Human and rodent imaging studies show that experience can lead to task-specific increases in brain structure, but the cellular and molecular basis of these changes is unknown. Here, we test the hypothesis that the these volume changes depend on the same signaling pathways required for learning and memory formation. We exposed mice lacking CREB (a transcription factor critical for memory) to an enriched housing environment, and imaged their brains longitudinally over two weeks. Surprisingly, enrichment altered the neuroanatomy of all mice, regardless of CREB genotype. These findings provide evidence that the volume changes are due to CREB-independent processes.