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. Author manuscript; available in PMC: 2022 May 1.
Published in final edited form as: Exp Eye Res. 2021 Mar 10;206:108525. doi: 10.1016/j.exer.2021.108525

Tree Shrews Do Not maintain Emmetropia in Initially-focused Narrow-band Cyan Light

Thomas T Norton 1, Safal Khanal 1, Timothy J Gawne 1,*
PMCID: PMC8087652  NIHMSID: NIHMS1685165  PMID: 33711339

Abstract

We asked if emmetropia, achieved in broadband colony lighting, is maintained in narrow-band cyan light that is well focused in the emmetropic eye, but does not allow for guidance from longitudinal chromatic aberrations (LCA) and offers minimal perceptual color cues. In addition, we examined the response to a −5 D lens in this lighting. Seven tree shrews from different litters were initially housed in broad-spectrum colony lighting. At 24 ± 1 days after eye opening (Days of Visual Experience, DVE) they were housed for 11 days in ambient narrow-band cyan light (peak wavelength 505 ± 17 nm) selected because it is in focus in an emmetropic eye. Perceptually, monochromatic light at 505 nm cannot be distinguished from white by tree shrews. While in cyan light, each animal wore a monocular −5 D lens (Cyan −5 D eyes). The fellow eye was the Cyan no-lens eye. Daily awake non-cycloplegic measures were taken with an autorefractor (refractive state) and with optical low-coherence optical interferometry (axial component dimensions). These measures were compared with the values of animals raised in standard colony fluorescent lighting: an untreated group (n=7), groups with monocular form deprivation (n=7) or monocular −5 D lens treatment (n=5), or that experienced 10 days in total darkness (n=5). Refractive state at the onset of cyan light treatment was low hyperopia, (mean ± SEM) 1.4 ± 0.4 diopters. During treatment, the Cyan no-lens eyes became myopic (−2.9±0.3 D) whereas colony lighting animals remained slightly hyperopic (1.0 ± 0.2 D). Initially, refractions of the Cyan −5 D eyes paralleled the Cyan no-lens eyes. After six days, they gradually became more myopic than the Cyan no-lens eyes; at the end of treatment, the refractions were −5.4 ± 0.3 D, a difference of −2.5 D from the Cyan no-lens eyes. When returned to colony lighting at 35 ± 1 DVE, the no-lens eye refractions rapidly recovered towards emmetropia but, as expected, the refraction of the −5 D eyes remained near −5 D. Vitreous chamber depth in both eyes was consistent with the refractive changes. In narrow-band cyan lighting the emmetropization mechanism did not maintain emmetropia even though the light initially was well focused. We suggest that, as the eyes diverged from emmetropia, there were insufficient LCA cues for the emmetropization mechanism to utilize the developing myopic refractive error in order to guide the eyes back to emmetropia. However, the increased myopia in the Cyan −5 D eyes in the narrow-band light indicates that the emmetropization mechanism nonetheless detected the presence of the lens-induced refractive error and responded with increased axial elongation that partly compensated for the negative-power lens. These data support the conclusion that the emmetropization mechanism cannot maintain emmetropia in narrow-band lighting. The additional myopia produced in eyes with the −5 D lens shows that the emmetropization mechanism responds to multiple defocus-related cues, even under conditions where it is unable to use them to maintain emmetropia.

Keywords: Myopia, Animal Models, Refraction, Development, Wavelength, Opponent dual detector, Longitudinal chromatic aberration

Graphical Abstract

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1. Introduction

During postnatal development, an emmetropization feedback mechanism in many species uses visual cues related to defocus to modulate the axial elongation of the eye so as to achieve a match between the location of the focal plane, where images are in focus, and the location of the retina, which detects the images (Norton, 1999; Schaeffel and Feldkaemper, 2015; Smith et al., 2014; Troilo et al., 2019; Wallman and Winawer, 2004; Wildsoet, 1997; Winawer and Wallman, 2002). This mechanism typically produces low hyperopia that is easily reduced with accommodation (Bradley et al., 1999; Graham and Judge, 1999; Gwiazda et al., 1993; Norton et al., 2006, 2010a; Norton and McBrien, 1992; Wallman and Adams, 1987; Ward et al., 2018); we will refer to that condition as “near emmetropia”.

