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Exp Eye Res. 2018 Jul; 172: 104–111.
PMCID: PMC6013296
PMID: 29608907
Sandra Gisbert and Frank Schaeffel∗
Author information Article notes Copyright and License information PMC Disclaimer
Abstract
Following a hypothesis raised by M. and J. Neitz, Seattle, we have tested whether the abundance and the ratio of Long wavelength-sensitive (L) to Middle wavelength-sensitive (M) cones may affect eye size and development of myopia in the chicken. Fourteen chickens were treated with frosted plastic diffusers in front of one eye on day 10 post-hatching for a period of 7 days to induce deprivation myopia. Ocular dimensions were measured by A-scan ultrasonography at the beginning and at the end of the treatment and development of refractive state was tracked using infrared photorefraction. At the end of the treatment period, L and M cone densities and ratios were analyzed in retinal flat mounts of both myopic and control eyes, using the red and yellow oil droplets as markers. Because large numbers of cones were counted (>10000), software was written in Visual C++ for automated cone detection and density analysis. (1) On average, 9.7±1.7D of deprivation myopia was induced in 7 days (range from 6.8D to 13.7D) with an average increase in axial length by 0.65±0.20mm (range 0.42mm–1.00mm), (2) the increase in vitreous chamber depth was correlated with the increase in myopic refractive error, (3) average central M cone densities were 10,498cells/mm2, and L cone densities 9574 cells/mm2. In the periphery, M cone densities were 6343 cells/mm2 and L cones 5735 cells/mm2 (4) M to L cone ratios were highly correlated in both eyes of each animal (p < 0.01 in all cases), (5) the most striking finding was that ratios of M to L cones were significantly correlated with vitreous chamber depths and refractive states in the control eyes with normal vision, both in the central and peripheral retinas (p < 0.05 to p < 0.01), (6) M to L cone ratios did however not predict the amount of deprivation myopia that could be induced. M and L cone ratios are most likely genetically determined in each animal. The more L cones, the deeper the vitreous chambers and the more myopic were the refractions in eyes. M to L cone ratios may determine the set point of emmetropization and thereby ultimately the probability of becoming myopic. Deprivation myopia was not determined by M to L cone ratios.
Keywords: Cone ratios, Chickens, Deprivation myopia, Refraction, Vitreous chamber depth, Set-point of emmetropization
Highlights
•
M to L cone ratios are genetically determined in each individual chicken.
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M to L cone ratios determine the “set-point” refraction of emmetropization.
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The amount of inducible deprivation myopia is not predicted by M to L cone ratios.
1. Introduction
Myopia represents a frequent disorder in juvenile eyes in which the axial length is too long for optical power of cornea and lens (Morgan et al., 2012). Studies in animals and humans have shown that development of myopia is regulated both by visual experience (Morgan and Rose, 2005) and by genetic factors (Fan et al., 2016); (Verhoeven et al., 2013). In the chicken model of myopia, the impact of genetics was nicely demonstrated by Chen et al. (2011). These authors showed that the individual susceptibility to deprivation myopia, induced by diffusers in front of the eye, is inherited. After only two generations of selective breeding for high and low myopia, two separate populations of chickens were isolated which either became highly myopic with diffusers or only little.
