PROJECT SUMMARY Visual information is transferred from the eye to the brain through ON and OFF pathways that signal the presence of light and dark features in visual scenes. ON and OFF pathways are present in all animals with image-forming visual-systems including flies and primates, however, we still have a poor understanding of how they interact in visual processing. While neuroscience textbooks describe ON and OFF pathways as sharing equal cortical space, recent work has demonstrated that the OFF pathway greatly dominates cortical responses. We hypothesize that this cortical OFF dominance originates from a difference in the contrast response function between ON and OFF pathways that we recently discovered. Because contrast saturation is more pronounced within the ON pathway, light stimuli are spatially distorted and less effective at driving cortical responses than dark stimuli, which causes the cortex to be OFF dominated. Because of this greater spatial distortion for lights, we predict that ON/OFF differences in contrast saturation will have major implications not only in cortical function but also in human visual perception and visual disease. Therefore, this proposal uses the differences in ON/OFF contrast saturation as a conceptual framework to predict and investigate how cortical OFF dominance changes under different stimulation conditions and the implications of these changes for the perception of lights and darks. Our conceptual framework predicts that cortical OFF dominance will increase when the image is out of focus either because of normal changes in lens accommodation (e.g. blurred background when fixating a target at close distance) or visual disease (e.g. amblyopia, myopia). In turn, cortical OFF dominance will decrease when seeing high spatial frequencies with high mean luminance, which are common outdoors. To test our predictions and investigate the dynamics of ON and OFF cortical function, we will measure the responses of cortical single neurons to dark and light targets under a large variety of stimulus conditions (e.g. different contrasts, spatial frequency, mean luminance, luminance distribution). We will then use the same stimulus conditions to measure changes in light/dark visual acuity and visual salience in humans. To fully characterize cortical responses of single neurons to multiple stimulus dimensions, we will use an innovative multielectrode array that we have been developing over the past years to record from well-isolated single neurons for prolonged periods of time. This novel technical approach allows us to obtain an unprecedented characterization of the stimulus space that modulates ON/OFF signaling by testing a large combination of stimulus conditions that could not be fully explored with previous methods.