Studies in animals have found that the emmetropization mechanism also actively maintains near emmetropia as the eyes continue to grow during adolescence (Gawne et al., 2017b; Norton et al., 2010a). For example, in a juvenile or young adult animal, if a negative-power spherical lens is placed over one eye, shifting the focal plane away from the cornea and producing a hyperopic refractive error, the emmetropization mechanism generates signals in that eye that increase the axial length (primarily the vitreous chamber), moving the retina toward the shifted focal plane. This reduces the imposed hyperopia until the refractive state, measured with the lens in place, has returned to near emmetropia, “compensating” for the lens (He et al., 2014; Hung et al., 1995; Irving et al., 1992; Shaikh et al., 1999). With the lens removed, the eye is myopic. The amount of myopia is dictated by the power of the negative lens; a −10 D lens produces twice as much myopia as a −5 D lens (Norton et al., 2010a; Norton et al., 2010b). However, the refractive state of the fellow, untreated “control” eye is essentially unaffected, maintaining a near-emmetropic refractive state. (He et al., 2014; Hung et al., 1995; Norton et al., 2010a; Wallman and Adams, 1987). The different responses of the treated (lens-wearing) and the untreated fellow control eyes confirms that an emmetropization mechanism exists in each eye. In the treated eye, it guides the eye to achieve near emmetropic with the lens in place; in the control eye, it guides that eye to remain at near emmetropia.

After compensating to a negative lens, if the lens is removed, the lens-treated eye is suddenly myopic (axial length longer than the focal plane), relative to the control eye, by the power of the negative lens. The emmetropization mechanism detects the myopic defocus and slows the rate of axial elongation. Over time, the optics of the eye mature, moving the focal plane away from the cornea until the refractive state fully recovers to emmetropia (Amedo and Norton, 2012; Qiao-Grider et al., 2004; Wallman and Adams, 1987). The emmetropization mechanism works throughout adolescence in animals and humans to make small adjustments in axial growth rate that maintains near-emmetropia within narrow limits despite a substantial increase in the size of the eyes (Gawne et al., 2017b; Norton et al., 2010a; Wong et al., 2010).

Normally, the visual conditions encountered by the two eyes are very similar, with the result that the emmetropization mechanism in each eye produces a very similar refractive state in both eyes. This is seen in normal development, where the difference in refractive state between the two eyes narrows in the postnatal period (Afsari et al., 2013; Bradley et al., 1999; Hung et al., 1995; Norton et al., 2010a; Norton and McBrien, 1992; Wallman and Adams, 1987). If both eyes are exposed to negative- or positive-power lenses, both eyes respond similarly and the inter-ocular difference remains low (Gawne et al., 2018; Siegwart and Norton, 2010), supplementary Figure S1)

An important question is: what visual cues are used by the emmetropization mechanism to guide axial elongation? Out-of-focus images contain many potential cues, including the amount and sign of the defocus (myopic or hyperopic), spherical aberrations, coma, trefoil, and other higher-order aberrations, along with information provided by longitudinal chromatic aberration (LCA). In most studies of refractive development, the functioning of the emmetropization mechanism has been examined in broad-band (often fluorescent) lighting conditions containing light of many wavelengths between 400 and 700 nm. Because of LCA, shorter wavelengths (the blue end of the spectrum) are focused in front of (closer to the cornea than) longer wavelengths (the red end of the spectrum). Vertebrate eyes across many species (bass, frog, chicken, rat, cat, pig, cow, and human) typically have on the order of two to three diopters of longitudinal chromatic aberration (LCA) across the spectrum of visible light (Mandelman and Sivak, 1983).

In broadband light, the emmetropization mechanism could use differential image focus at short and long wavelengths to determine the sign of defocus, and studies in chick, guinea pig, tree shrew and macaque monkey suggest that LCA information is used (Gawne et al., 2017a; Hung et al., 2018; Liu et al., 2011; Rucker and Wallman, 2008). Based on studies in tree shrews (small dichromatic mammals closely related to primates), Gawne & Norton (2020) developed an opponent dual-detector spectral drive model of emmetropization in which defocus is separately evaluated by arrays of the short-wavelength sensitive (SWS) and long-wavelength sensitive (LWS) cones. In broadband light, neither cone array can simultaneously have optimally-focused images. In the model, sharper image contrast across the SWS cone array on the retina (blue wavelengths in better focus) produces a positive “spectral drive” that signals the emmetropization mechanism to increase axial elongation. Sharper image contrast across the LWS cone array (red wavelengths in better focus) produces a negative spectral drive that slows the axial elongation rate. The axial length where the two opponent detector systems are in balance (drive ≈ 0) defines near emmetropia and indicates that an axial length has been achieved that matches the focal plane. However, this match must be maintained because the focal plane moves away from the cornea over time as the cornea flattens and the power of the crystalline lens decreases. If axial growth is too slow (or too fast), the spectral drive increases (or decreases) to restore near emmetropia.

