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Merigan, W. H.

Publications and source records attributed to Merigan, W. H..

4 recordsLinked to original sources

Asymmetric Activation of Retinal ON and OFF Pathways by AOSLO Raster-Scanned Visual Stimuli

Adaptive optics scanning light ophthalmoscopy (AOSLO) enables high-resolution retinal imaging, eye tracking, and stimulus delivery in the living eye. AOSLO-mediated visual stimuli are created by temporally modulating the excitation light as it scans across the retina. As a result, each location within the field of view receives a brief flash of light during each scanner cycle (every 33-40 ms). Here we used in vivo calcium imaging with AOSLO to investigate the impact of this intermittent stimulation on the retinal ON and OFF pathways. Raster-scanned backgrounds exaggerated existing ON-OFF pathway asymmetries leading to high baseline activity in ON cells and increased response rectification in OFF cells.

neuroscience↗

Cone-opponent ganglion cells in the primate fovea tuned to non-cardinal color directions

A long-standing question in vision science is how the three cone photoreceptor types - long (L), medium (M) and short (S) wavelength sensitive - combine to generate our perception of color. Hue perception can be described along two opponent axes: red-green and blue-yellow. Psychophysical measurements of color appearance indicate that the cone inputs to the red-green and blue-yellow opponent axes are M vs. L+S and L vs. M+S, respectively. However, the "cardinal directions of color space" revealed by psychophysical measurements of color detection thresholds following adaptation are L vs. M and S vs. L+M. These cardinal directions match the most common cone-opponent retinal ganglion cells (RGCs) in the primate retina. Accordingly, the cone opponency necessary for color appearance is thought to be established in cortex. However, small populations with the appropriate M vs. L+S and L vs. M+S cone-opponency have been reported in large surveys of cone inputs to primate RGCs and their projections to the lateral geniculate nucleus (LGN), yet their existence continues to be debated. Resolving this long-standing open question is necessary because a complete account of the coneopponency in the retinal output is critical for efforts to understand how downstream neural circuits process color. Here, we performed adaptive optics calcium imaging to longitudinally, noninvasively measure foveal RGC light responses in the living macaque eye. We confirm the presence of L vs. M+S and M vs. L+S neurons with non-cardinal coneopponency and demonstrate that cone-opponent signals in the retinal output are more diverse than classically thought.

neuroscience↗

In vivo physiology of foveal retinal ganglion cells in Macaca fascicularis

The primate fovea is specialized for high acuity chromatic vision, with the highest density of cone photoreceptors and a disproportionately large representation in visual cortex. The unique visual properties conferred by the fovea are conveyed to the brain by retinal ganglion cells, the somas of which lie at the margin of the foveal pit. Microelectrode recordings of these centermost retinal ganglion cells have been challenging due to the fragility of the fovea in the excised retina. Here we overcome this challenge by combining high resolution fluorescence adaptive optics ophthalmoscopy with calcium imaging to optically record functional responses of foveal retinal ganglion cells in the living eye. We use this approach to study the chromatic responses and spatial transfer functions of retinal ganglion cells using spatially uniform fields modulated in different directions in color space and monochromatic drifting gratings. We recorded from over 350 cells across three Macaca fascicularis primates over a time period of weeks to months. We find that the majority of the L vs. M cone opponent cells serving the most central foveolar cones have spatial transfer functions that peak at high spatial frequencies (20-40 c/deg), reflecting strong surround inhibition that sacrifices sensitivity at low spatial frequencies but preserves the transmission of fine detail in the retinal image. In addition, we fit to the drifting grating data a detailed model of how ganglion cell responses draw on the cone mosaic to derive receptive field properties of L vs. M cone opponent cells at the very center of the foveola. The fits are consistent with the hypothesis that foveal midget ganglion cells are specialized to preserve information at the resolution of the cone mosaic. By characterizing the functional properties of retinal ganglion cells in vivo through adaptive optics, we characterize the response characteristics of these cells in situ.

neuroscience↗

In vivo directed evolution of AAV in the primate retina

Efficient AAV-mediated gene delivery remains a significant obstacle to effective retinal gene therapies. Here, we apply directed evolution - guided by deep sequencing and followed by direct in vivo secondary selection of high-performing vectors with a GFP-barcoded library - to create AAV viral capsids with new capabilities to deliver genes to the outer retina in primates. A replication incompetent library, produced via providing rep in trans, was created to mitigate risk of AAV propagation. Six rounds of in vivo selection with this library in primates - involving intravitreal library administration, recovery of genomes from outer retina, and extensive next generation sequencing of each round - resulted in vectors with redirected tropism to the outer retina and increased gene delivery efficiency to retinal cells. These new viral vectors expand the toolbox of vectors available for primate retina, and may enable less invasive delivery of therapeutic genes to patients, potentially offering retina-wide infection at a similar dosage to vectors currently in clinical use.

neuroscience↗