Cone-driven, geniculo-cortical responses in canine models of outer retinal disease.

Canine models of inherited retinal degeneration are used for proof-of-concept of emerging gene and cell-based therapies that aim to produce functional restoration of cone-mediated vision. We examined functional MRI measures of the post-retinal response to cone-directed stimulation in wild type (WT) dogs, and in three different retinal disease models. Temporal spectral modulation of a uniform field of light around a photopic background was used to target the canine L/M (hereafter "L") and S cones and rods. Stimuli were designed to separately target the post-receptoral luminance (L+S) and chrominance (L-S) pathways, the rods, and all photoreceptors jointly (light flux). These stimuli were presented to WT, and mutant Pupil responses in WT dogs to light flux, L+S, and rod-directed stimuli were consistent with responses being driven by cone signals alone. For WT animals, both luminance and chromatic (L-S) stimuli evoked fMRI responses in the lateral geniculate nucleus (LGN) or visual cortex; RCD1 animals with predominant rod loss had similar responses. Responses to cone-directed stimulation were reduced in XLPRA2 and absent in CRD2. NPHP5 gene augmentation restored the cortical response to luminance stimulation in a CRD2 animal. Cone-directed stimulation during fMRI can be used to measure the integrity of luminance and chrominance responses in the dog visual system. The fMRI assessment of cone driven cortical response provides a tool to translate cell/gene therapies for vision restoration.