Eye Growth Regulation Research Articles

OPTICAL BLUR AFFECTS DIFFERENTLY ON AND OFF VISUAL PATHWAYS.

The human eye has a crystalline lens that focuses retinal images at the point of fixation. Outside this fixation region, images are distorted by optical blur, which increases light scatter and reduces the spatial resolution and contrast processed by neuronal pathways. The spectacle lenses that humans use for optical correction also minify or magnify the images, affecting neuronal surround suppression in visual processing. Because light and dark stimuli are processed with ON and OFF pathways that have different spatial resolution, contrast sensitivity and surround suppression, optical blur and image magnification should affect differently the two pathways and the perception of lights and darks. Our results provide support for this prediction in cats and humans. We demonstrate that optical blur expands ON receptive fields while shrinking OFF receptive fields, as expected from the expansion of light stimuli and shrinkage of dark stimuli with light scatter. Spectacle-induced image magnification also shrinks OFF more than ON receptive fields, as expected from the stronger surround suppression in OFF than ON pathways. Optical blur also decreases the population response of OFF more than ON pathways, consistent with the different effects of light scatter on dark and light stimuli and the ON-OFF pathway differences in contrast sensitivity. Based on these results, we conclude that optical blur and image magnification reduce the receptive field sizes and cortical responses of OFF more than ON pathways, making the ON-OFF response balance a reliable signal to optimize the size and quality of the retinal image.

Dynamic BMP gene expression regulation in chick RPE during recovery from short term optical defocus and form-deprivation.

This study investigated the differential gene expression of BMPs in chick retinal pigment epithelium (RPE) during recovery from short term exposure to optical defocus and form-deprivation (FD) treatments. 14-day old White-Leghorn chicks wore either monocular +10 or -10 D lenses, or diffusers for 2 or 48 h, after which eyes were allowed unobstructed vision for up to 96 h. Over this recovery period, refractive errors and choroidal thickness (ChT) were tracked using retinoscopy and high-frequency A-scan ultrasonography. Real-time PCR was used to examine the expression of BMP2, 4, and 7 genes in RPE samples collected 0, 15 min, 2, 24, 48, and 96 h after the termination of treatments. Expression levels in treated eyes and their contralateral control eyes were compared. After the termination of the lens and diffuser treatments, eyes gradually recovered from induced shifts in refractive error. With all three treatments, ChT changes reached statistical significance after 48 h of treatment, be it thinning with the -10 D lens and diffuser treatments (-0.06 ± 0.03mm, p < 0.05; -0.11 ± 0.04 mm, p < 0.05, resp.), or thickening with the +10 D lens (0.31 ± 0.04 mm, p < 0.001). BMP2 gene expression was rapidly upregulated in eyes wearing the +10 D lens, being statistical significance after 2 h, as well as 48 h of treatment. With the 2 h treatment, the latter gene expression pattern persisted for 15 min into the recovery period, before decreasing to the same level as that of contralateral control eyes, with a short-lived rebound, i.e., upregulation, 24 h into the recovery period. With the longer, 48 h treatment, BMP2 gene expression decreased more gradually, from 739 ± 121% at the end of the treatment period, to 72 ± 14% after 48 h of recovery. Two and 48 h of both -10 D and FD treatments resulted in BMP2 gene expression downregulation, with the time taken for gene expression levels to fully recover varying with the duration of initial treatments. In both cases, BMP2 gene expression downregulation persisted for 15 min into the recovery period, but reversed to upregulation by 2 h. Similar gene expression patterns were also observed for BMP4, although the changes were smaller. The observed changes in BMP gene expression in chick RPE imply dynamic, albeit complex regulation, with the duration of exposure and recovery being critical variables for all three types of visual manipulations. This study provides further evidence for a role of the RPE as an important signal relay linking the retina to the choroid and sclera in eye growth regulation.

Chromatic Light Therapy for Inhibiting Myopia Progression: Human Studies.