A striking feature of myopia is its large variability among subjects. Until now, despite large multi-ethnic studies with impressive numbers of subjects (n = 160,420; Klaver, Proceedings of the 16. International Myopia Conference (IMC, 2017), Birmingham, UK, #030) only a small proportion of the variance in myopia can be explained by genetic disposition (about 10% in chickens, Yu Huang et al., IMC, 2017; #031; about 8% in humans, Verhoeven et al., IMC, 2017; #032). While many epidemiological studies were performed to identify environmental factors that may determine the rate of myopia (Morgan and Rose, 2005) (Ip et al., 2008) (Jones et al., 2007) (Rose et al., 2008), only a few biochemical or physiological factors were studied to predict myopia development, like individual retinal dopamine levels (Ohngemach et al., 1997), melanopsin input (Schaeffel et al. ARVO abstract, #2494, 2016), choroidal thickness (Wildsoet, key note lecture 1, IMC, 2017), individual accommodation behaviour (Mutti et al., 2006), or reading distances (Parssinen and Lyyra, 1993). At the 13th International Myopia Conference in Tuebingen in 2010, M. and J. Neitz, Seattle, proposed yet another factor, namely the relative abundancy of M (mid wavelength sensitivie, MWS) and L (long wavelength snesitive, LWS) cones (Neitz and Neitz, Optometry and Vision Science 88, p424, 2011). They assumed that up to 80 percent of the variance in refraction in children can be explained by variability in genetic factors affecting the M to L cones, including cone ratios. Why and how the abundancy of different cones types may have an effect on myopia, remained an unresolved question. Some years earlier (Rucker and Kruger, 2006), had already proposed that “… if luminance contrast is maximized by accommodation, long wavelengths will be imaged behind the photoreceptors. Individuals in whom luminance is dominated by L-cones may maximize luminance contrast both by accommodating more … and by increased ocular elongation, resulting in myopia …” However, more recent experiments (Smith et al., 2015) showed that monkeys raised with red spectacles (transmission at wavelengths above 650 nm) became consistently more hyperopic, just the opposite from what was expected. The same was found in tree shrews (Gawne et al., 2017). On the other hand, chickens and guinea pigs responded as predicted by Rucker and Kruger (2006). These findings suggest that predominant stimulation of L cones is not sufficient to induce myopia. It may rather be the inherited relative numbers of M to L cones. Later studies (Zhou et al., 2015) provide evidence for such an assumption. Using multifocal visually evoked potentials with silent substitution paradigms to estimate the M to L cone ratios in human subjects, they found that “… more myopic refractive error was associated with lower LWS/MWS amplitude modulation ratio; the refraction explained 16% (p = 0.02) of variation in ratio.” However, why different L to M cone ratios may have an effect on eye growth remains currently unclear.
We have studied these questions in the chicken model. A major advantage in chickens is that L and M cones can be readily identified in unfixed retinal flatmounts since that have differently colored oil droplets which are located between the inner and outer segments and serve as cut-off filters to the photopigment (Hart, 2001a) (Wilby et al., 2015). They narrow the absorption curves of the photopigments, reducing the bandwidth predicted by the Dartnall nomogram. Spectral sensitivity of the chicken extends from about 660 nm down to 360 nm (Rohrer et al., 1992). With the exception of UV cones, oil droplets of blue-, green- and red-cones contain a mixture of carotenoid pigments.
The L cone photopigment is combined with the red oil droplet, the M cone with a dark yellow oil droplet (Goldsmith et al., 1984). In addition, there are also ultraviolet sensitive (UV) cones, blue (B) cones, and double cones. As in other animal models, deprivation myopia in chickens is inherently variable but, despite of independent emmetropization in both eyes, highly correlated in both eyes of an animal (Schaeffel and Howland, 1991). Therefore, the chick represents a perfect model to study the link between inter-individual variability in cone abundancies, eye sizes and deprivation myopia.
2. Methods
2.1. Animals
All experiments involving animals were conducted in accordance with the ARVO-statement for the use of Animals and approved by the University of Tuebingen Commission for Animal Welfare. A total of 14 male chickens (Gallus gallus domesticus) were used for this study. They were obtained one day after hatching from a chicken farm located in Kirchberg, Germany, and raised in the in the animal facility of the Institute until day 10. Diurnal light cycles were 12 h light/12 h dark. Room temperature was set at 30 °C during the first week and then it was decreased to 28 °C. Food and water were provided ad libitum.
