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Circadian rhythm, ipRGCs, and dopamine signalling in myopia

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Licheng Li
Licheng Li
Licheng Li
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Yang Yu
Yang Yu
Yang Yu
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Zihao Zhuang
Zihao Zhuang
Zihao Zhuang
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Qi Wu
Qi Wu
Qi Wu
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Abstract and Figures

Myopia, a common ophthalmic disorder, places a high economic burden on individuals and society. Genetic and environmental factors influence myopia progression; however, the underlying mechanisms remain unelucidated. This paper reviews recent advances in circadian rhythm, intrinsically photosensitive retinal ganglion cells (ipRGCs), and dopamine (DA) signalling in myopia and proposes the hypothesis of a circadian rhythm brain retinal circuit in myopia progression. The search of relevant English articles was conducted in the PubMed databases until June 2023. Based on the search, emerging evidence indicated that circadian rhythm was associated with myopia, including circadian genes Bmal1, Cycle, and Per. In both humans and animals, the ocular morphology and physiology show rhythmic oscillations. Theoretically, such ocular rhythms are regulated locally and indirectly via the suprachiasmatic nucleus, which receives signal from the ipRGCs. Compared with the conventional retinal ganglion cells, ipRGCs can sense the presence of light because of specific expression of melanopsin. Light, together with ipRGCs and DA signalling, plays a crucial role in both circadian rhythm and myopia. In summary, regarding myopia progression, a circadian rhythm brain retinal circuit involving ipRGCs and DA signalling has not been well established. However, based on the relationship between circadian rhythm, ipRGCs, and DA signalling in myopia, we hypothesised a circadian rhythm brain retinal circuit.
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Graefe's Archive for Clinical and Experimental Ophthalmology (2024) 262:983–990
https://doi.org/10.1007/s00417-023-06276-x
MINI REVIEW
Circadian rhythm, ipRGCs, anddopamine signalling inmyopia
LichengLi1 · YangYu1 · ZihaoZhuang1 · QiWu2 · ShuLin2,3 · JianminHu1,4
Received: 22 June 2023 / Revised: 1 October 2023 / Accepted: 9 October 2023 / Published online: 21 October 2023
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2023
Abstract
Myopia, a common ophthalmic disorder, places a high economic burden on individuals and society. Genetic and environmental
factors influence myopia progression; however, the underlying mechanisms remain unelucidated. This paper reviews recent
advances in circadian rhythm, intrinsically photosensitive retinal ganglion cells (ipRGCs), and dopamine (DA) signalling in
myopia and proposes the hypothesis of a circadian rhythm brain retinal circuit in myopia progression. The search of relevant
English articles was conducted in the PubMed databases until June 2023. Based on the search, emerging evidence indicated that
circadian rhythm was associated with myopia, including circadian genes Bmal1, Cycle, and Per . In both humans and animals,
the ocular morphology and physiology show rhythmic oscillations. Theoretically, such ocular rhythms are regulated locally and
indirectly via the suprachiasmatic nucleus, which receives signal from the ipRGCs. Compared with the conventional retinal gan-
glion cells, ipRGCs can sense the presence of light because of specific expression of melanopsin. Light, together with ipRGCs and
DA signalling, plays a crucial role in both circadian rhythm and myopia. In summary, regarding myopia progression, a circadian
rhythm brain retinal circuit involving ipRGCs and DA signalling has not been well established. However, based on the relation-
ship between circadian rhythm, ipRGCs, and DA signalling in myopia, we hypothesised a circadian rhythm brain retinal circuit.
Keywords Myopia· Circadian rhythm· ipRGCs· Dopamine signalling
Introduction
Myopia or near-sightedness is a refractive error [1]. Glob-
ally, an estimated 4.758 billion and 938 million people may
be affected by myopia and high myopia, respectively, by
Key messages
What is known:
Myopia places a high economic burden on individuals and society.
What is new:
Genetic and environmental factors are known to influence myopia progression; however, the underlying mechanisms
remain unelucidated.
This paper reviews recent advances in circadian rhythm, ipRGCs and dopamine signalling in myopia.
We propose the existence of a circadian rhythm brain retinal circuit in myopia progression, based on the relationship
between circadian rhythm, ipRGCs, and dopamine signalling.