Myopia, a common refractive error, has been associated with various risk factors, but time outdoors has emerged as a significant protective factor against its onset. This association is believed to be mediated by the influence of sunlight on dopamine release, a neurotransmitter crucial for regulating eye growth. Recent research has explored the specific properties of light in order to identify potential interventions for myopia control in children. Low-level red light therapy has gained attention, and has shown promise in inhibiting myopia progression, although there are concerns about safety and rebound effects. Similarly, blue light stimulation aims to upregulate retinal dopamine activity, yet conclusive evidence supporting its efficacy is lacking. Moreover, researchers explored the use of the entire visible light spectrum by digitally imposing longitudinal chromatic aberration to adjust proper eye growth. Preliminary findings suggest that digitally simulated chromatic aberration could potentially serve as a myopia control strategy and highlights the need for further investigation into long-term effects. As research progresses, understanding the efficacy and safety of light-based interventions for myopia control remains crucial for informing clinical practice and optimizing patient outcomes.

Increase in choroidal thickness after blue light stimulation of the blind spot in young adults.

Blue light activates melanopsin, a photopigment that is expressed in intrinsically photosensitive retinal ganglion cells (ipRGCs). The axons of ipRGCs converge on the optic disc, which corresponds to the physiological blind spot in the visual field. Thus, a blue light stimulus aligned with the blind spot captures the ipRGCs axons at the optic disc. This study examined the potential changes in choroidal thickness and axial length associated with blue light stimulation of melanopsin-expressing ipRGCs at the blind spot. It was hypothesized that blue light stimulation at the blind spot in adults increases choroidal thickness. The blind spots of both eyes of 10 emmetropes and 10 myopes, with a mean age of 28 ± 6 years (SD), were stimulated locally for 1-minute with blue flickering light with a 460nm peak wavelength. Measurements of choroidal thickness and axial length were collected from the left eye before stimulation and over a 60-minute poststimulation period. At a similar time of day, choroidal thickness and axial length were measured under sham control condition in all participants, while a subset of 3 emmetropes and 3 myopes were measured after 1-minute of red flickering light stimulation of the blind spot with a peak wavelength of 620nm. Linear mixed model analyses were performed to examine the light-induced changes in choroidal thickness and axial length over time and between refractive groups. Compared with sham control (2 ± 1μm, n = 20) and red light (-1 ± 2μm, n = 6) stimulation, subfoveal choroidal thickness increased within 60min after blue light stimulation of the blind spot (7 ± 1μm, n = 20; main effect of light, p < 0.001). Significant choroidal thickening after blue light stimulation occurred in emmetropes (10 ± 2μm, p < 0.001) but not in myopes (4 ± 2μm, p > 0.05). Choroidal thickening after blue light stimulation was greater in the fovea, diminishing in the parafoveal and perifoveal regions. There was no significant main effect of light, or light by refractive error interaction on the axial length after blind spot stimulation. These findings demonstrate that stimulating melanopsin-expressing axons of ipRGCs at the blind spot with blue light increases choroidal thickness in young adults. This has potential implications for regulating eye growth.

Choroidal Morphology and Photoreceptor Activity Are Related and Affected by Myopia Development.

The choroid is critical for the regulation of eye growth and is involved in the pathogenesis of myopia-associated ocular complications. This study explores the relationship among choroidal biometry, photoreceptor activity, and myopic growth in marmosets (Callithrix jacchus) with lens-induced myopia. A total of 34 common marmosets aged 92 to 273days old were included in this study. Axial myopia was induced in 17 marmosets using negative soft contact lenses and 17 marmosets served as untreated controls. Cycloplegic refraction (RE) and vitreous chamber depth (VCD) were measured using autorefraction and A-scan ultrasonography, respectively. Choroidal scans were obtained using spectral-domain optical coherence tomography and binarized to calculate subfoveal choroidal thickness (ChT), total choroidal area (TCA), luminal area (LA), stromal area (SA), choroidal vascularity index (CVI), and LA/SA. To assess photoreceptor activity, the a-wave of the full-field electroretinogram was measured. Regression models were used to investigate the relationship between outcome measures. Eyes induced with axial myopia (RE = -7.14 ± 4.03 diopters [D], VCD = 6.86 ± 0.39mm) showed significant reductions (4.92-21.24%) in all choroidal parameters (ChT, TCA, LA, SA, CVI, and LA/SA) compared to controls (RE = -1.25 ± 0.60 D, VCD = 6.58 ± 0.26mm, all P < 0.05), which changed as a function of refraction and vitreous elongation, and were associated with a decrease in the a-wave amplitude. Further, multiple regression showed that a combination of ChT and CVI could well predict RE and VCD. This study reports the existence of significant alterations in choroidal morphology in non-human primate eyes induced with myopia. The changes in choroidal anatomy were associated with reduced light-adapted a-wave amplitude. These findings may represent early markers for reduced visual performance and chorioretinal complications known to occur in eyes with large degrees of myopia.

