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Application of Optical Coherence Tomography to a Mouse Model of Retinopathy
Published on: January 12, 2022
Cone-driven, geniculo-cortical responses in canine models of outer retinal disease
Huseyin O Taskin1, Jacqueline Wivel2, Gustavo D Aguirre2
1Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Purpose:
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.
Methods:
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 PDE6B-RCD1, RPGR-XLPRA2, and NPHP5-CRD2 dogs during pupillometry and fMRI.
Results:
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.
Conclusions:
Cone-directed stimulation during fMRI can be used to measure the integrity of luminance and chrominance responses in the dog visual system. The NPHP5-CRD2 model is appealing for studies of recovered cone function.
Translational Relevance:
fMRI assessment of cone driven cortical response provides a tool to translate cell/gene therapies for vision restoration.
Insights
Functional MRI in dogs assesses cone vision restoration for inherited retinal diseases. The NPHP5-CRD2 model shows promise for gene therapy studies aiming to recover cone function.
Area of Science:
- Ophthalmology
- Neuroscience
- Genetics
Background:
- Canine models of inherited retinal degeneration are crucial for evaluating gene and cell therapies aimed at restoring cone-mediated vision.
- Assessing post-retinal responses to cone-directed stimuli is key to understanding visual pathway integrity.
Approach:
- Functional magnetic resonance imaging (fMRI) and pupillometry were employed to analyze visual responses in wild-type (WT) dogs and three distinct inherited retinal degeneration models (PDE6B-RCD1, RPGR-XLPRA2, NPHP5-CRD2).
- Stimuli were temporally spectrally modulated to selectively target canine L/M-cones, S-cones, rods, luminance pathways (L+S), chrominance pathways (L-S), and all photoreceptors (light flux).
Key Points:
- Pupil responses in WT dogs confirmed cone-driven signals for light flux, luminance, and rod stimuli.
- fMRI revealed distinct cortical responses to luminance and chromatic stimuli in WT and RCD1 dogs.
- Cone-directed stimulation responses were diminished in XLPRA2 models and absent in CRD2 models, highlighting the impact of specific genetic defects.
Conclusions:
- Cone-directed stimulation via fMRI effectively measures luminance and chrominance pathway integrity in the canine visual system.
- The NPHP5-CRD2 model demonstrates potential for studying recovered cone function following gene augmentation therapy.
- fMRI assessment of cone-driven cortical responses offers a valuable tool for translating vision restoration therapies.
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