Extended author information available on the last page of the article
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Rare variant analyses across multiethnic cohorts identify novel genes for refractive error
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  • Jan 2023
Refractive error, measured here as mean spherical equivalent (SER), is a complex eye condition caused by both genetic and environmental factors. Individuals with strong positive or negative values of SER require spectacles or other approaches for vision correction. Common genetic risk factors have been identified by genome-wide association studies (GWAS), but a great part of the refractive error heritability is still missing. Some of this heritability may be explained by rare variants (minor allele frequency [MAF] ≤ 0.01.). We performed multiple gene-based association tests of mean Spherical Equivalent with rare variants in exome array data from the Consortium for Refractive Error and Myopia (CREAM). The dataset consisted of over 27,000 total subjects from five cohorts of Indo-European and Eastern Asian ethnicity. We identified 129 unique genes associated with refractive error, many of which were replicated in multiple cohorts. Our best novel candidates included the retina expressed PDCD6IP, the circadian rhythm gene PER3, and P4HTM, which affects eye morphology. Future work will include functional studies and validation. Identification of genes contributing to refractive error and future understanding of their function may lead to better treatment and prevention of refractive errors, which themselves are important risk factors for various blinding conditions. A multi-ethnic meta-analysis of exome array data from over 27,000 participants identifies several rare variants that could contribute to risk of ocular refractive error.
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Time Outdoors in Reducing Myopia: A School-Based Cluster Randomized Trial with Objective Monitoring of Outdoor Time and Light Intensity
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  • Jun 2022
  • OPHTHALMOLOGY
Purpose To evaluate the efficacy of time outdoors per school day over 2 years on myopia onset and shift. Design A prospective, cluster-randomized, examiner-masked, three-arm trial. Participants A total of 6295 students aged 6 to 9 years from 24 primary schools in Shanghai, China, stratified and randomized by school in a 1:1:1 ratio to control (n=2037), test I (n=2329), or test II (n=1929) group. Methods An additional 40 or 80-minutes of outdoor time was allocated to each school day for test I and II groups. Children in the control group continued their habitual outdoor time. Objective monitoring of outdoor and indoor time and light intensity each day was measured with a wrist-worn wearable during the second-year follow-up. Main Outcome Measures The 2-year cumulative incidence of myopia (defined as cycloplegic spherical equivalent [SE] of ≤-0.5 diopters[D] at the right eye) among the students without myopia at baseline and changes in SE and axial length (AL) after 2 years. Results The unadjusted 2-year cumulative incidence of myopia was 24.9%, 20.6%, and 23.8% for control, test I, and II groups. The adjusted incidence decreased by 16% [Incidence Risk Ratio (IRR)=0.84, 95%CI: 0.72∼0.99; P =0.035] in test I and 11% (IRR=0.89, 95%CI: 0.79∼0.99; P =0.041) in test II when compared with the control group. The test groups showed less myopic shift and axial elongation compared with the control group (test I: -0.84D and 0.55mm, test II: -0.91D and 0.57mm, control: -1.04D and 0.65mm). There was no significant difference in the adjusted incidence of myopia and myopic shift between the two test groups. The test groups had similar outdoor time and light intensity (test I: 127±30 minutes/day and 3557±970 lux/minute; test II: 127±26 minutes/day and 3662±803 lux/minute), but significantly more outdoor time and higher light intensity compared with the control group (106±27 minutes/day and 2984±806 lux/minute). Daily outdoor time of 120∼150 minutes at 5000 lux/minutes or cumulative outdoor light intensity of 600,000∼750,000 lux significantly reduced the IRR by 17%∼31%. Conclusions Increasing outdoor time reduced the risk of myopia onset and myopic shifts, especially in nonmyopic children. The protective effect of outdoor time was related to the duration of exposure as well as light intensity. The dose-response effect between test I and test II was not observed probably due to insufficient outdoor time achieved in the test groups, which suggests that proper monitoring on the compliance on outdoor intervention is critical if one wants to see the protective effect.
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The role of ipRGCs in ocular growth and myopia development
Article
Full-text available
  • Jun 2022
The increasing global prevalence of myopia calls for elaboration of the pathogenesis of this disease. Here, we show that selective ablation and activation of intrinsically photosensitive retinal ganglion cells (ipRGCs) in developing mice induced myopic and hyperopic refractive shifts by modulating the corneal radius of curvature (CRC) and axial length (AL) in an opposite way. Melanopsin- and rod/cone-driven signals of ipRGCs were found to influence refractive development by affecting the AL and CRC, respectively. The role of ipRGCs in myopia progression is evidenced by attenuated form-deprivation myopia magnitudes in ipRGC-ablated and melanopsin-deficient animals and by enhanced melanopsin expression/photoresponses in form-deprived eyes. Cell subtype-specific ablation showed that M1 subtype cells, and probably M2/M3 subtype cells, are involved in ocular development. Thus, ipRGCs contribute substantially to mouse eye growth and myopia development, which may inspire novel strategies for myopia intervention.