Glucagon Increases Retinal Rod Bipolar Cell Inhibition Through a D1 Dopamine Receptor-Dependent Pathway That Is Altered After Lens-Defocus Treatment in Mice.

Members of the secretin/glucagon family have diverse roles in retinal physiological and pathological conditions. Out of them, glucagon has been associated with eye growth regulation and image defocus signaling in the eye, both processes central in myopia induction. On the other hand, dopamine is perhaps the most studied molecule in myopia and has been proposed as fundamental in myopia pathogenesis. However, glucagonergic activity in the mammalian retina and its possible link with dopaminergic signaling remain unknown. To corroborate whether glucagon and dopamine participate together in the modulation of synaptic activity in the retina, inhibitory post-synaptic currents were measured in rod bipolar cells from retinal slices of wild type and negative lens-exposed mice, using whole cell patch-clamp recordings and selective pharmacology. Glucagon produced an increase of inhibitory post-synaptic current frequency in rod bipolar cells, which was also dependent on dopaminergic activity, as it was abolished by dopamine type 1 receptor antagonism and under scotopic conditions. The effect was also abolished after 3-week negative lens-exposure but could be recovered using dopamine type 1 receptor agonism. Altogether, these results support a possible neuromodulatory role of glucagon in the retina of mammals as part of a dopaminergic activity-dependent synaptic pathway that is affected under myopia-inducing conditions.

Changes in Expression in BMP2 and Two Closely Related Genes in Guinea Pig Retinal Pigment Epithelium during Induction and Recovery from Myopia.

We previously reported differential gene expression of the bone morphogenetic protein 2 (Bmp2) in guinea pig retinal pigment epithelium (RPE) after 1 day of hyperopic defocus, imposed with a negative contact lens (CLs). The study reported here sought to obtain insights into the temporal profiles of gene expression changes in Bmp2, as well as those of two closely related genes, the inhibitor of DNA binding 3 (Id3) and Noggin (Nog), both during myopia induction and when the CL treatment was terminated to allow recovery from induced myopia. To induce myopia, 2-week-old pigmented guinea pigs (New Zealand strain, n = 8) wore monocular -10 diopter (D) rigid gas-permeable (RGP) CLs for one week, while the other eye served as a control. Ocular measurements were made at baseline, 3 days, and 7 days after the initiation of CL wear, with treatment then being terminated and additional measurements being made after a further 3 days, 1 week, and 2 weeks. Spherical equivalent refractive errors (SERs), axial length (AL), choroidal thickness (ChT), and scleral thickness (ScT) data were collected using retinoscopy, optical biometry (Lenstar), and spectral domain optical coherence tomography (SD-OCT), respectively. RPE samples were collected from both eyes of the guinea pigs after either 1 day or 1 week of CL wear or 1 day or 2 weeks after its termination, and RNA was subsequently isolated and subjected to quantitative real-time PCR (qRT-PCR) analyses, targeting the Bmp2, Id3, and Nog genes. Mean interocular differences (treated-control) in AL and SER were significantly different from baseline after 3 and 7 days of CL wear, consistent with induced myopia (p < 0.001 for all cases). Termination of CL wear resulted in the normalization (i.e., recovery) of the ALs and SERs of the treated eyes within 7 days, and the earlier significant ChT thinning with CL wear (p = 0004, day 7) was replaced by rapid thickening, which remained significant on day 7 (p = 0.009) but had normalized by day 14. The ChT changes were much smaller in magnitude than the AL changes in both phases. Interocular differences in the ScT showed no significant changes. The Bmp2 and Id3 genes were both significantly downregulated with CL wear, after 1 day (p = 0.012 and 0.016) and 7 days (p = 0.002 and 0.005), while Bmp2 gene expression increased and Nog gene expression decreased after the termination of CL wear, albeit transiently, which was significant on 1 day (p = 0.004 and 0.04) but not 2 weeks later. No change in Id3 gene expression was observed over the latter period. Conclusions: The above patterns of myopia induction and recovery validate this negative RGP-CL model as an alternative to traditional spectacle lens models for guinea pigs. The defocus-driven, sign-dependent changes in the expression of the Bmp2 gene in guinea pig RPE are consistent with observations in chicks and demonstrate the important role of BMP2 in eye growth regulation.

