Current evidence indicates reorganization of motor cortex in association with motor behavior. To investigate the molecular basis for these changes rats were fitted with limb-restricting vests which forced the use of one forelimb for 10 days. Using cDNA macroarrays, expression profiles of the corresponding motor cortices connected to the overused and immobilized limbs were analyzed. In the overused motor cortex up-regulations were observed exclusively, including genes coding for voltage-gated ion channels, trafficking and targeting proteins, and intracellular kinase network members (10 genes). In the contralateral immobilized cortex changes were restricted to down-regulation, mainly involving genes pertaining to DNA-binding, translation, neuronal signaling and metabolic pathways (9 genes). At least some of these changes are likely to represent the molecular substrate of use-dependent plasticity, NeuroReport 13:953-956 (C) 2002 Lippincott Williams Wilkins.