In tree shrews, at near emmetropia, there is a wavelength in between the peak sensitivities of the SWS and LWS cones (Figure 1) that is in optimal focus. The SWS cones in tree shrews have a peak sensitivity at 428 ± 15 nm peak; the peak sensitivity of the LWS cones is at 555 ± 6 nm (Petry and Harosi, 1990). Based on our modeling (Gawne and Norton, 2020) a juvenile tree shrew placed in ambient narrow-band cyan light initially will experience similar defocus on each cone array, producing a spectral drive approximately zero, indicative of an emmetropic refractive state. However, because there are no direct measures of what wavelength is in perfect focus, this estimate could be in error by perhaps as much as 0.3 D. This wavelength also produces the same amount of defocus on the SWS and LWS cone arrays as is produced by daylight for an eye with approximately 1 D of hyperopia. In addition, in a behavioral study (Jacobs and Neitz, 1986), tree shrews could not distinguish this wavelength from broadband white light, indicating that it perceptually appears as “white” and thus offers minimal perceptual chromatic cues. However, the cyan light with this peak only contains a narrow band of wavelengths (Figure 1) and cannot provide significant LCA information.

Figure 1.

Figure 1.

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A. Normalized absorbance spectra of the tree shrew short wavelength sensitive (SWS) and long-wavelength sensitive (LWS) cones (data from Petry and Harosi (1990)). These data take into consideration the pre-retinal absorbance, which limits the sensitivity of the SWS cones at the far blue end of the spectrum. B. Spectrum of the cyan light source, taken at the cage floor directly under the light array at the point of maximum intensity.

The present study was designed to ask whether just this narrow band of initially in-focus wavelengths is sufficient to maintain the eyes at near emmetropia. We placed juvenile tree shrews, which had completed early emmetropization in colony light, into a cage illuminated with narrow-band cyan light (peak wavelength 505 nm) and followed their refractive state and axial component dimensions during an 11-day treatment period. Our hypothesis was that, without LCA feedback, the emmetropization mechanism would be in an open-loop condition and the eyes would not remain emmetropic. As both the optics and the axial length change over time, the eyes would deviate from near emmetropia. However, the narrow-band light would not provide sufficient feedback from LCA to modulate eye growth and return the eyes to near emmetropia. The model did not predict the direction of this deviation. However, in other open-loop conditions (form-deprivation, dark treatment) tree shrew eyes elongate and become myopic (McBrien and Norton, 1992; Norton et al., 2006; Siegwart and Norton, 1998).

In the same animals, we also examined whether the emmetropization mechanism could respond to a −5 D lens placed over one eye while in the cyan lighting. If the lens had no effect, the lens-wearing eye should respond in a very similar manner as the fellow, no-lens eye as has been the case when tree shrews have been exposed binocularly to either narrow-band short wavelength (457 or 464 nm) or long wavelength (628 nm) light (supplementary figure S1). However, if the response to the monocular lens were the same as in broadband light, the lens-wearing eye should elongate and become myopic, relative to the no-lens eye. After 11 days of cyan light treatment the lens-wearing eye should have fully compensated to the lens, so the eye would be −5 D myopic compared to the no-lens eye. If the difference between the no-lens and the −5 D lens eyes was significantly less than −5 D, it would indicate that the narrow-band light impaired the ability of the emmetropization mechanism to modulate the axial growth of the lens-wearing eye.

2. Materials and methods

The tree shrews used in these experiments were all raised by their mothers in the University of Alabama at Birmingham (UAB) Tree Shrew Core. Tree shrews are born with their eyes closed and the eyes remain closed for approximately three weeks, so we used the first day both eyes were open as the first day of visual experience (DVE). Cyan light treatment began at roughly six weeks of age, which is the typical age of weaning. All procedures complied with the Association for Research in Vision and Ophthalmology (ARVO) for the use of animals in ophthalmic and visual research and were approved by the Institutional Animal Care and Use Committee of UAB.

2.1. Ambient Lighting Conditions

The colony is maintained on a 14-hour light on/10-hour light-off schedule. Fluorescent lighting (F34CW RS WM ECO; General Electric lighting, East Cleveland, OH) containing a wide range of wavelengths provided an illuminance of approximately 100 to 300 human lux on the floor of the cages. These conditions match those used in previous studies over many years from this laboratory (Guo et al., 2013; He et al., 2014; McBrien and Norton, 1992; Norton and McBrien, 1992; Siegwart and Norton, 2002).

