Acquisition of a novel behavior induces higher levels of Arc mRNA than does overtrained performance.

Arc (also termed activity-regulated cytoskeleton-associated protein or Arg3.1), is an effector immediate early gene whose upregulation has been demonstrated during events of synaptic plasticity. In the present study, the possibility that Arc would be specifically upregulated in rats during the acquisition of a quickly learned behavioral task but not in overtrained animals was investigated. Three groups of rats, pseudotrained, newly trained and overtrained, were examined with respect to Arc expression following training on a simple operant lever-pressing task. Newly trained animals were killed 30 min following the session in which they demonstrated acquisition of the task, and overtrained animals were trained on the same task for 13-14 days and then killed. Relative to base level measures taken 6 h following the session, all three groups demonstrated significant levels of induction of Arc mRNA; however, newly trained animals exhibited heightened induction of Arc mRNA relative to both pseudotrained and overtrained animals. The increased levels of Arc mRNA in newly trained animals were located in the CA1 and CA3 fields of hippocampus, the subiculum, and the anterior cingulate, piriform, infra/prelimbic, perirhinal and entorhinal cortical areas. Additionally, Arc mRNA was expressed differentially across the above anatomic structures in a relative pattern that was the same in all three groups. Finally, levels of Arc mRNA in specific brain regions of newly trained animals correlated negatively with the rate of task acquisition, such that slow learners exhibited higher levels of Arc mRNA than fast learners. From these results we suggest that Arc is upregulated in an experience-dependent manner, with higher levels of induction occurring during the initial stage of learning. Furthermore, the finding of increased Arc levels in slow versus fast learners indicates that Arc expression may be associated with the length of time required to: (1) form new associations or (2) remodel existing connections. These results confirm other reports that Arc is a critical substrate for the synaptic plasticity underlying the acquisition of new behaviors.