Friday, May 9, 2025
5/9/2025
Retinal mechanisms underlying the optokinetic reflex - PROJECT SUMMARY/ABSTRACT There is a fundamental gap in the mechanistic understanding of the optokinetic reflex (OKR), used in the clinic to diagnose a variety of visual and neurological disorders. The OKR provides a unique system in which the visual system input, and eye movement output, are well-controlled and quantifiable, and the information bottleneck at dedicated ganglion cell types is accessible. The long-term goals are to reveal the mechanistic basis of the OKR from the molecular programming of circuit wiring to computations to stimulus (in)dependence and to translate this knowledge into diagnostics. The overall objective of this proposal is to determine how the individual and population properties of two specific ganglion cell types influence eye movements. This proposal’s focus is on the vertical OKR, which is subserved by up/Superior and down/Inferior preferring ON direction selective ganglion cells (Superior and Inferior oDSGCs). Preliminary work leads to a central hypothesis: The vertical OKR is influenced by properties that can be traced to retinal direction selective circuits and specifically, motion encoding in Superior and Inferior oDSGCs individually and as a population. Previous studies show that the OKR is contrast sensitive and asymmetric, with higher gain in the up vs. down directions. Differences in intrinsic properties, e.g., dendritic morphology, and synaptic inputs can explain these phenomena with contrast sensitive spike tuning curves and greater responses in Superior vs. Inferior oDSGCs. Recent single-cell sequencing supports the asymmetry with identification of differentially expressed genes in Superior vs. Inferior oDSGCs, including molecular guidance cues that could be integral to the development of direction selective circuits. We propose to examine the fundamental molecular and computational mechanisms that support and preserve the vertical OKR across diverse stimulus statistics. We will achieve this by (1) using mouse genetics to elucidate the molecular processes that construct and maintain direction selective circuitry, and (2) measuring oDSGC population responses and OKR in the context of stimulus perturbations including noise. (Aim 1) Identify essential signaling pathways for the development of direction selective circuits and the OKR, and (Aim 2) Elucidate the mechanisms of noise correlations among populations of oDSGCs and their impact on the OKR. The aims will be accomplished by using stimulus manipulations, genetic perturbations, cellular physiology, circuit mapping, and computational modeling to identify characteristics of the reflex, their potential mechanistic basis, and their stability or adaptability under different visual environments. The expected outcomes for Aim 1 will be a concise link between molecules, retinal circuits, and behavior, and for Aim 2 will be insight into how stimulus statistics, including noise correlations, influence behavior. The proposed work is significant because it will reveal—from molecules to behavior—how cells, circuits, computations, and their behavioral output operate in health and change in disease in an evolutionarily conserved system with the potential for clinical application of knowledge gained in this proposal.
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