Visual stimulation targeting distinct retinal processing channels can exert divergent regulatory effects on the structural and physiological progression of experimental myopia, according to a controlled investigation conducted in guinea pigs. Researchers found that exposing animals with lens-induced myopia to dynamic ON visual stimulation significantly attenuated the progression of myopic refractive error, whereas dynamic OFF visual stimulation selectively protected the vascular and structural integrity of the choroid without curbing refractive changes. The study, published in the journal Eye and Vision, demonstrates that these two visual processing pathways recruit independent biological mechanisms across the posterior eye. While the ON pathway modulated refractive development alongside elevated retinal dopamine turnover, the OFF pathway drove an over-compensatory remodeling of structural proteins within the choroidal extracellular matrix. These findings provide new laboratory evidence demonstrating that refractive growth and vascular remodeling can uncouple during visually guided ocular development, suggesting that future visual interventions for myopia may need to recruit both pathways simultaneously to achieve comprehensive ocular protection.
Myopia represents an escalating global public health priority, with projections indicating that the condition could affect nearly 4.8 billion individuals worldwide by the middle of the twenty-first century. Extensive clinical and epidemiological research has linked intensive near work, especially sustained activity at working distances closer than thirty centimeters and durations exceeding thirty minutes, to accelerated refractive progression. Beyond basic optical defocus and crystalline lens accommodation, visual tasks alter the balance of contrast and temporal luminance signals reaching the retina. Specialized ON and OFF retinal channels process visual scenes through distinct response profiles, with ON pathways responding preferentially to rapid increases in illuminance and OFF pathways responding to rapid decreases. In natural viewing conditions, ON and OFF signals are roughly balanced, but artificial tasks such as reading dark text against a bright background preferentially activate the OFF channel, triggering acute choroidal thinning in human subjects. Conversely, reading bright text on a dark background stimulates the ON pathway and promotes choroidal thickening. Prior investigations in young chicks revealed that prolonged artificial ON or OFF flickering could paradoxically promote ocular growth and alter retinal catecholamine production, leaving the specific mammalian responses to pathway-biased visual stimulation poorly understood.
To rigorously examine how these contrasting visual signals modulate mammalian ocular growth, the investigators established an animal study using sixty-three juvenile pigmented guinea pigs aged three weeks, with baseline body weights ranging from 150 to 180 grams. The animals were housed under strictly controlled environmental conditions maintained at twenty-five degrees Celsius, featuring an established twelve-hour light and twelve-hour dark cycle commencing at eight in the morning, with unlimited access to water and standardized diet supplemented daily with fresh vegetables. Ethical approval was granted by the Animal Care and Ethics Committee of Wenzhou Medical University under protocol number wydw2023-0063. The sixty-three animals were randomized equally into three visual stimulation cohorts of twenty-one animals each: a dynamic ON stimulation group, a dynamic OFF stimulation group, and a natural control group maintained under standard ambient laboratory illumination. Ocular myopia was unilaterally induced in every animal by mounting a minus four diopter lens over either the left or right eye chosen at random, while the contralateral partner eye remained entirely uncovered to serve as an internal fellow-eye reference.
The experimental visual regimens were administered across seven consecutive days, delivering active visual stimulation for twelve continuous hours daily between eight in the morning and eight in the evening, followed immediately by total darkness. Visual stimuli were delivered within custom-designed enclosures measuring sixty centimeters in each dimension, where four computer monitors formed the interior walls to completely surround the animals. A dedicated software application generated approximately two thousand geometric squares across the display monitors, presenting asymmetric sawtooth-wave temporal illuminance modulation cycling at one Hertz to selectively bias retinal pathway activation. Each square element measured ten by ten millimeters, subtending fifty-seven arcminutes and yielding approximately 1.05 cycles per degree at maximum viewing distance. High-precision photometers verified that display output across all three experimental environments remained carefully luminance-matched at an average cage illumination of approximately 150 lux, ensuring that the biological differences observed between cohorts were driven by the temporal luminance profiles rather than discrepancies in total photon exposure.
Ocular dimensions and optical properties were measured prior to the seven-day regimen and immediately following its conclusion using specialized non-invasive diagnostic platforms. Refractive state was evaluated without pharmacological cycloplegia using eccentric infrared photorefraction, excluding any animals showing baseline interocular differences greater than two diopters. Axial length was measured along the visual axis using high-precision A-scan ultrasonography under topical proparacaine anesthesia, taking the mean of ten consecutive scans which demonstrated an internal coefficient of variation consistently below one percent. Simultaneous cross-sectional measurements of choroidal thickness and choroidal blood perfusion were gathered using spectral-domain optical coherence tomography and optical coherence tomography angiography in enhanced depth imaging mode. Scans were centered vertically through the optic nerve head, and image processing was performed using custom MATLAB algorithms. Independent evaluations by two observers on twenty percent of the dataset confirmed strong measurement repeatability, with inter-operator bias under two micrometers and intraclass correlation coefficients exceeding 0.90.
Following seven days of lens wear, all negative-lens eyes developed pronounced myopia relative to their contralateral fellow control eyes, while baseline biometric assessments confirmed strict ocular symmetry across all groups. Calculations of interocular change revealed striking contrasts in refractive development between visual conditions. Animals exposed to dynamic ON stimulation exhibited an average refractive change of minus 2.13 plus or minus 0.40 diopters, reflecting a significantly smaller myopic progression than the minus 4.03 plus or minus 0.35 diopters observed in the natural control group and the minus 3.98 plus or minus 0.50 diopters observed under OFF stimulation. Statistical comparisons established that the ON pathway significantly attenuated myopic progression by nearly two diopters compared to both control conditions, whereas OFF stimulation provided no measurable refractive protection. Interestingly, axial length elongation did not differ significantly among the experimental cohorts, with the ON, natural control, and OFF groups demonstrating interocular extensions of 0.085, 0.087, and 0.093 millimeters respectively. The absence of axial differences suggests that the refractive protection conferred by ON stimulation may have involved anterior segment or crystalline lens alterations rather than macroscopic axial suppression alone.