2.2. Treatments and measurements
Deprivation myopia was induced by attaching frosted plastic diffusers (Schaeffel and Howland, 1991) over one eye for 7 days. Fellow eyes had a normal vision and served as controls. Refractive state was measured without cycloplegia from the first day of diffuser treatment every two days until treatment was finished by automated infrared photoretinoscopy (Seidemann and Schaeffel, 2002). Averages of three measurements were taken for each eye. Ocular dimensions were determined by A-scan ultrasonography as previously describe (Schaeffel and Howland, 1991), at the beginning and at the end of the treatment period. Averages of three repeated measurements were used for statistical analysis.
2.3. Samples
At the end of the 7 day treatment period, animals were sacrificed by an overdose of ether and eyes were immediately enucleated. They were cut with a razor blade perpendicular to the anterior-posterior axis and the anterior segment was discarded. Vitreous was removed from the posterior segment and retina was flattened out on a microscope slide. The retinal pigment epithelium (RPE) was peeled away to make use of the transparency of the retina for visualization of the oil droplet pattern.
To facilitate handling, the retina was placed in 4% paraformaldehyde in 0.1 M phosphate buffer for 2 min. Subsequently, it was rinsed in 0.1 M phosphate buffer for 1 min to remove the fixative (Ullmann et al., 2012). In retinal whole-mounts, the retina was positioned on the slides photoreceptors up. Radial cuts were made to flatten it out and a cover slide was applied for optimal visualization of the oil droplets under the light microscope.
Each type of oil droplet is associated with a specific type of photoreceptor. Oil droplets can be identified in fresh retina without any staining (Goldsmith et al., 1984) (Hart, 2001b). In the current study, abundance of L and M cones was determined by counting the number of oil droplets across the retina using pictures taken with bright field illumination at 200× magnification (Olympus B×60; Software cellSens Standart 1.15, providing a magnification in the final pictures of 2.5 pixels/μm).
As stated by Valerie Morris (1982), the chick retina lacks a fovea which is specific for primates and a number of sauropsides. Instead, it exhibits an “afoveate area centralis” that is situated about 2 mm from the dorsal edge of the optic disc. The “area centralis” extends from the retinal center into the tempero-superior quadrant of the retina and has a diameter of up to 4 mm. At 3 weeks of age, the horizontal and vertical diameters of the Area centralis were found to be about 3.00 mm from carnial to caudal and between 3.07 mm and 2.83 mm from nasal to temporal. Their centers are between 2.33 and 1.83 mm nasal of the temporal end of the pecten (Straznicky and Chehade, 1987). In the current study, cone counts were performed in the “central area” which was defined as a circular region with a diameter of 3 mm just above the root of the pecten. This means that the selected area included the classical Area centralis but may not have been in perfect match. The angular subtense in the visual field of the “central area” was calculated from axial length of the chickens (about 8.5 mm) and the posterior nodal distance (5.1 mm; Schaeffel and Howland, 1991). A linear distance on the retina of 3 mm corresponds to arctan (3/5.1) = 30.5 deg of visual angle. Furthermore, cones were counted in the “peripheral areas”, defined as 4 circular fields with a diameter of 3 mm on the retina, adjacent to the central area in the nasal, temporal, cranial and caudal segments. Accordingly, their visual angles ranged from 15 to about 45 deg, relative to the “center”. Counts from the 4 peripheral fields were averaged. A total of 28 retinas were counted for the present study.
In order to facilitate the work load in cone counts, a software for automated cone detection and analysis was created in Visual C++ for rapid automated cone detection and analysis (Fig. 1). The user marked one type of oil droplets with the computer mouse in JPEG pictures of retinal flat mounts. The software searched in the image for pixels with a similar R:B:G ratio and similar brightness. Tolerance levels were adjustable for best detection. Since many single pixels in the images were detected with similar color, they needed to be assigned to individual oil droplets. This was done by the software by detecting neighboured pixels within a distance that was similar to the average diameter of the oil droplets. Pixels could then be assigned to single oil droplets. The software counted all oil droplets of a kind, determined the distributions of nearest neighbour distances and estimated visual acuity. This was done by determining the number of cones (“pixels”) per degree of visual angle (89 μm/deg in our chickens with a posterior nodal distance of about 5.1 mm). Thereafter the user could click with the mouse on another type of oil droplets and the analysis was restarted.
