An optimized optokinetic behavioral assay to assess central nervous system function in mice

In humans, there are five general classes of eye movements: saccades, smooth pursuit, vergence, the vestibular-ocular reflex (VOR), and the optokinetic reflex (OKR). In vertebrates, the VOR and OKR are the most conserved eye movements and have been described in a number of mammals including mice, cats, rabbits, monkeys and humans. With the introduction of targeted and transgenic technology, there is a high premium on identifying phenotypes in targeted and transgenic mice. Here I describe a computer-assisted optokinetic behavioral assay to rapidly identify CNS defects in mice.;Using this system, I quantified the basic stimulus-response properties in two different mouse strains - C57B1/6J and 129Sv/Ev. I showed that the mouse OKR is a conjugated response and it is direction selective - preferring stimuli moving in the temporal to nasal direction. With a series of targeted and transgenic mice, I determined the photoreceptors required for the OKR response. Furthermore, I identified the functional role two genes in vision - Brn3b and Frizzled-4.;To address whether the OKR could be used to assess central nervous system deficits, I tested the effect of several CNS drugs on mouse eye movements. I observed that several drugs, including gabapentin and anandamide, disrupted OKR without disturbing general motor acitivity, as measured by the rotorod. Several other stereotyped eye movements were generated in drug-induced states - including changes in the slow component of the OKR (ketamine and baclofen) and spontaneous eye movements (cocaine and memantine).;The final series of experiments utilized the OKR as a behavioral measure to assess restoration of vision. In these experiments, we tested mice with no functional light response before and after the delivery of a Channelrhodopsin-2 virus. We observed a very inefficient restoration of the direct light response (1/24) and no restoration of image forming responses with the OKR.;In my thesis, I put forth a novel OKR technology to identify visual and central nervous system function in a variety of experimental paradigms including phenotyping visual defects in gene targeted and transgenic mice, identifying CNS deficits under drug-induced mental states, and quantifying the severity of CNS disease in mouse models.