Isolation of Retinal Pigment Epithelial Cells from Guinea Pig Eyes.

This protocol describes the isolation of cells of the retinal pigment epithelium (RPE) from the eyes of young pigmented guinea pigs for potential application in molecular biology studies, including gene expression analyses. In the context of eye growth regulation and myopia, the RPE likely plays a role as a cellular relay for growth modulatory signals, as it is located between the retina and the two walls of the eye, such as the choroid and sclera. While protocols for isolating the RPE have been developed for both chicks and mice, these protocols have proven not to be directly translatable to the guinea pig, which has become an important and widely used mammalian myopia model. In this study, molecular biology tools were used to examine the expression of specific genes to confirm that the samples were free of contamination from the adjacent tissues. The value of this protocol has already been demonstrated in an RNA-Seq study of RPE from young pigmented guinea pigs exposed to myopia-inducing optical defocus. Beyond eye growth regulation, this protocol has other potential applications in studies of retinal diseases, including myopic maculopathy, one of the leading causes of blindness in myopes, in which the RPE has been implicated. The main advantage of this technique is that it is relatively simple andonce perfected, yields high-quality RPE samples suitable for molecular biology studies, including RNA analysis.

Hubungan Aktivitas Luar Ruangan dengan Miopia Mahasiswa Kedokteran Angkatan 2019 Universitas Andalas

Background: Myopia or nearsightedness is a condition in which light entering the eye is focused in front of the retina, resulting in the blurry appearance of distant objects. This can be caused by disturbances in the regulation of eye growth that can be hereditary or coming from the environment, for example from outdoor activities. Based on research in 2017 in Beijing stated that more frequent outdoor activities can reduce the risk of myopia.Objective: The purpose of this study was to analyze the relationship between outdoor activity and myopia in medical students of Andalas University batch 2019.Methods: This is an analytic study with a case-control design through consecutive sampling techniques. The sample consisted of 60 respondents, 30 of them which suffered myopia and another 30 with ametropia. Data was collected using a questionnaire that has been tested for validity. Outdoor activities, namely all activities carried out in the wild or outdoors and exposed to sunlight for approximately three hours per day. The processing of the data was done with a statistical chi-square test.Results: 45% of the respondents with outdoor activity less than three hours have myopia and 5% of respondents with outdoor activity more than three hours have myopia. Statistical chi-square test was performed to see the relationship between outdoor activity and myopia with p-value = 0.001 (p &lt;0.05).Conclusion: It was concluded that there was a significant relationship between outdoor activity and myopia in medical students of Andalas University batch 2019.

The influence of the choroid on the onset and development of myopia: from perspectives of choroidal thickness and blood flow.

Myopia is the most common type of refractive errors characterized by excessive elongation of the ocular globe. With the increasing prevalence of myopia, improved knowledge of factors involved in myopia development is of particular importance. There are growing evidence suggesting that the choroid plays an important role in the regulation of eye growth and the development of myopia. Studies have demonstrated that thinning choroid is a structural feature of myopia, with a negative correlation between choroidal thickness and axial length, suggesting that the change in choroidal thickness may be a predictive biomarker for long-term changes in ocular elongation. Given the fact that the choroid is primarily a vascular structure capable of rapidly changing blood flow, variations of choroidal thickness might be primarily caused by changes in choroidal blood flow. Considering that hypoxia is associated with myopia and choroidal blood flow is the main source of oxygen and nourishment supply, apart from the effect on myopia possibly by changing choroidal thickness, decreasing choroidal blood flow may contribute to scleral ischaemia and hypoxia, resulting in alterations in the scleral structure and thus leading to myopia. This review aims to provide an overview of recent work exploring the influence of the choroid on myopia from perspectives of choroidal thickness and blood flow, which may present new predictive indicators for the onset of myopia and new targets for the development of novel therapeutic approaches for myopia.

