Abstract

Retinal ganglion cells (RGCs) form the only connection between the eye and the brain via their axons in the optic nerve. In diseases such as glaucoma, RGCs undergo irreversible neurodegeneration leading to vision loss. RGCs consist of multiple types differing in morphology, gene expression, and signaling properties. Moreover, these types exhibit differential survival after axon injury. What cellular properties vary between RGC types that could underlie their heterogeneous response to neurodegeneration? Given that energy metabolism is tightly optimized for the homeostatic and active functions of different neurons, physiologically distinct RGC types likely exhibit divergent energetic characteristics. Furthermore, energy metabolism is known to influence the cellular response to neurodegeneration. We therefore asked whether distinct RGC types exhibit differences in energy metabolism that relate to their resilience. To study energetic heterogeneity in the murine RGC population at single cell resolution, we performed transpupillary in vivo imaging of RGCs expressing a genetically-encoded fluorescent ATP biosensor. Correlating in vivo imaging with post hoc immunostaining enabled determination of RGC type. We found that Alpha RGCs (aRGCs), a known well-surviving type, had lower baseline ATP compared to other types. Paradoxical to this observation, aRGCs had higher expression of mitochondrial electron transport chain (ETC) components, and demonstrated the highest rate of activity-dependent ATP consumption under ETC inhibition. However, although pharmacologic activation or silencing showed that population-wide mean ATP depended on activity, inter-RGC ATP differences were not affected by activity changes, suggesting that factors other than activity may determine baseline ATP levels. We also found that low baseline ATP is correlated with increased RGC survival after optic nerve crush; this relationship persists even after accounting for the enrichment of highly resilient aRGCs among the surviving population. Taken together, these data suggest that ATP metabolism is divergent across RGC types and is a feature that correlates with survival after axon injury. Future works should seek to understand the basis of baseline ATP differences within the RGC population and mechanisms leading to neuronal resilience.

Committee Chair

Rajendra Apte

Committee Members

Philip Williams

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

3-12-2026

Language

English (en)

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Available for download on Friday, September 11, 2026

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Neurosciences Commons

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