During exposure to narrow-band ambient cyan lighting, the animals were housed individually in cages placed in bays inside a larger darkened room with two cages that provided the same wavelength stimulus placed side-by-side in each bay. The bays were separated from each other by heavy blackout curtains to prevent light leakage between bays. The cages were cubes 60 cm x 60 cm x 60 cm, with stainless steel walls and open mesh on the front and top of the cage. Arrays of LED lights were placed on top of each cage with an open frame that allowed light to spill out into the bay so that the animals could see up to approximately three meters.

The cyan light (peak wavelength 505 ± 17 nm) was provided by LUXEON Rebel LEDs (Quadica Development Inc., Alberta, Canada) mounted on a Tri-Star Coolbase. Four of these were mounted to an aluminum T-profile suspended over the top of the cage, pointing downwards, and focused with a Carclo 44° 20 mm circular beam optic. These four arrays were driven by a 1400 mA BuckBlock LED driver. The spectrum of the cyan light at the cage floor (Figure 1B) was measured with an Ocean Optics (Largo, FL) STS Microspectrometer, 350-800 nm, 50 μm slit, with a cosine corrector at the end of a fiber optic cable. This cyan stimulus should result in the SWS cones catching approximately 30% of the photons as the LWS cones, which is the same relative photon catch as with the CIE D65 standard daylight spectrum. The illuminance of the light at the cage floor was measured using an LX1330B digital illuminance meter (Hisgadget Inc., Union City, CA). The average illuminance was approximately 1500 human lux, but if the animals climbed on the wire mesh at the top of the cage, their exposure rose to approximately 3000 lux.

It must be noted that, to perform these experiments, we needed a light source that produced a specific band of wavelengths, rather than an RGB computer monitor, which uses an array of red, green, and blue light sources. That type of stimulus presentation will not work when examining the effect of wavelengths on the emmetropization mechanism because the RGB arrays produce three sets of wavelengths instead of the single band of wavelengths that is needed and produced by the LEDs. The three wavelength bands from an RGB monitor will not have the same effect on the SWS and LWS cones arrays as will the narrow band of wavelengths provided by the LEDs.

2.2. Pedestal Installation

To hold a goggle frame in place with the monocular −5 D lens and to allow us to accurately and consistently align the animals for awake refractive and axial component measures, a dental acrylic pedestal was installed on the skull of the experimental animals 2 to 3 days before cyan light treatment began using procedures described previously (Siegwart and Norton, 1994). In summary, the animals were removed from their mother’s cage and anesthetized intramuscularly with 100 mg/kg ketamine and 7 mg/kg xylazine. After initial anesthesia but before the procedure began, they were given intraperitoneal atropine 0.27 mg/kg, intramuscular buprenorphine 0.02 mg/kg, and subcutaneous carprofen 5 mg/kg. Anesthesia was supplemented with 0.5 to 2% isoflurane as needed. After recovery from anesthesia, the animals were weaned and housed singly, in broad-spectrum colony lighting. At the start of cyan light treatment, they were moved into the wavelength treatment cages.

2.3. Experimental Groups

Seven female tree shrews from different litters were placed in narrow-band cyan light starting at 24 ± 1 DVE; at the same time, they also began monocular negative-power lens wear. Cyan light treatment and monocular lens wear continued for 11 days. Normally, our groups contain both male and female animals, but limitations in the animals born in the UAB Tree Shrew Core and shared amongst multiple investigators precluded adding males in this study. In past studies, we have not found significant differences between male and female tree shrews in either normal refractive development or in the refractive response to a monocular −5 D lens (see supplementary Table 1).

After initial refractive and axial component measures, moments before cyan light treatment began, a goggle frame was clipped onto the pedestal that held a −5 D lens in front of one randomly-selected eye, the “Cyan −5 D” eye. The other “Cyan no-lens” eye had unobstructed vision except for the edges of an open goggle frame. At 35 DVE, the animals were returned to colony lighting for 10 days. The eye wearing the −5 D lens continued to wear the lens in colony lighting (“Colony −5 D”). The other, “Colony no-lens” eye continued to have unobstructed vision.

The refractive and axial measures of the cyan animals were compared with the refractions (mean of right and left eyes) from a group of animals (n=7) raised in fluorescent colony lighting (Ward et al., 2018), with age-matched animals (n=5) that wore a monocular −5 D lens (Norton et al., 2010a) or experienced monocular form deprivation with a translucent diffuser (n=7) in colony lighting (Norton et al., 2010b), and with a group of animals (n=5) that were treated with complete darkness for 10 days (Norton et al., 2006).