Fig. 1
Automated analysis of L and M cone abundancies in retinal flatmounts. (A) Red oil droplets belong to the L cones, (B) yellow oil droplets to the M cones. The user marks an oil droplet with the computer mouse and the software finds all the other ones of the same type, accepting a certain variance in R:G:B values as indicated in the upper right side in each measurement. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
To exclude that the software may have confused some oil droplets, we have done a correlation analysis of manual counts and automated counts, both for the M and L cones. The correlation was highly significant (p < 0.0001) for both red cones (LWS) R2=0.9934 (software count versus manual count y=0.981x+10.9, data range 527–1656) and green cones (MWS) R2=0.9907 (software count versus manual count y=0.986x+27.7, data range 684–1689). Also, a t-test for the counts by hand and using the software (for red and green cones) showed no significant differences.
A problem is that, even in fixed tissue, the amount of stretching remains unknown if placed under a cover slide. We did not use complete fixation, but exposed the retina to 4% paraformaldehyde for only 2 min to harden it before placing it under the cover slide. Stretching becomes apparent if the absolute densities of M and L cones are plotted against each other (Fig. 2). They were correlated in all retinas. It is highly unlikely that chicks which have fewer M cones also have fewer L cones since this would generate large differences in their visual acuity. The different cone densities were therefore attributed to differences in tissue stretching. However, our goal was NOT to measure absolute cone densities but rather ratios of M to L cones which are not affected by stretching.
Fig. 2
Absolute M cone densities plotted against absolute L cone densities in all the studied retinas. The high positive correlation can only be explained by various amounts of retinal stretching during preparation which changes both M and L cone densities.
3. Results
3.1. Deprivation myopia induced by diffusers and axial elongation
After one week of diffuser wear, eyes with diffusers developed a refraction of −6.8±1.7D (a relative myopic shift of 9.7 D) while the control eyes remained hyperopic with an average refraction of +2.9±0.4D. Deprivation myopia ranged from −6.8 to −13.3D (with an average of −9.7 ± 1.7D; Fig. 3A).
Fig. 3
(A) Refractions in control and deprived eyes after the treatment period of 7 days. Note the large variability in deprivation myopia in each animal. (B) Axial lengths in control and deprived eyes after 7 days.
The average increase in axial length over the 7 day treatment period was 0.65 ± 0.20 mm (range 0.42 mm–1.00 mm; Fig. 3B) and the increase in vitreous chamber depth was 0.50 ± 0.17 mm (range 0.17 mm–0.72 mm). While the induced deprivation myopia (inter-ocular difference in refraction) was not significantly correlated with the increase in axial length (inter-ocular difference in axial length; R2 = 0.1434; p > 0.05), there was a significant correlation with vitreous chamber growth (R2 = 0.4102; p < 0.05), indicating that the induced myopia was at least partially axial, as in other studies.
3.2. Average L and M cone densities
L and M cones could be easily identified based on their colored oil droplets which are located between the inner and outer segment (Fig. 4).
Fig. 4
Patterns of oil droplets in retinal flat mounts. Different cone photoreceptor type can be identified based on their oil droplets according to Goldsmith et al. (1984): R: red cone (long wavelength sensitive LWS cone), Y: yellow cone (mid wavelength sensitive MWS cone), C: colorless (short wavelength sensitive SWS cone, appearing greenish) and T: transparent (UV cone, appearing clear). Magnification bar 50 μm (left) and 20 μm (right). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
The average densities for central M cones in all animals were 10,498 cells/mm2 and 9574 cells/mm2 for L cones but, as shown in Fig. 2, these numbers are confounded by variable amounts of tissue stretching. Peripheral cone densities were determined from the averages in the dorsal, ventral, cranial and caudal fields in each animal. In the periphery, M cone densities were 6343 cells/mm2 and 5735 cells/mm2 for L cones.
