulation of eye growth.

Developmental aspects of experimental myopia in chicks: Susceptibility, recovery and relation to emmetropization

Chicks deprived of form-vision in the lateral part of their visual fields become severely myopic largely because of elongation of the vitreous chamber. The myopia mostly affects the visually deprived nasal retina; the nondeprived temporal retina is unaffected. These changes occur most rapidly early in life, being evident then after only 3 days of visual restriction. The susceptibility declines with age, being proportional to the rate of increase of axial length. Recovery from this myopia occurs if the visual restriction is removed during the first 6 weeks of life, as a result of the cessation of elongation of the vitreous chamber. The rate of recovery is directly related to the degree of myopia and inversely related to age. The pattern of changes in refractive status and variability argue for the probable existence of an active mechanism regulating eye growth in a manner dependent on refractive error, thereby producing emmetropization.

Researches on the texture of iron

A large body of data is available to support the hypothesis that dopamine (DA) is one of the retinal neurotransmitters involved in the signaling cascade that controls eye growth by vision. Initially, reduced retinal DA levels were observed in eyes deprived of sharp vision by either diffusers (“deprivation myopia”, DM) or negative lenses (“lens induced myopia”, LIM). Simulating high retinal DA levels by intravitreal application of a DA agonist can suppress the development of both DM and LIM. Also more recent studies using knock-out mouse models of DA receptors support the idea of an association between decreased DA levels and DM. There seem to be differences in the magnitude of the effects of DA on DM and LIM, with larger changes in DM but the degrees of image degradation by both treatments need to be matched to support this conclusion. Although a number of studies have shown that the inhibitory effects of dopamine agonists on DM and LIM are mediated through stimulation of the D2-receptor, there is also recent evidence that the balance of D2- and D1-receptor activation is important. Inhibition of D2-receptors can also slow the development of spontaneous myopia in albino guinea pigs. Retinal DA content displays a distinct endogenous diurnal, and partially circadian rhythm. In addition, retinal DA is regulated by a number of visual stimuli like retinal illuminance, spatial frequency content of the image, temporal contrast and, in chicks, by the light input from the pineal organ. A close interaction was found between muscarinergic and dopaminergic systems, and between nitric oxide and dopaminergic pathways, and there is evidence for crosstalk between the different pathways, perhaps multiple binding of the ligands to different receptors. It was shown that DA agonists interact with the immediate early signaling molecule ZENK which triggers the first steps in eye growth regulation. However, since long treatment periods were often needed to induce significant changes in retinal dopamine synthesis and release, the role of dopamine in the early steps is unclear. The wide spatial distribution of dopaminergic amacrine cells in the retina and the observation that changes in dopamine levels can be locally induced by local retinal deprivation is in line with the assumption that dopaminergic mechanisms control both central and peripheral eye growth. The protective effect of outdoor activity on myopia development in children seems to be partly mediated by the stimulatory effect of light on retinal dopamine production and release. However, the dose–response function linking light exposure to dopamine and to the suppression of myopia is not known and requires further studies.