DESCRIPTION (provided by applicant): The human visual system has a remarkable capacity to detect differences in contrast (i.e., differences in luminance across space or time) as small as 1:500. This ability underlies the performance of everyday visual tasks such as reading, driving, and face recognition. Indeed, deficits in contrast sensitivity are used as diagnostic signs for the assessment of retinal disease. Despite its importance, the underlying cellular and network mechanisms that encode and limit contrast sensitivity remain elusive. Past work has assigned the photoreceptor frequency response as one mechanism that limits temporal contrast sensitivity (TCS); however, this has not been demonstrated empirically. The goal of this proposal is to determine how rod photoresponse kinetics contributes to visual TCS in mesopic conditions, when rod photoreceptors integrate the response of multiple photoisomerizations. The underlying hypothesis is that rod inactivation kinetics constrains TCS by limiting the speed of the responses of rods to light decrements. To test the hypothesis, a novel operant behavioral assay was developed which establishes in mouse a model of human temporal vision that matches fundamental properties of human visual psychophysics. In the operant assay, mice are trained to detect and respond to a flickering visual stimulus, an action that requires cortical inpt and decision-making. The preliminary data collected with the operant behavior assay suggest that transgenic mice with fast rod inactivation kinetics have higher temporal contrast sensitivity than control mice. Combined with standard electrophysiological tools and transgenic models, the behavioral assay allows dissection of the contributions of rod kinetics to vision. Aim 1 test how rods respond to dynamic stimuli and what impact adaptation mechanisms have on the sensitivity to different frequencies of stimulation in mesopic light levels. Aim 2 tests the contribution of rod photoresponses kinetics to visual (behavioral) contrast sensitivity. Aim 3 test retinal and visual temporal contrast sensitivity in a rhodopsin P23H mouse model of retinitis pigmentosa to test the hypothesis that mutant mice harboring this mutation will exhibit higher TCS than control mice. We predict this because patients and mouse models harboring the P23H rhodopsin mutation exhibit faster rod recovery responses than control subjects. Results of this aim may well provide proof-of-principle for an early and practical visual function test that i diagnostic of certain forms of autosomal dominant retinitis pigmentosa. This project will be significant because it will help understand 1) the contributions of rod kinetics to visual TCS in normal and diseased retinas, and 2) provide insights into the dynamic retinal interactions between rod and cone signals that determine the temporal, spatial, and spectral sensitivities of mesopic vision. The proposed research is innovative, because it examines visual prope...