Altered Expression of GJD2 Messenger RNA and the Coded Protein Connexin 36 in Negative Lens–induced Myopia of Guinea Pigs

Decreased expression of the retinal GJD2 gene messenger RNA (mRNA) and connexin 36 (Cx36) protein in the guinea pig negative lens-induced myopia (LIM) model suggests their involvement in local retinal circuits regulating eye growth. Previous studies suggest that the GJD2 gene and Cx36 protein encoded by the GJD2 gene play important roles in retinal signaling pathways and eye development. The aim of this study was to investigate the changes in GJD2 mRNA and Cx36 protein expression in the guinea pig lens-induced myopia model. Four-week-old guinea pigs were randomly divided into two groups. Animals in the experimental group were fitted with monocular -10 D lenses; and animals in the control group, with monocular plano lenses. Biometric measurements, including the spherical equivalent refractive error and axial length, were monitored. Animals were killed after 0, 1, 2, and 3 weeks of treatment, and their retinas were isolated. Retinal GJD2 mRNA and Cx36 protein expression levels were assessed by quantitative real-time polymerase chain reaction and Western blot analysis, respectively. Spherical equivalent refractive error values indicated that negative lens-treated eyes became significantly more myopic than plano lens-treated eyes (P = .001), consistent with their longer axial lengths compared with those of control eyes. Both GJD2 mRNA and Cx36 protein expression levels were decreased in the retinas of negative lens-treated eyes compared with levels in the retinas of plano lens-treated eyes, although there were differences in the timing; GJD2 mRNA, levels were significantly decreased after 1 and 2 weeks of treatment (P = .01 and P = .004, respectively), whereas Cx36 protein expression was significantly decreased after only 1 week (P = .01). That both retinal GJD2 mRNA and Cx36 protein expression levels were decreased after induction of myopia with negative lenses points to retinal circuits involving Cx36 in myopia development in the guinea pig.

Optical Aberrations of Guinea Pig Eyes.

PurposeThe guinea pig is widely used in studies of refractive error development and myopia which often involve experimental optical manipulations. The study described here investigated the optical quality of the guinea pig eye, for which there are limited data, despite its fundamental importance to understanding visually guided eye growth.MethodsThe ocular aberrations of eight adolescent New Zealand pigmented guinea pigs (6–11 weeks old) were measured after cycloplegia using a custom-built Shack–Hartmann aberrometer and fit with a Zernike polynomial function to the 10th order (65 terms). The optical quality of their eyes was assessed in terms of individual Zernike coefficients, and data were further analyzed to derive root-mean-square (RMS) wavefront errors, modulation transfer functions (MTFs), point spread functions (PSFs), Strehl ratios, and depth of focus. A 4-mm pupil was used in all computations. The derived data are compared with equivalent data from normal young adult human eyes.ResultsThe guinea pigs exhibited low hyperopia and a small amount of positive spherical aberration, with other aberration terms decreasing with increasing order. Their average depth of focus, estimated from through-focus modulation, was 3.75 diopters. The RMS wavefront error of the guinea pig eye was found to be larger than that of the human eye for the same pupil size, reflecting a higher degree of aberrations, although the PSF (area) on the retina was smaller and sharper due to its shorter focal length. The radial average best-focus MTF derived for the guinea pig eye showed good performance at very low spatial frequencies, with a steeper decline with increasing frequency than for the human eye, dropping below 0.3 at 9 cpd. When converted to linear units (cycles/mm), the guinea pig eye had a higher spatial frequency cutoff and a slight contrast advantage for low spatial frequencies compared to the human eye.ConclusionsThe optical quality of the guinea pig eye is far superior to their reported behavioral visual acuity. This implies a neuroanatomical limit to their vision, which contrasts with the close match of optical and neural limits to spatial resolution in human eyes. The significance for eye growth regulation of the relative optical advantages exhibited by guinea pig eyes, when optical quality is expressed in linear rather than angular retinal units, warrants further consideration.

