National Eye Institute Receives Intramural 2022 NIH Grant for Evaluation of Visual Function in Animal Models
National Eye Institute Receives Intramural 2022 NIH Grant for $201,678 for Evaluation of Visual Function in Animal Models. The principal investigator is Haohua Qian. Below is a summary of the proposed work.
During the past year, we investigated functional regulation of an outer retina hyporeflective band on optical coherence tomography images. In particular, we studied the mechanisms of light-induced OCT responses in rodent eye and examined hypothesis that two light-evoked OCT indices in the outer retina, subretinal space elongation and hyporeflective band reflect two stages in an outer retinal signaling pathway. Human and animal retinal optical coherence tomography (OCT) images show a hyporeflective band between the photoreceptor tip and retinal pigment epithelium layers whose mechanisms are unclear. In mice, hyporeflective band magnitude and the external limiting membrane-retinal pigment epithelium (ELM-RPE) thickness appear to be dependent on light exposure, which is known to alter photoreceptor mitochondria respiration. Here, we test the hypothesis that these two OCT biomarkers are linked to metabolic activity of the retina. Acetazolamide, which acidifies the subretinal space, had no significant impact on hyporeflective band magnitude but produced ELM-RPE thinning. Mitochondrial stimulation with 2,4-dinitrophenol reduced both hyporeflective band magnitude and ELM-RPE thickness in parallel, and also reduced F-actin expression in the same retinal region, but without altering ERG responses. For mice strains with relatively lower (C57BL/6J) or higher (129S6/ev) rod mitochondrial efficacy, light-induced changes in hyporeflective band magnitude and ELM-RPE thickness were correlated. Humans, analyzed from published data captured with a different protocol, showed a similar light-dark change pattern in hyporeflective band magnitude as in the mice. Our results indicate that mitochondrial respiration underlies changes in hyporeflective band magnitude upstream of the pH-sensitive ELM-RPE thickness response. These two distinct OCT biomarkers could be useful indices for non-invasively evaluating photoreceptor mitochondrial metabolic activity. In summary, we provide evidence that the light-induced changes in hyporeflective band magnitude, ELM-RPE thickness, and ERG recordings probe different functional aspects of the outer retina. The OCT biomarkers, unlike ERG, do not require assumptions of unchanging retinal resistance to interpret functional changes. We note that the largest light-dark change in hyporeflective band magnitude was seen in C57BL/6J mice which has a relatively less efficient mitochondria, raising the possibility that a large light-dark hyporeflective band magnitude response is an index of poorly regulated mitochondria; more work is needed to test this notion. If this hypothesis is proved to be true and could also be extended to human, hyporeflective band might indicate regions of high susceptibility to damage, an intriguing possibility that warrants further investigation. Hyporeflective band can be detected on human OCT images captured with commercial instruments commonly used in eye clinic. These considerations support future animal and human studies measuring hyporeflective band magnitude, together with the ELM-RPE thickness, as a functional biomarker tool kit for diagnosing and treating various photoreceptor mitochondria-based retinopathies.