Differential regulation of myopia progression by ON and OFF stimulation in guinea pigs

BACKGROUND: The effects of ON and OFF retinal pathway stimulation on lens-induced myopia (LIM) in mammalian models remain unclear. This study examined refractive, choroidal, and dopamine (DA)-related responses to artificial dynamic ON and OFF stimulation during the development of LIM in guinea pigs. METHODS: Sixty-three guinea pigs were randomly assigned to ON, OFF, and natural control (NC) stimulation for 12 h/day over 7 days. LIM was induced using a - 4.0 D monocular lens. Refraction, axial length (AL), choroidal thickness (ChT), and choroidal blood perfusion (ChBP) were assessed before and after treatment. DA and metabolites were measured by high-performance liquid chromatography (HPLC), interocular differences were calculated, and choroidal proteomes were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) based bioinformatics analysis. RESULTS: ON stimulation significantly reduced myopic shift compared with NC and OFF stimulation (Δ refraction: - 2.13 ± 0.40 D vs. - 4.03 ± 0.35 D and - 3.98 ± 0.50 D, respectively; both P < 0.01). No significant differences in AL were observed among groups. OFF stimulation uniquely preserved ChBP (ΔChBP: 0.51% ± 2.18%), significantly different from ON (- 6.11% ± 1.76%, P = 0.0330) and NC (- 7.78% ± 1.44%, P = 0.0057). OFF stimulation also showed less choroidal thinning (ΔChT: - 3.06 ± 2.23 μm) compared to NC (- 12.35 ± 2.7 μm, P = 0.0171). In non-lens eyes, ON stimulation produced higher ChBP than NC or OFF stimulation, and ChT changes were positively correlated with ChBP under all conditions (P < 0.0001). Retinal 3,4-dihydroxyphenylacetic acid (DOPAC) levels were significantly higher in the ON group (17.65 ± 12.67) than in the NC group (- 25.75 ± 9.23, P = 0.0095). Vitreal DA markers showed no significant differences among groups. Proteomic analysis revealed distinct choroidal remodeling signatures among ON, OFF, and NC groups, with ON stimulation associated with the smallest number of differentially expressed proteins and a relatively preserved pattern of collagen and fibrillin expression compared with more pronounced extracellular matrix (ECM) depletion under NC and over-compensatory ECM upregulation under OFF stimulation. CONCLUSIONS: ON and OFF stimulation differentially regulated ocular responses to myopia. ON stimulation was associated with attenuated myopic shift and increased retinal DOPAC levels, suggesting enhanced DA metabolism. OFF stimulation was associated with preserved ChT and ChBP, accompanied by upregulation of ECM components. These findings suggest that effective myopia control strategies may require coordinated engagement of both ON- and OFF-pathway-mediated mechanisms.