Retinal defocus and form-deprivation induced regional differential gene expression of bone morphogenetic proteins in chick retinal pigment epithelium.

We previously reported bidirectional gene expression regulation of the Bone Morphogenetic Proteins (BMP2, 4, and 7) in chick retinal pigment epithelium (RPE) in response to imposed optical defocus and form-deprivation (FD). This study investigated whether there are local (regional) differences in these effects. 19-day old White-Leghorn chicks wore monocular +10 or - 10 D lenses, or diffusers (FD) for 2 or 48 hr, after which RPE samples were collected from both eyes, from a central circular zone (3 mm radius), and 3 mm wide annular mid-peripheral and peripheral zones in all cases. BMP2, 4, and 7 gene expression levels in RPE from treated and fellow control eyes were compared as well as differences across zones. With the +10 D lens, increased expression of both BMP2 and BMP4 genes was observed in central and mid-peripheral zones but not the peripheral zone after 2 and 48 hr. In contrast, with the -10 D lens BMP2 gene expression was significantly decreased in all three zones after 2 and 48 hr. Similar patterns of BMP2 gene expression were observed in all three zones after 48 hr of FD. Smaller changes were recorded for BMP4 and BMP7 gene expression for both myopia-inducing treatments. That optical defocus- and FD-induced changes in BMP gene expression in chick RPE show treatment-dependent local (regional) differences suggest important differences in the nature and contributions of local retinal and underlying RPE regions to eye growth regulation.

Visual Image Quality Impacts Circadian Rhythm-Related Gene Expression in Retina and in Choroid: A Potential Mechanism for Ametropias.

PurposeStimulated by evidence implicating diurnal/circadian rhythms and light in refractive development, we studied the expression over 24 hours of selected clock and circadian rhythm–related genes in retina/retinal pigment epithelium (RPE) and choroid of experimental ametropias in chicks.MethodsNewly hatched chicks, entrained to a 12-hour light/dark cycle for 12 to 14 days, either experienced nonrestricted vision OU (i.e., in both eyes) or received an image-blurring diffuser or a minus 10-diopter (D) or a plus 10-D defocusing lens over one eye. Starting 1 day later and at 4-hour intervals for 24 hours, the retina/RPE and choroid were separately dissected. Without pooling, total RNA was extracted, converted to cDNA, and assayed by quantitative PCR for the expression of the following genes: Opn4m, Clock, Npas2, Per3, Cry1, Arntl, and Mtnr1a.ResultsThe expression of each gene in retina/RPE and in choroid of eyes with nonrestricted vision OU varied over 24 hours, with equal levels OU for most genes and times. Altered visual input influenced gene expression in complex patterns that varied by gene, visual input, time, and eye, affecting experimental eyes with altered vision and also contralateral eyes with nonrestricted vision.DiscussionAltering visual input in ways known to induce ametropias alters the retinal/RPE and choroidal expression of circadian rhythm–related genes, further linking circadian biology with eye growth regulation. While further investigations are needed, studying circadian processes may help understand refractive mechanisms and the increasing myopia prevalence in contemporary societies where lighting patterns can desynchronize endogenous rhythms from the natural environmental light/dark cycle.