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Light Signaling and Myopia Development: A Review
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Relationship Between Myopia and Other Risk Factors With Anxiety and Depression Among Chinese University Freshmen During the COVID-19 Pandemic
Article
Full-text available
  • Dec 2021
Purpose: To investigate the association of myopia and other risk factors with anxiety and depression among Chinese university freshmen during the coronavirus disease 2019 (COVID-19) pandemic. Methods: This cross-sectional study was conducted at the Tianjin Medical University from October 2020 to December 2020. Ophthalmic examination of the eyes was performed by an experienced ophthalmologist. Detailed information on depression, anxiety, and other risk factors was collected via the Self-rating Anxiety Scale and Self-rating Depression Scale. Results: The overall prevalence of anxiety and depression in our study was 10.34 and 25.13%, respectively. The prevalence of myopia and high myopia as 92.02 and 26.7%, respectively. There were significant associations between anxiety and spectacle power [odds ratios (OR) = 0.89; 95% CI: 0.81–0.98, P = 0.019], sphere equivalent (OR = 0.89; 95% CI: 0.81– 0.98, P = 0.025), sleep time (OR = 0.53; 95% CI: 0.35–0.79, P = 0.002), and body mass index (OR = 0.93; 95% CI: 0.86–0.99, P = 0.047). In the multivariable linear regression models, spectacle power (β = −0.43; 95% CI: −0.68 to −0.19, P = 0.001) and sphere equivalent (β = −0.36; 95% CI: −0.60 to −0.11, P = 0.005) were negatively associated with anxiety scores, whereas axial length (β = 0.54; 95% CI: 0.02–1.07, P = 0.044) was positively correlated with anxiety scores. Every 1 h decrease in sleep time was associated with a 0.12-point increase in depression score. Conclusion: Myopia was associated with anxiety and anxiety scores. The greater the degree of myopia, the higher the anxiety score. However, myopia was not found to be associated with depression. The results highlight the importance of providing psychological support to students with myopia during the COVID-19 pandemic.
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Circadian Rhythm Dysregulation and Restoration: The Role of Melatonin
Article
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  • Sep 2021
Sleep is an essential component of overall human health but is so tightly regulated that when disrupted can cause or worsen certain ailments. An important part of this process is the presence of the well-known hormone, melatonin. This compound assists in the governing of sleep and circadian rhythms. Previous studies have postulated that dysregulation of melatonin rhythms is the driving force behind sleep and circadian disorders. A computer-aided search spanning the years of 2015–2020 using the search terms melatonin, circadian rhythm, disorder yielded 52 full text articles that were analyzed. We explored the mechanisms behind melatonin dysregulation and how it affects various disorders. Additionally, we examined associated therapeutic treatments including bright light therapy (BLT) and exogenous forms of melatonin. We found that over the past 5 years, melatonin has not been widely investigated in clinical studies thus there remains large gaps in its potential utilization as a therapy.
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Effects of morning and evening exposures to blue light of varying illuminance on ocular growth rates and ocular rhythms in chicks
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Recent evidence indicates that moderate levels of blue light are sufficient to suppress the nighttime rise in serum melatonin in humans, suggesting that luminous screens may be deleterious to sleep cycles and to other functions. Little is known however, about the effects of exposures to blue light on ocular physiology. We tested the effects of transient blue light exposures of various illuminances on ocular growth rates and ocular rhythms in chicks. 10-day old chicks were exposed to narrow band blue light (460 nm) of specific illuminance for 4 h in the evening (ZT8-ZT12) or the morning (ZT0-ZT4) for 9 days; for the remainder of the day they were in white light (588 lux). For the evening, four illuminances were tested: 0.15 lux; n = 15), 200 lux (radiometrically matched to white controls; n = 16), 600 lux (photometrically matched to white controls; n = 15) or 1000 lux (n = 8). The 600 lux condition was also tested using a 2-hr duration (n = 8). The 200 and 600 lux conditions were extended to 14 and 21 days (n = 8 each). For morning exposures, 200 lux (n = 9), 600 lux (n = 9) and 1000 lux (n = 8) were tested. Controls remained in white light (n = 23). Ocular dimensions were measured by A-scan ultrasonography on days 1 and 9 to assess growth rates. On day 8 or 9, measurements were made at 6-h intervals over 24 h starting at noon to assess rhythm parameters. Evening exposure to blue light stimulated ocular growth rates relative to controls for all except the bright condition (0.15 lux, 200 lux, 600 lux vs bright and white respectively: 845 μm, 838 μm, 898 μm vs 733 μm and 766 μm; p < 0.05 for all comparisons). 2 hr exposures to 600 lux were similarly effective (915 μm vs 766 μm; p < 0.05). Morning exposures only resulted in growth stimulation for the 200 lux condition (200 lux vs white: 884 μm vs 766 μm; p < 0.05). Furthermore, for this group only, growth of the anterior chamber had a significant contribution to the overall effect (vs white: p < 0.05), and choroids showed significant thickening. For evening exposures to 200 and 600 lux, the growth stimulatory effect lasted for 14 days (p = 0.01); by 21 days only the 600 lux cohort still differed (p < 0.0001). Evening exposures caused circadian disruptions in the choroidal thickness rhythms, and morning exposures disrupted both axial and choroidal rhythms. Exposure to 4 h of blue light at lower illuminances (less than 1000 lux) at transition times of lights-on and lights-off stimulates ocular growth rates and affects ocular rhythms in chicks, suggesting that such exposures may be deleterious to emmetropization in children.