2.4. Refractive and Axial Measures

The refractive state was measured daily during cyan light treatment and recovery in colony lighting between approximately 10 AM and 11 AM. The refractive state of each eye was measured with a Nidek ARK-700A infrared autorefractor (Marco Ophthalmic, Jacksonville, FL) while the animals were awake and gently restrained. One person held the animal and used the pedestal to align the eye while a second person viewed the alignment on a secondary monitor and used a custom-installed foot pedal to initiate five measurements of sphere, cylinder, and axis. These were converted to spherical equivalent at the corneal plane, averaged and corrected for the “small eye artifact” previously shown to be approximately +4 diopters in tree shrews (Norton et al., 2003; Sajdak et al., 2019). As in previous studies from this laboratory, non-cycloplegic measures were made because atropine may interfere with emmetropization (McBrien et al., 1993), and because non-cycloplegic refractions have been shown to provide a valid estimate of refractive state. When measured in the same animals, cycloplegic refractions for control and for myopic eyes were approximately 0.8 diopters hyperopic in comparison with non-cycloplegic refractions (Norton et al., 2003), indicating the presence of a small tonic accommodation in non-cycloplegic eyes.

Animals were kept in darkness while being transported between their treatment cage and the measurement room. While the measurements were being made, the room was dimly illuminated with cyan LEDs identical to those used in their treatment cages. The internal incandescent target light of the autorefractor was disabled to further avoid spurious wavelength stimulation.

Axial component dimensions also were measured daily in the awake, gently-restrained cyan light-treated animals, immediately after the measurements of refractive state, with optical low-coherence optical interferometry (LenStar LS-900, Haag-Streit, Mason, OH) using tree-shrew specific refractive indices (El Hamdaoui et al., 2019). This system has been found to typically give similar dimensions to those using other techniques such as ultrasonography, but with better repeatability (Penha et al., 2012). These daily measurements allowed us to follow changes in ocular components over time to assess whether changes in the refractive state were due to changes in the ocular components, such as vitreous chamber depth, rather than to changes in accommodation. The axial measures were compared with ones made less frequently in the animals raised in colony lighting.

2.5. Data Analysis

Measures of refraction and axial component dimensions were entered into Excel spreadsheets. Data were imported and analyzed in R (R Core Team, 2020). Separate statistical models were conducted to analyze measures during cyan light treatment (24 to 35 DVE) and recovery in colony lighting (35 to 45 DVE). Measurements were compared between Cyan no-lens and Cyan −5 D eyes using repeated measures two-way ANOVA with “DVE” and “Eye” as two within-subject factors. The degrees of freedom were adjusted using the Greenhouse-Geisser correction when the assumption of sphericity was not met. Measurements were compared across the experimental groups using mixed ANOVA with “Groups” as a between-subject factor and “DVE” as a within-subject factor. If the interaction effect was significant, simple main effects were analyzed by conducting separate one-way models at each level of DVE, with Bonferroni correction for multiple testing. Posthoc pairwise comparisons were performed with unpaired or paired t-tests, as appropriate. When two samples had unequal variances, Welch modification was applied to the degrees of freedom during pairwise comparisons. Results were verified with equivalent non-parametric tests. The value of alpha was set at 0.05 for statistical significance.

3. Results

3.1. Effect of Cyan Light Treatment

3.1.1. Refractive state.

Figure 2A shows the effect of the cyan light treatment on the refractive state of the Cyan no-lens and Cyan −5 D eyes compared with the eyes of the colony lighting animals (Ward et al., 2018). When placed into cyan light at 24 DVE, the refractive states of the eyes (mean ± standard error of the mean [SEM]; Cyan no-lens, 1.3 ± 0.2 and Cyan −5 D, 1.2 ± 0.2 D) were not statistically different from each other (P = 0.76, paired t-test) or from the normal colony-raised animals at the same age (1.7 ± 0.3 D; P = 0.38 vs Cyan no-lens and P = 0.28 vs Cyan −5 D, unpaired t-tests). After one day of cyan light treatment, the refractive state of both the Cyan no-lens and the Cyan −5 D eyes departed from the initial age-normal refractive state and became myopic after 2 days of cyan light treatment. The rate of myopia development in the Cyan no-lens eyes was rapid at first, then slowed and appeared to stabilize for the last 4 days. At the end of the 11 days of cyan light treatment, the refractive state of the Cyan no-lens eyes was −2.9 ± 0.3 D, which was significantly more myopic than the age-matched colony light animals (1.0 ± 0.2 D, P < 0.0001, unpaired t-test) (Ward et al., 2018). When returned to colony lighting, the refractive state of the Colony no-lens eyes moved back towards near emmetropia. After ten days in colony lighting, the Colony no-lens eyes were still slightly myopic (−0.6 ± 0.4 D).

