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...