Alpha2‐adrenoceptor agonists inhibit form‐deprivation myopia in the chick

BackgroundThe putative myopia‐controlling receptor is thought to be muscarinic acetylcholine receptor subtype M4, because mamba toxin‐3 can inhibit form‐deprivation myopia in chicks at a far lower concentration than atropine. However, mamba toxin‐3 is equally potent at the human α1A‐, α1D‐, and α2A‐adrenoceptors. To test the hypothesis that α‐adrenoceptors might be involved in regulation of eye growth, the treatment effects of α2‐adrenoceptor agonists brimonidine, clonidine, and guanfacine, and antagonist yohimbine, on form‐deprivation myopia in the chick were measured.MethodsRight eyes of White Leghorn chicks were goggled with diffusers to induce form‐deprivation myopia; left eyes were left open as controls. Goggled eyes were injected intravitreally with 20 μL of vehicle, or 2, 20, or 200-nmol of brimonidine, clonidine, guanfacine, or yohimbine, 24, 72, and 120-hours after goggle application. Alternatively, myopia was inhibited physiologically by goggle removal for two-hours, and the α2‐adrenoceptor antagonist, yohimbine, was injected to test whether it could block this type of myopia inhibition. One day after the last injection, refractive error and axial length were measured.ResultsBrimonidine (20 and 200-nmol) and clonidine (200-nmol) effectively inhibited experimentally induced increases in negative refractive error and axial elongation. All doses of guanfacine significantly inhibited induced negative refractive error, but only 20 and 200-nmol significantly inhibited axial elongation. Yohimbine had no effect on form‐deprivation myopia, but 200-nmol reduced the myopia‐inhibiting effect of goggle removal.ConclusionHigh concentrations of α2‐adrenoceptor agonists, similar to those required by atropine, inhibited chick form‐deprivation myopia; antagonism by yohimbine had no effect. High‐concentration yohimbine partially interfered with emmetropisation in form‐deprived chicks experiencing normal vision for two-hours per day. These data support the hypothesis that treatment with high concentrations of adrenergic drugs can affect experimentally induced myopia and normal visual processes.

Retinal Defocus and Form-Deprivation Exposure Duration Affects RPE BMP Gene Expression

In the context of ocular development and eye growth regulation, retinal defocus and/or image contrast appear key variables although the nature of the signal(s) relayed from the retina to the sclera remains poorly understood. Nonetheless, under optimal visual conditions, eye length is brought into alignment with its optical power to achieve approximate emmetropia, through appropriate adjustment to eye growth. The retinal pigment epithelium (RPE), which lies between the retina and choroid/sclera, appears to play a crucial role in this process. In the investigations reported here, we used a chick model system to assess the threshold duration of exposure to lens-imposed defocus and form-deprivation necessary for conversion of evoked retinal signals into changes in BMP gene expression in the RPE. Our study provides evidence for the following: 1) close-loop, optical defocus-guided (negative and positive lenses) bidirectional BMP gene expression regulation, 2) open-loop, form-deprivation (diffusers)-induced down-regulation of BMP gene expression, and 3) early, transient up-regulation of BMP gene expression in response to both types of lens and diffuser applications. The critical exposure for accurately encoding retinal images as biological signals at the level of the RPE is in the order of minutes to hours, depending on the nature of the visual manipulations.

IMI - Report on Experimental Models of Emmetropization and Myopia.

The results of many studies in a variety of species have significantly advanced our understanding of the role of visual experience and the mechanisms of postnatal eye growth, and the development of myopia. This paper surveys and reviews the major contributions that experimental studies using animal models have made to our thinking about emmetropization and development of myopia. These studies established important concepts informing our knowledge of the visual regulation of eye growth and refractive development and have transformed treatment strategies for myopia. Several major findings have come from studies of experimental animal models. These include the eye's ability to detect the sign of retinal defocus and undergo compensatory growth, the local retinal control of eye growth, regulatory changes in choroidal thickness, and the identification of components in the biochemistry of eye growth leading to the characterization of signal cascades regulating eye growth and refractive state. Several of these findings provided the proofs of concepts that form the scientific basis of new and effective clinical treatments for controlling myopia progression in humans. Experimental animal models continue to provide new insights into the cellular and molecular mechanisms of eye growth control, including the identification of potential new targets for drug development and future treatments needed to stem the increasing prevalence of myopia and the vision-threatening conditions associated with this disease.