While OFF stimulation failed to impede refractive progression, it exerted a powerful protective influence over the vascular bed and tissue volume of the choroid. Animals subjected to natural control lighting experienced severe choroidal thinning, losing an average of 12.35 plus or minus 2.70 micrometers of choroidal depth, whereas OFF stimulation restricted choroidal thinning to just 3.06 plus or minus 2.23 micrometers. The ON group demonstrated an intermediate thinning of 7.94 micrometers that did not differ statistically from the other groups. Furthermore, optical coherence tomography angiography showed that OFF stimulation uniquely preserved choroidal microvascular perfusion, registering a positive interocular change of 0.51 plus or minus 2.18 relative units. In sharp contrast, choroidal blood flow dropped by 6.11 units under ON stimulation and plunged by 7.78 units in natural control conditions, representing statistically significant perfusion deficits compared to the OFF group. Across all experimental conditions, choroidal thickness and choroidal perfusion showed strong positive correlations, confirming that vascular hemodynamic maintenance is tightly linked to structural choroidal preservation under myopigenic challenge.
Biochemical evaluations of neurochemical signaling explained potential mechanisms underlying the pathway-specific ocular adaptations. Levels of dopamine and its primary metabolic breakdown products, 3,4-dihydroxyphenylacetic acid and homovanillic acid, were quantified in freshly dissected retinal and vitreal tissues using high-performance liquid chromatography coupled with electrochemical detection. While vitreal catecholamine concentrations showed no significant differences among experimental cohorts, retinal tissue analysis revealed distinct pathway-dependent responses. The interocular level of retinal 3,4-dihydroxyphenylacetic acid was significantly elevated in the ON group at 17.65 plus or minus 12.67 nanograms per gram of tissue, in contrast to the negative shift of minus 25.75 plus or minus 9.23 nanograms per gram recorded in the natural control group. Although gross retinal dopamine levels trended higher in both the ON and OFF cohorts relative to control lighting, only ON stimulation induced a statistically significant elevation in metabolite production, indicating enhanced dopamine turnover and release that may stabilize retinal refractive signaling during defocus challenge.
High-resolution liquid chromatography-tandem mass spectrometry further uncovered pronounced molecular remodeling within the choroidal proteome across the three lighting conditions. Among 8306 identified choroidal proteins, 490 exhibited differential abundance across experimental comparisons. The ON stimulation group demonstrated the mildest proteomic disruption, displaying only 126 differentially expressed proteins, which suggests that ON signaling helped preserve choroidal molecular equilibrium. Conversely, the natural control group exhibited 225 differentially expressed proteins, characterized by widespread downregulation of essential extracellular matrix constituents including type IV collagen alpha 4 chain and fibrillin 2. In marked contrast, OFF stimulation provoked extensive proteomic reorganization involving 203 differentially expressed proteins, featuring substantial upregulation of type IV collagen alpha 4, fibrillin 2, contactin-associated protein-like 2, and nucleolar protein 7. Functional pathway analysis confirmed that while natural control eyes suffered degradation of vascular matrix integrity, OFF stimulation triggered compensatory extracellular matrix assembly and collagen biosynthesis, mechanically reinforcing choroidal tissue despite relentless refractive progression.
Together, these findings indicate that retinal ON and OFF pathways govern distinct biological facets of ocular growth, with ON stimulation restraining refractive shift through dopaminergic modulation and OFF stimulation reinforcing choroidal architecture through matrix synthesis. The study authors emphasized several procedural caveats, noting that contralateral fellow eyes may experience subtle consensual growth adjustments through central neural feedback, and that physical sawtooth illumination cannot achieve absolute physiological isolation of intertwined ON and OFF circuits. Furthermore, the downstream molecular mechanisms connecting choroidal vascular shifts to dopamine signaling require deeper inquiry, and rodent visual physiology differs substantially from primate ocular biology. Electrophysiological validation, including photopic negative responses and oscillatory potentials, will be essential in higher animal models before therapeutic translation. Nonetheless, uncovering this functional dissociation between refractive control and choroidal matrix remodeling offers a valuable theoretical framework for engineering contrast-tailored optical displays and screen-based visual paradigms capable of mitigating myopia progression during near-work tasks.
Subject of Research: Differential regulation of refractive development, choroidal perfusion, and dopamine metabolism by retinal ON and OFF stimulation in guinea pigs
Article Title: Differential regulation of myopia progression by ON and OFF stimulation in guinea pigs
Article References: Xie, Q., Dai, Q., Zhu, X., Chen, X., Shen, B., Fang, Y., Li, X., Lu, F., Zhou, X., & Wang, M. (2026). Differential regulation of myopia progression by ON and OFF stimulation in guinea pigs. Eye and Vision, 13(1), Article 24. https://doi.org/10.1186/s40662-026-00495-z
Image Credits: AI Generated
DOI: 10.1186/s40662-026-00495-z
Keywords: myopia, retinal pathways, choroidal thickness, choroidal blood perfusion, dopamine metabolism, extracellular matrix, lens-induced myopia, guinea pigs, Differential, regulation, progression, stimulation
News Source: Ophelia Keating. (November 7, 2026). Retinal Pathway Stimulation Differentially Regulates Myopia Progression in Animal Study. Scienmag.