3.3. M to L cone ratios: correlations in both eyes
M to L cone ratios varied between 0.83 and 1.39 among animals. To test whether this was a random variable in each eye, we plotted M to L cone ratios from the left versus the right eyes (Fig. 5). The high correlations show that M to L cone ratios were typical for each animal and were, most likely, genetically determined.
Fig. 5
Correlations of M to L cone ratios in both eyes. (A) Central retina (B) peripheral retina. The high correlations between both eyes suggest that M to L cone ratios were genetically determined.
3.4. M to L cone ratios: correlations with refractive errors and vitreous chamber depths
With deprivation myopia, M to L cone ratios were neither correlated with the induced myopia nor with vitreous chamber depth (Fig. 6).
Fig. 6
M to L cone ratios, measured in both in the center or periphery in eyes that had developed deprivation myopia, were not correlated either with refractive state (A) or vitreous chamber depth (B).
However in the fellow eyes with normal vision, M to L cone ratios were correlated with refractive state (p < 0.05 for M to L cone ratios in the center and p < 0.05 in the periphery). The correlation was even more obvious for the vitreous chamber depths (p < 0.05 for M to L cone ratios in center and p < 0.01 in periphery). The M to L cone ratio in the periphery explained 76% of the variance in vitreous chamber depths in different animals. In general, the more L cones in the retina, the relatively more myopic and the longer were the eyes (Fig. 7).
Fig. 7
(A) M to L cone ratios, both when measured in the center or periphery, were correlated with refractive state in the control eyes. The more L cones, the more relative myopia. (B) M to L cone ratios had even higher correlations with vitreous chambers depths. The more L cones, the deeper the vitreous chamber is.
Given that there was an association between both vitreous chamber depth and refractive states with the M to L cone ratios of control eyes, it could be expected that also refractive states were correlated with vitreous chamber depths or axial lengths. In support of our hypothesis, we found a significant correlation between refractive states and axial lengths in the control eyes (R = 0.67, n = 14, p < 0.05).
4. Discussion
The current study shows that the M to L cone ratio is related to eye size and refractive state in chickens that had normal visual experience. Since there was a large inter-individual variability in M to L cone ratios among individuals, but a high correlation between both eyes, it can be assumed that M to L cone ratios are genetically determined. Apparently, M to L cone ratios represent one of the possible factors that determine the baseline refractive state and therefore the “set point” of emmetropization. Tepelus and Schaeffel found that the refractions of eyes of individual chicks return to their set-points after a period of induced refractive errors (Tepelus and Schaeffel, 2010). Their study raised the question as to how the set points may be determined - M to L cone ratios may represent a possible factor. However, cone ratios did not predict the amount of deprivation myopia that could be induced, suggesting that susceptibility to deprivation myopia is determined by other genetic factors (Chen et al., 2011).
It is known that M to L cone ratios are also highly variable among human subjects but inter-ocular correlations have not yet been analyzed (Roorda and Williams, 1999); (Hofer et al., 2005). An important question is therefore whether M to L cone ratios determines the variability in refractive states also in near-emmetropic human subjects. It does matter whether children are exactly emmetropic or slightly hyperopic. Zadnik et al. showed (1999) that the amount of hyperopia at the age of 8 years is a powerful predictor of myopia at the age of 15 years in US schoolchildren (Zadnik et al., 1999). Children with a hyperopic buffer of +0.75D had only a chance of 2–4 percent chance of becoming myopic whereas children who were already close to zero refractive error at the age of 8 years had a chance of 30 percent. It should be kept in mind that, in chickens, the M to L cone ratios had not predictive power for the amount of deprivation myopia that could be induced.
