Cortical responses after sound discrimination learning were investigated using transcranial flavoprotein fluorescence imaging in mice. Water-deprived mice were trained to discriminate between rewarded (S+) and unrewarded (S-) sound stimuli. After the learning, they were anesthetized, and cortical responses to S+ and S- were recorded in the right auditory cortex. When a pure tone (PT) at 10 kHz and a 10 kHz amplitude-modulated (AM) sound were used as S+ and S-, the cortical responses to S using AM were significantly depressed but those to S- using PT were not. The cortical responses to S+ showed no significant change. Upward frequency-modulated sounds from 5 kHz to 40 kHz (FM up arrow) and downward frequency-modulated sounds from 40 kHz to 5 kHz (FM down arrow) were also used as S+ and S. Cortical responses to S- using FM up arrow and FM down arrow were significantly depressed after learning, while those to S+ were unchanged. No significant change of cortical responses to S using FMs was observed in the left auditory cortex after learning. The learning-induced depression of S using FMs was most clearly observed in the medial part of the tonotopic band to 40 kHz in the right primary auditory cortex, which might be involved in processing FM sounds. (C) 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.