# Synaptic and circuit mechanisms of compensation following loss of cone inputs in the mature retina

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $561,584

## Abstract

PROJECT SUMMARY/ABSTRACT
More than 50% of cones can be lost before vision degrades, a discrepancy which can prevent earlier diagnosis
of retinal diseases. A gap exists in understanding the relationships between the degrees of cone loss and impact
on specific visual circuits and behavior. Rigorously establishing such links would benefit earlier diagnosis and
treatment monitoring. Barriers to understanding these relationships and to the long-term goal of improving
diagnosis and treatment of photoreceptor degenerations, include (1) simultaneous examination of a visual
behavior and its underlying physiology in ganglion cells specialized for that visual behavior; and (2) identification
of factors that influence vulnerability. To address the knowledge gap, this proposal will pursue the following
objectives: (1) Define links among the degree of cone deficit, the fidelity of a visually-evoked behavior, and the
physiological properties of specific ganglion cell types that underlie that behavior, and (2) Identify factors that
enable the prediction of the relative vulnerability of ganglion cells to cone loss. Our central hypothesis is that the
optokinetic reflex can provide an accurate psychophysical reflection of cone loss, and further, that ganglion cells
with more original cone inputs are uniformly more vulnerable to cone loss than ganglion cells with fewer cones.
This is bolstered by evidence that the most sensitive retinal ganglion cells can be resilient to 50% cone loss,
particularly when its dendritic field is smaller, which implicates cell size as a determinant of resilience.
Additionally, prior work has identified a reflexive behavior exclusively driven by ON direction selective ganglion
cells (oDSGCs), identifying a system to link graded cone loss in a specific circuit from ganglion cell to behavior.
Furthermore, the vertical optokinetic reflex has more robust eye movements in the superior vs. inferior directions,
which can be attributed to asymmetric excitatory synaptic inputs to oDSGCs, with greater excitation to superior
preferring than the inferior preferring oDSGCs. This visual reflex will be used to understand how original cone
inputs influence the vulnerability of a circuit and ultimately a behavior. The hypothesis will be tested in the
following aims: (Aim 1) Determine how varying degrees of cone loss affects a specific behavioral readout and
the underlying population of ganglion cells critical to that behavior, and (Aim 2) Identify circuit mechanisms that
determine the vulnerability of specific ganglion cell types to partial cone loss. The aims will be accomplished by
inducing graded cone loss, single-cell retinal physiology, quantifying a visual reflex, and computational models.
The significance includes (1) a systematic definition of how a circuit performs at specified degrees of input loss,
and (2) knowledge about circuit mechanisms that influence ganglion cell vulnerability. The positive impact of this
work is to enable the prediction...

## Key facts

- **NIH application ID:** 10881549
- **Project number:** 2R01EY029772-06A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Felice A Dunn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $561,584
- **Award type:** 2
- **Project period:** 2019-02-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881549

## Citation

> US National Institutes of Health, RePORTER application 10881549, Synaptic and circuit mechanisms of compensation following loss of cone inputs in the mature retina (2R01EY029772-06A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10881549. Licensed CC0.

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