Figure 2.

Figure 2.

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A. Refractive state measures (mean ± standard error of the mean [SEM]) of the Cyan no-lens and Cyan −5 D eyes when placed in narrow-band cyan light (peak wavelength 505 ± 17 nm) and when returned to colony lighting. Also shown are the refractions of a group of animals raised in colony lighting (Ward et al., 2018). B. Change in vitreous chamber depth (normalized to 24 DVE) of the eyes in cyan light and upon return to colony lighting compared with the colony lighting animals.

For the first four days of cyan light treatment, the refractive state of the Cyan −5 D eyes paralleled that of the Cyan no-lens eyes. However, after this point, changes in refractive state differed between the two groups of eyes (Eye*DVE, p < 0.001, repeated measures ANOVA, supplementary Table 2). By the sixth day of −5 D lens wear in cyan light, the Cyan −5 D eyes became more myopic than the Cyan no-lens eyes (P = 0.009, paired t-test), and the myopia development continued in a nearly linear manner until the end of the cyan light treatment period when the refractive state was −5.5 ± 0.3 D; this was significantly more myopic than the Cyan no-lens eyes (P = 0.003, paired t-test). However, because the Cyan no-lens eyes also were myopic, the difference between the lens-wearing Cyan −5 D eyes and the Cyan no-lens eyes was only −2.5 D. This is smaller than the −5 D difference which would indicate full compensation to the minus lens. When returned to colony lighting, the refractive state of the Colony −5 D eyes remained at approximately the same level throughout the 10-day recovery period, indicating full compensation for the lens in the colony lighting. The final group refraction in the −5 D colony eyes was −5.6 ± 0.3 D; because the Colony no-lens eyes had recovered back toward emmetropia, the Colony −5 D eyes differed from the recovering Colony no-lens eyes by −5.0 ± 0.6 D.

3.12. Axial component dimensions.

Vitreous chamber depth and, as a result, the axial length of the eyes, were the only ocular components that changed significantly as a result of treatment with cyan lighting (values for all components are shown in supplementary table S3). Figure 2B plots the normalized change in vitreous chamber depth of the Cyan no-lens and Cyan −5 D eyes during cyan light treatment and when returned to colony lighting. The depth of the vitreous chamber of the eyes in both groups increased with the same time course as the refractive changes, and the depth of the vitreous chamber of the Cyan −5 D eyes became significantly larger than that of the Cyan no-lens eyes. Between the start of cyan light treatment (24 DVE) and the end of cyan light treatment (35 DVE), the depth of the vitreous chamber in the Cyan −5 D eyes increased 0.13 ± 0.01 mm, which is significantly more than that in the Cyan no-lens eyes (0.05 ± 0.01 mm, P = 0.004, paired t-test, supplementary Tables 2B and 5). In contrast, the vitreous chamber depth of the colony lighting group decreased during this period (−0.03 ± 0.01 mm). Upon return to colony lighting, the vitreous chamber of the Colony no-lens eyes returned toward the dimensions of the colony lighting animals, while the vitreous chamber of the −5 D colony eyes remained elongated. Consistent with the changes in vitreous chamber depth, there was a significantly greater axial length change in Cyan −5 D than Cyan no-lens eyes between the start and the end of cyan light treatment (P = 0.001, paired t-test). By contrast, changes in central corneal thickness, aqueous depth, lens thickness, and retinal thickness were not different between Cyan −5 D and Cyan no-lens eyes (P = 0.77, 0.20, 0.80, 0.95, respectively, paired t-tests).

3.2. Comparison with Other Myopiagenic Treatments.

As shown in Figure 3A, the change in refractive state of the Cyan no-lens eyes over time was very similar to that of the myopia development in a group of tree shrews (n=5) (Norton et al., 2006) placed in total darkness for 10 days (solid line) (mean ± SEM, start 0.7 ± 0.3 D; end −3.6 ± 0.7 D), a condition where there could be no visual guidance. For technical reasons, the dark-treated animals were only measured at the start, just before entering darkness, and immediately after they were removed from darkness. Comparisons of those measures with the refractions of the Cyan no-lens eyes at the start and at 34 DVE (after 10 days of cyan light treatment) showed that the groups were not significantly different (P = 0.14, pre; P=0.31 post, unpaired t-tests).

Figure 3.

Figure 3.

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A. Refractive measures of the Cyan no-lens eyes while in cyan lighting compared with the response of eyes to form deprivation (FD) (Norton et al., 2010b), and −5 D lens wear (Norton et al., 2010a) in colony lighting, and compared with myopia development of eyes in total darkness. B. Refractive measures of the Cyan −5 D eyes compared with the same eyes as in A.

