Owls reared wearing prismatic spectacles learn to make adaptive orienting movements. This instructed learning depends on re-calibration of the midbrain auditory space map, which in turn involves the formation of new synapses. Here we investigated whether these processes are associated with differential gene expression, using longSAGE. Newly fledged owls were reared for 8-36 days with prism or control lenses at which time the extent of learning was quantified by electrophysiological mapping. Transciptome profiles were obtained from the inferior colliculus (IC), the major site of synaptic plasticity, and the optic tectum (OT), which provides an instructive signal that controls the direction and extent of plasticity. Twenty-two differentially expressed sequence tags were identified in IC and 36 in OT, out of more than 35,000 unique tags. Of these, only four were regulated in both structures. These results indicate that regulation of two largely independent gene clusters is associated with synaptic remodeling (in IC) and generation of the instructive signal (in OT). Real-time PCR data confirmed the changes for two transcripts, ubiquitin/polyubiquitin and tyrosine 3-monooxgenase/tryotophan 5-monooxygenase activation protein, theta subunit (YWHAQ; also referred to as 14-3-3 protein). Ubiquitin was downregulated in IC, consistent with a model in which protein degradation pathways act as an inhibitory constraint on synaptogenesis. YWHAQ was up-regulated in OT, indicating a role in the synthesis or delivery of instructive information. In total, our results provide a path towards unraveling molecular cascades that link naturalistic experience with synaptic remodeling and, ultimately, with the expression of learned behavior.