Optomotor reflex in the mouse optic nerve crush model for glaucomatous optic neuropathies

Abstract

Purpose : Experimental optic nerve crush (ONC) in rodents has been widely used as a model for traumatic optic nerve injury, glaucomatous optic neuropathy, and, more generally, retinal ganglion cell (RGC) damage. The purpose of this Study was to evaluate the structure-function relationships in the mouse ONC, focusing on the longitudinal in-life assessment of visual function by pattern electroretinography (PERG) and optomotor reflex (OMR), and retinal structure by spectral domain optical coherence tomography (SD-OCT).

Methods : ONC was induced in the right eye of wild-type C57BL/6JRj mice (9 mo old, 6 females and 11 males for ONC group, 5 females and 8 males for naïve group) using self-closing forceps and a crush duration of 3 s. Successful retinal perfusion was verified using Doppler imaging immediately after ONC. PERG (Celeris, Diagnosys LLC) and SD-OCT (Envisu R2200, Bioptigen Inc./Leica Microsystems) were performed at baseline and at week 8. OMR, measured as photopic visual acuity and contrast sensitivity at 0.019 and 0.06 cyc/° (OptoDrum Plus, Striatech GmbH), was evaluated at baseline, and at weeks 3 and 8 post-ONC. Retinal thickness was measured from SD-OCT images using a proprietary convolutional neural network. Data were analyzed by Two-Way ANOVA with Holm-Šidák’s multiple comparison test.

Results : ONC resulted in significant impairment of visual function. PERG amplitudes at week 8 decreased by 68% in ONC eyes (P<0.001), but remained unchanged in contralateral eyes (P>0.05). ONC eyes had only minimal visual acuity (P<0.001) or contrast sensitivity (P<0.001) at Week 3 or at Week 8, as assessed by OMR. Contralateral eyes showed a significant increase in visual acuity, both at Week 3 (P<0.01) and Week 8 (P<0.01). Functional decline correlated with structural changes, notably the significant thinning of the RGC and inner plexiform layers (P<0.001).

Conclusions : ONC resulted in severe functional and structural changes with no recovery of the phenotype up to 8 weeks. Mice had no functional vision despite measurable PERG amplitudes. OMR measurements revealed a significant increase in visual acuity in the contralateral eye, attributable to a compensatory effect. Combining PERG and OMR in the ONC offers longitudinal in-life quantification of retinal circuitry and functional vision with great utility for evaluation of novel therapeutic approaches for regeneration of the visual system.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.