Project Summary This proposal stems from discoveries made during the last project period, the goal of which was to understand the high-gain state of the primary visual cortex (V1) that was turned on during locomotion in mice. During the current project period we discovered, among other things, that the high-gain state of the visual cortex is mediated by the action of local vasoactive intestinal peptide positive (VIP) interneurons. This circuit gates rapid plasticity in visual cortical responses that is stimulus-specific, cell-specific, and persistent at least for weeks in adult mice. The major hypothesis to be tested in the current proposal is that this form of stimulus- specific plasticity in primary visual cortex is a substrate of visual perceptual learning. The present proposal seeks first to elucidate the properties of this form of adult plasticity that are relevant to perceptual learning, specifically its specificity for stimulus configuration and retinal locus. Second, it seeks to understand the cellular signaling mechanisms responsible for this plasticity and to determine whether its persistence is due of rewiring of excitatory and inhibitory connectionsa in the visual cortex. Finally, it seeks to measure the specificity of visual perceptual learning in mice behaviorally and to determine whether the VIP-cell circuit that enhances responses and neural plasticity is a substrate of visual perceptual learning. The findings from this study may guide approaches to therapy for amblyopia and dyslexia.