BRAIN WIDE CORRELATES OF OPTOGENETIC VISION RESTORATION

Optogenetic therapies offer a mutation-independent strategy for restoring light sensitivity in advanced retinitis pigmentosa (RP), yet the extent to which restored retinal signals engage downstream visual circuits remains poorly characterized. Using functional ultrasound (fUS) imaging, we investigated brain-wide functional correlates of optogenetic vision restoration in the rd1 mouse model of RP. Blind mice received intravitreal injections of ChReef, a recently engineered variant of ChRmine designed for efficient and sustained optogenetic control. Preliminarily, Opsin expression was verified using autofluorescence fundus imaging, retinal structure was assessed using optical coherence tomography, and photo-perception was evaluated behaviorally using the Light dark assay. Visually evoked whole-brain hemodynamic responses were recorded using fUS for an array of visual stimuli including temporally modulated full-field flashes as well as complex stimuli such as drifting gratings, random dot kinematograms, and naturalistic images to investigate the restoration of multiple aspects of visual processing. Optogenetically treated rd1 mice exhibited robust stimulus-locked increases in cerebral blood volume across numerous subcortical and cortical visual processing centers. While response profiles showed partial similarity to those observed in sighted wild-type animals, distinct differences in activation magnitude and spatial distribution were observed, indicating altered network dynamics following sensory restoration. To further validate fUS-derived signals, in vivo electrophysiological recordings were performed in the superior colliculus and primary visual cortex of visually restored animals. Together, these results demonstrate that ChReef-mediated retinal re-sensitization drives large-scale functional engagement of the visual brain network and highlights the utility of brain-wide multimodal approaches for evaluating circuit-level outcomes of optogenetic vision restoration therapies.