Animals spent 15 days learning to reliably respond to presentation of the target noise stimulus and then spent 3 days learning to discriminate between the target and distracter noise Alectinib stimuli. During discrimination, the target stimulus was presented during 50% of trials and the distracter stimulus was presented during the remaining 50% of trials. Animals next moved on to NBS-tone pairing and then frequency discrimination learning (Figure 2A). For the low-frequency discrimination tasks, the target sound was always a train

of six tone pips (25 ms duration, 60 dB SPL intensity, 1.78 kHz carrier frequency, presented at a rate of 5 Hz), whereas the distracter sounds differed from the target only in carrier frequency (from 1.9 to 9.5 kHz, or 0.1 to 2.4 octaves above the CS+ stimulus). During Tone Learning for

Experiment 1 (Figure 2A, light gray), the distracter tones were 0.5, 1.0, and 2.4 octaves above the target stimulus. The target tone was presented during 60% of trials, whereas distracter tones were equally represented during the remaining 40% of trials during the first 3 days of training for all rats. Thereafter, the target tone was presented during 50% of trials and the distracter tones were equally represented during the remaining 50% of trials. During Tone Testing (10 days after Tone Learning; see Figure 5) the distracter tones were 0.1, 0.26, 0.38, 0.5, 0.75, 1, 1.5, and 2.4 octaves above the target tone. During Tone BMN 673 clinical trial Testing the target tone was presented during 50% of trials and the distracter tones were equally represented during the remaining 50% of trials. The Pretrained groups learned to perform the and frequency discrimination task before tone exposure. The target tone for this group was again a 1.78 kHz tone train and distracter tones ranged from 0.1 to 1.0 octaves above the

target. During Tone Learning (Figure 3A, light gray), Pretrained rats spent 20 days learning to reliably respond after presentation of the target, and then spent 10 days learning to respond to target tones and ignore a distracter 1.0 octave above the target. During Tone Testing (Figure 3A, dark gray), the distracter tones were 0.1, 0.2, 0.25, 0.32, 0.38, 0.44, 0.5, 0.7, and 1.0 octaves above the target. The target tone was presented during 50% of trials and the distracter tones were equally represented during the remaining 50% of trials. NBS-tone pairing was conducted using previously reported methodology (Kilgard and Merzenich, 1998 and Puckett et al., 2007). All NBS animals and the Pretrained Control group underwent implantation surgery 2–3 weeks before training.