4.1. Possible mechanisms
The question as to how M and L cone densities might affect eye growth is difficult to answer. One possible mechanism could be biochemical. Since opsins are extremely densely packed in the outer retina, differences in their biochemical properties may have large effects on the diffusion rates of molecules that are released from the amacrine cells and have to pass through the photoreceptor layer to control choroidal thickness and scleral growth. Another option is that a higher abundance of L cones results in higher contrast sensitivity in the long wavelength range. Due to longitudinal aberration, the best focus should be somewhat behind the retina and this condition could bias the defocus detector in the retina to trigger the development of a longer eye. At least two studies have shown that chickens become more myopic in deep red light (Seidemann and Schaeffel, 2002); (Foulds et al., 2013). Another speculative assumption could be that also the UV and blue cones, with the transparent and greenish oil droplets, also interfere with the baseline refractions and perhaps myopia development.
Are chicken L and M cones related to human L and M cones?
Phylogenetic studies suggest that common ancestors of mammals, birds, reptiles, amphibians and fish had already photopic vision, with four single cone types and double cones for motion detection (Collin et al., 2009). Today, oil droplets are typical only for diurnal lizards, turtles and birds. Amphibians, snakes, crocodiles and mammals have lost their oil droplets in the course of evolution, perhaps as an adaptation to (temporary) nocturnal life styles (Ahnelt and Kolb, 2000). For the same reason, mammals may have become dichromatic, with a cone pigment absorbing in the short wavelengths range (blue or UV), and a second pigment in the long wavelengths yellow-green range (Yoshinori Shichida et al., 2013). Dichromatic vision remained typical for non-primate mammals until today. Only primates and some new world monkeys developed an additional cone pigment by gene duplication of the L cone opsins which gave rise to M cones and made them trichromatic (Nathans et al., 1986). However, while the human L cone may indeed be derived from sauropside L cones, the M cone in the chicken is not related to the human M cone. Will this exclude any extrapolation of our findings in chickens to humans? We believe not. It does not really matter whether the opsins have an evolutionary link. The general conclusion is that different opsins may have different effects on eye growth.
4.2. Chicken cone densities in different studies
According to Kram et al. (2010), M cones are most abundant in the chicken retina (21.1%), followed by L (17.1%), S (12.6%) and UV cones (8.5%) (Kram et al., 2010). Bowmaker and Knowles found 21% red cones, 20% UV cones, 45% double cones (Bowmaker and Knowles, 1977). In this study the density of M and L cones across the retina was estimated in control and deprived eyes. There was an impressive amount of variability. L cone densities in the center ranged from 4738 to 13,830 cells/mm2 and in the periphery from 3699 to 8545 cells/mm2. M cone densities in the center ranged from 5716 to 13,869 cells/mm2 and in the periphery from 4553 to 9891 cells/mm2. For comparison, Kram et al. found 32,500 cones/mm2 in mid periphery in 15-day-old chickens (Kram et al., 2010). Bueno et al. determined 20,000 cones/mm2 in the central retinal area in 2–3 week old chickens (Bueno et al., 2011). Morris et al. found 16,576 cones/mm2 in the central and 13,760 cones/mm2 in the peripheral retina (Morris, 1970). That cones are more abundant in the center than in the periphery was previously confirmed by Kram et al. (2010). Some of the variability might have been attributed to different levels of tissue stretching under the cover slides. However, the conclusions of our study are not affected by tissue stretching because absolute numbers were not important but rather only the ratios of M to L cones.
In conclusion, our study shows a convincing link between a physiological variable (the M to L cone ratio) and a morphological variable (eye growth, and the associated baseline refractions) in the chicken model of myopia. It could be that M to L cone ratios have also predictive value in human eye growth and myopia but this needs to be found out future studies.
Funding
This work was supported by the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Research training Network MyFun Grant MSCA-ITN-2015-675137.
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