Linking rare primate ganglion cells to downstream visual functions

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ABSTRACT Retinal ganglion cells (RGCs) provide the sole source of visual information to the brain and form the building blocks for all downstream vision. In primates, considerable progress has been made in characterizing the three most common RGC types, which make up 80% of the retinal output, and much less is known about the remaining 15+ rarer RGC types. A key barrier to progress has been the difficulty of targeting these rare RGCs in acute experiments. These challenges have been overcome with an approach for visualizing the structure and function of foveal RGCs in the living macaque eye by combining calcium imaging, retrograde tracers and fluorescence adaptive optics scanning light ophthalmoscopy (FAOSLO). FAOSLO imaging is non-invasive and enables study of the same RGC populations for months or years. This technique has enabled in vivo classification of foveal RGCs to identify the elusive rarer types. This proposal aims to extend the capabilities of FAOSLO imaging to directly test the roles of these rare RGCs in vision while establishing the foundation for an independent research career. Aim One will implement high-speed scanning strategies and voltage indicators to read the retinal code in the living eye and achieve the temporal resolution necessary to study rare motion-sensitive RGCs. Aim Two will directly test the hypothesis that the rare ON direction selective RGC type contributes to optokinetic eye movements in primates using targeted laser lesions of individual RGCs. Aim Three will establish a paradigm to isolate rare RGCs and the visual functions they mediate through transneuronal retrograde degeneration following V1 lesions. This line of investigation will also clarify the timeline of RGC loss and the underlying physiological changes that occur in RGCs following V1 damage in strokes. The research goals of this proposal are reinforced by a comprehensive training plan that will provide the new skills and knowledge necessary to achieve the candidate’s research goal of establishing the links between rare primate RGCs and visual functions. The candidate will carry out the mentored phase with Dr. David Williams, a pioneer in the use of adaptive optics for imaging the eye. Co-mentor Dr. Bill Merigan will contribute expertise in behavioral experiments, lesions and viral vectors. Additional training from a first-rate advisory committee (Drs. Krystel Huxlin, Tony Movshon and Jesse Schallek) will put the candidate on a strong pathway to independence. Together, the research and training proposed will facilitate the candidate’s successful transition to a tenure-track faculty position at a research- intensive university.