Figure 3A also shows that the myopia development of the Cyan no-lens eyes after 11 days was significantly less than that previously found, in colony lighting, when eyes (n=7) were treated for 11 days with form deprivation (FD, P < 0.0001, unpaired t-test) (Norton et al., 2010b) or when eyes (n=5) wore a −5 D lens (P < 0.0001, unpaired t-test) (Norton et al., 2010a).

In contrast, as shown in figure 3B, the myopia development of the Cyan −5 D eyes was very similar to the development of myopia in these same groups (form deprivation [P = 0.18, unpaired t-test (Norton et al., 2010b)]; (−5 D lens wear [P = 0.289, unpaired t-test (Norton et al., 2010a)]).

4. Discussion

No-lens eyes.

When placed in narrow-band cyan lighting, the no-lens eyes of juvenile tree shrews that had achieved near emmetropia in colony lighting, elongated and became myopic, even though the cyan light was in good focus at the start of cyan light treatment. With only the narrow-band cyan lighting available, the emmetropization mechanism seemed unable to use the increasing myopic defocus to maintain or restore near emmetropia. When the animals were returned to broadband colony lighting, the emmetropization mechanism was again able to respond to the myopic defocus to slow the axial elongation rate and return the eyes toward near emmetropia. Taken together with our previous studies (Gawne et al., 2017a; Gawne et al., 2017b; Ward et al., 2018), this result provides further evidence that, when differential wavelength cues from LCA are unavailable, the emmetropization mechanism is unable to use refractive error and the other available cues to control axial elongation and maintain near emmetropia.

These data do not distinguish between whether LCA is the primary visual cue used by the emmetropization mechanism to achieve and maintain minimal defocus or whether a broad band of wavelengths in the environment is needed to enable the emmetropization mechanism to use defocus and other cues inherent in out-of-focus images to achieve and maintain near emmetropia. Either way, the results of the present study reinforce the conclusion that a visual environment containing many wavelengths is essential for the emmetropization mechanism to function properly (Gisbert et al., 2020; Hung et al., 2018; Qian et al., 2013; Rucker et al., 2020; Rucker and Wallman, 2009; Smith et al., 2015). Moreover, it appears that the presence of a continuous band of wavelengths is necessary; tree shrews raised in colony lighting and then exposed to lighting composed of both short and long wavelengths, but with no intermediate wavelengths, also did not remain emmetropic (Gawne, 2019).

That the Cyan no-lens eyes failed to remain at near emmetropia was not surprising because there was insufficient LCA feedback to maintain the eyes at near emmetropia, but the direction (becoming myopic) and rate (similar to eyes in darkness) are of interest. The absence of LCA guidance in narrow band lighting placed the emmetropization mechanism in an open-loop situation. Why that led to elongation and myopia, rather than to slowed elongation and hyperopia, is unknown. However, a similar response occurs in other open-loop situations: form deprivation and darkness. In both those conditions, there was no possibility for clear images to occur on the retina to generate what have been called STOP signals to slow the elongation rate. As proposed in our model, without LCA cues, the retina could not produce a negative spectral drive (a STOP signal) to prevent the growing eyes from elongating even though the illuminance of the cyan light (1500 – 3000 human lux) was substantially greater than was the colony lighting (100-300 lux). Why the rate of myopia development in cyan lighting was slower than in form-deprived and eyes wearing a −5 D lens in colony lighting is unclear.

Although normal emmetropization in tree shrews and other species seems to require the presence of broadband light, the effect of narrow-band lighting depends not only on the specific wavelength used, but also on the species. For instance, narrow-band lighting of approximately the same bandwidth but a longer (red) peak wavelength (624 or 626 nm) that only activates the LWS cones, consistently produces slowed elongation and a hyperopic refractive state in tree shrews. Short wavelength (blue) light (457 or 464 nm) produces initially variable refractions that eventually become myopic. Rhesus monkeys seem to respond similarly (Hung, 2020; Hung et al., 2018). In contrast, steady short-wavelength (blue/violet) light produces hyperopia in chicks (Foulds et al., 2013), guinea pigs (Liu et al., 2011) and mice (Strickland et al., 2020). These species differences in narrow-band light may not be surprising given that the emmetropization mechanism evolved in broadband lighting but in a variety of environments in species that have differing ocular transmission characteristics and differing numbers of cones with absorption peaks that differ across species. When stimulated with only a narrow bandwidth, the impact on emmetropization, other than its disruption, seems highly variable.

Cyan −5 D eyes.