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Advances in biomedical study of the myopia-related signaling pathways and mechanisms
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Myopia has become one of the most critical health problems in the world with the increasing time spent indoors and increasing close work. Pathological myopia may have multiple complications, such as myopic macular degeneration, retinal detachment, cataracts, open-angle glaucoma, and severe cases that can cause blindness. Mounting evidence suggests that the cause of myopia can be attributed to the complex interaction of environmental exposure and genetic susceptibility. An increasing number of researchers have focused on the genetic pathogenesis of myopia in recent years. Scleral remodeling and excessive axial elongating induced retina thinning and even retinal detachment are myopia's most important pathological manifestations. The related signaling pathways are indispensable in myopia occurrence and development, such as dopamine, nitric oxide, TGF-β, HIF-1α, etc. We review the current major and recent progress of biomedicine on myopia-related signaling pathways and mechanisms.
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Melanopsin modulates refractive development and myopia
Article
  • Nov 2021
  • EXP EYE RES
Myopia, or nearsightedness, is the most common form of refractive abnormality and is characterized by excessive ocular elongation in relation to ocular power. Retinal neurotransmitter signaling, including dopamine, is implicated in myopic ocular growth, but the visual pathways that initiate and sustain myopia remain unclear. Melanopsin-expressing retinal ganglion cells (mRGCs), which detect light, are important for visual function, and have connections with retinal dopamine cells. Here, we investigated how mRGCs influence normal and myopic refractive development using two mutant mouse models: Opn4−/− mice that lack functional melanopsin photopigments and intrinsic mRGC responses but still receive other photoreceptor-mediated input to these cells; and Opn4DTA/DTA mice that lack intrinsic and photoreceptor-mediated mRGC responses due to mRGC cell death. In mice with intact vision or form-deprivation, we measured refractive error, ocular properties including axial length and corneal curvature, and the levels of retinal dopamine and its primary metabolite, L-3,4-dihydroxyphenylalanine (DOPAC). Myopia was measured as a myopic shift, or the difference in refractive error between the form-deprived and contralateral eyes. We found that Opn4−/− mice had altered normal refractive development compared to Opn4+/+ wildtype mice, starting ∼4D more myopic but developing ∼2D greater hyperopia by 16 weeks of age. Consistent with hyperopia at older ages, 16 week-old Opn4−/− mice also had shorter eyes compared to Opn4+/+ mice (3.34 vs 3.42 mm). Opn4DTA/DTA mice, however, were more hyperopic than both Opn4+/+ and Opn4−/− mice across development ending with even shorter axial lengths. Despite these differences, both Opn4−/− and Opn4DTA/DTA mice had ∼2D greater myopic shifts in response to form-deprivation compared to Opn4+/+ mice. Furthermore, when vision was intact, dopamine and DOPAC levels were similar between Opn4−/− and Opn4+/+ mice, but higher in Opn4DTA/DTA mice, which differed with age. However, form-deprivation reduced retinal dopamine and DOAPC by ∼20% in Opn4−/− compared to Opn4+/+ mice but did not affect retinal dopamine and DOPAC in Opn4DTA/DTA mice. Lastly, systemically treating Opn4−/− mice with the dopamine precursor L-DOPA reduced their form-deprivation myopia by half compared to non-treated mice. Collectively our findings show that disruption of retinal melanopsin signaling alters the rate and magnitude of normal refractive development, yields greater susceptibility to form-deprivation myopia, and changes dopamine signaling. Our results suggest that mRGCs participate in the eye's response to myopigenic stimuli, acting partly through dopaminergic mechanisms, and provide a potential therapeutic target underling myopia progression. We conclude that proper mRGC function is necessary for correct refractive development and protection from myopia progression.
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Delayed circadian rhythms and substance abuse: dopamine transmission’s time has come
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