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.