Daily morning light therapy is associated with an increase in choroidal thickness in healthy young adults

Ambient light exposure is one environmental factor thought to play a role in the regulation of eye growth and refractive error development, and choroidal thickness changes have also been linked to longer term changes in eye growth. Therefore in this study we aimed to examine the influence of a 1-week period of morning light therapy upon choroidal thickness. Twenty two healthy young adult subjects had a series of macular choroidal thickness measurements collected with spectral domain optical coherence tomography before, and then following a 7-day period of increased daily light exposure. Increased light exposure was delivered through the use of commercially available light therapy glasses, worn for 30 minutes in the morning each day. A significant increase in subfoveal choroidal thickness (mean increase of +5.4 ± 10.3 µm) was found following 7-days of increased daily light exposure (p = 0.02). An increase in choroidal thickness was also observed associated with light therapy across the central 5 mm macular region. This study provides the first evidence in the human eye that daily morning light therapy results in small magnitude but statistically significant increases in choroidal thickness. These changes may have implications for our understanding of the impact of environmental factors upon eye growth.

Genome-Wide Scleral Micro- and Messenger-RNA Regulation During Myopia Development in the Mouse.

PurposeMicroRNA (miRNAs) have been previously implicated in scleral remodeling in normal eye growth. They have the potential to be therapeutic targets for prevention/retardation of exaggerated eye growth in myopia by modulating scleral matrix remodeling. To explore this potential, genome-wide miRNA and messenger RNA (mRNA) scleral profiles in myopic and control eyes from mice were studied.MethodsC57BL/6J mice (n = 7; P28) reared under a 12L:12D cycle were form-deprived (FD) unilaterally for 2 weeks. Refractive error and axial length changes were measured using photorefraction and 1310-nm spectral-domain optical coherence tomography, respectively. Scleral RNA samples from FD and fellow control eyes were processed for microarray assay. Statistical analyses were performed using National Institute of Aging array analysis tool; group comparisons were made using ANOVA, and gene ontologies were identified using software available on the Web. Findings were confirmed using quantitative PCR in a separate group of mice (n = 7).ResultsForm-deprived eyes showed myopic shifts in refractive error (−2.02 ± 0.47 D; P < 0.01). Comparison of the scleral RNA profiles of test eyes with those of control eyes revealed 54 differentially expressed miRNAs and 261 mRNAs fold-change >1.25 (maximum fold change = 1.63 and 2.7 for miRNAs and mRNAs, respectively) (P < 0.05; minimum, P = 0.0001). Significant ontologies showing gene over-representation (P < 0.05) included intermediate filament organization, scaffold protein binding, detection of stimuli, calcium ion, G protein, and phototransduction. Significant differential expression of Let-7a and miR-16-2, and Smok4a, Prph2, and Gnat1 were confirmed.ConclusionsScleral mi- and mRNAs showed differential expression linked to myopia, supporting the involvement of miRNAs in eye growth regulation. The observed general trend of relatively small fold-changes suggests a tightly controlled, regulatory mechanism for scleral gene expression.

The pattern ERG in chicks – Stimulus dependence and optic nerve section

The chick is widely used in studies of eye growth regulation and myopia. The aim of this study was to explore the utility of pattern (p)ERG as a tool to assess retinal function in such studies. Effects of optical defocus and diffusing blur, manipulations used to alter eye growth experimentally, were evaluated. PERGs were recorded from White-Leghorn chickens, using a checkerboard pattern, including 8 spatial frequencies (0.05–2.2c/d SF), 13 contrast levels (1–100%), and 8 temporal reversal frequencies (0.5–20Hz). The acute effects of defocus and diffusing blur were examined. Flash- and pERGs were also recorded from chicks that underwent monocular optic nerve section (ONS), to explore the contribution of retinal ganglion cells (RGCs). Measurements were made up to 6weeks post-ONS, complemented with SD-OCT imaging. In normal chicks, the response to 1Hz, 100% contrast stimuli showed positive- and negative-going waveforms at 43ms (P1) and 75ms (N95), respectively, with 0.06–0.1c/d SF eliciting the largest P1 amplitudes of 21.9±2.5μV. Contrast levels above 5% yielded measurable P1 responses. Responses were transient and monophasic for 0.5–5Hzreversal rates, with higher temporal frequencies yielding steady state responses. Defocus and diffusing blur decreased pERG amplitude across all SFs. pERG responses remained normal after ONS, despite the loss of RGCs. In conclusion, chicks show robust pERG responses, which are attenuated by defocus and diffusing blur. The pERG response is not affected by ONS, suggesting that RGCs do not contribute to the chick pERG.