The Cyan −5 eyes responded to the presence of the −5 D lens. Otherwise, their refractive state would have closely paralleled that of the no-lens eyes (supplementary figure S1), resulting in myopia of about −2.9 D. Instead, they elongated and became more myopic than the Cyan no-lens eyes by−2.5 D. The myopia at the end of cyan light treatment was −5.4 D, a value very similar to the myopic produced in colony lighting by a −5 D lens. However, only about half of that final amount can be attributed to the lens wear because some of the myopia must have occurred in response to the cyan light itself. That said, the myopia in the Cyan −5 D eyes was still progressing at the end of the cyan light treatment period, so it is not possible to know whether a longer cyan exposure would have produced a full −5 D difference between the lens-wearing and non-lens wearing eyes.

Although It should not be surprising that a mechanism as fundamental as emmetropization would utilize multiple cues in an attempt to guide and maintain eyes to low refractive error, one might ask if the additional myopia in the −5 D lens eyes occurred specifically because of the lens imposed hyperopic defocus? If so, it would contrast with the situation in the Cyan no-lens eyes, where the emmetropization mechanism failed to utilize the developing myopic defocus to slow eye growth and return the eyes to emmetropia. It is possible that, in cyan lighting, the emmetropization mechanism can detect both myopic and hyperopic defocus but is unable to utilize myopic defocus to slow axial elongation. Such a scenario has been found in guinea pigs following optic nerve section (McFadden and Wildsoet, 2009), where eyes respond with axial elongation when exposed both to hyperopic and myopic defocus. To test that possibility, tree shrews in cyan lighting would need to wear a positive lens.

4.1. Possible Applicability to Humans

Because tree shrews are dichromats and most humans are trichromats, with cones maximally sensitive to long (red), medium (green), and short (blue) wavelengths of light, it is uncertain as to what degree results in tree shrew might apply to humans. As we have argued previously (Gawne and Norton, 2020; Gawne et al., 2018), several lines of evidence suggest that the human emmetropization system likely utilizes LCA cues in a similar manner to tree shrews. A difference between these species is that most humans possess a middle-wavelength sensitive (MWS) cone class, absent in tree shrews and most vertebrates, that has a peak sensitivity (530 nm) close to the LWS cone peak (560 nm) and very different from the SWS cone peak of 420 nm in humans and 428 nm in tree shrews. In humans, the difference in focus between the MWS and LWS cones is approximately 0.1 D. The differences in focus between the SWS and MWS, and between the SWS and LWS cones are approximately 1.0 and 1.1 D, respectively. Thus, there is relatively little LCA information about focus between MWS and LWS cones, but a great deal more defocus information between the SWS and the combination of the MWS and LWS cone profiles that we suggest performs the same signaling function as the LWS cones in tree shrews. With this small alteration, the human trichromatic opponent dual-detector system processes LCA cues similarly as do dichromatic tree shrews. This may help to explain why dichromatic humans generally are emmetropic (Qian et al., 2009). Indeed, it has been argued that dichromacy is the baseline state of mammals (Jacobs, 1993). Emmetropization is likely an old and evolutionarily conserved process, and as trichromacy only evolved recently in some primates, it seems unlikely that emmetropization underwent a fundamental change.

4.2. Conclusions

Placing tree shrews that emmetropized in colony lighting into a visual environment containing only a narrow band of wavelengths (cyan in this case) disrupts the functioning of the emmetropization mechanism and produces myopia. When returned to colony lighting the emmetropization mechanism again was able to use visual cues to restore near emmetropia. The Cyan no-lens eyes developed myopia at a rate that resembled the myopia that develops when no visual cues are present in complete darkness. The greater myopia in the Cyan −5 D eyes shows that the emmetropization mechanism can respond to defocus cues even in the narrow band light. However, it remains to be learned if the emmetropization mechanism was responding to the sign of the defocus or simply to the presence of additional defocus.

Supplementary Material

1
3

Highlights.

  • In narrow-band cyan light, eyes do not remain emmetropic; myopia develops

  • Wearing a −5 diopter (D) lens in cyan light produces additional myopia

  • The no-lens vs. −5 D lens eye difference was less than observed in broadband light

  • The emmetropization mechanism responds to both wavelength and defocus cues

Acknowledgements

This work was supported by the National Institutes of Health NEI R21 EY025254 and NEI RO1 028578, and P30EY003909 (Core). The authors acknowledge the technical assistance of Russell Veale, Johanna Henry, Eric Worthington, and the UAB Animal Resources Program veterinarians and staff. We thank Dr. Frank Schaeffel for the suggestion that we test the effect of a narrow-band focused “white” light in our tree shrews.

Footnotes

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