Working memory is a temporary memory store where information is held briefly until the appropriate behavior is produced. However, the improvement in the performance of working memory tasks with practice over days points to the existence of a long-lasting component associated with learning strategies that lead to optimal performance. Here we show that the improvement in the performance of mice in a radial maze working memory task required the integrity of the medial prefrontal cortex (mPFC). We further demonstrate that this improvement of working memory performance requires the synthesis of de novo proteins in the mPFC. We suggest that in addition to storing memory briefly the mPFC is also involved in the consolidation and storage of the long-term learning strategies used in working memory.anisomycin ͉ mice ͉ prelimbic/infralimbic ͉ radial maze M ore than half a century ago, Hebb (1) proposed a dualtrace theory of memory in which he distinguished between short-term memory, a memory of recent events, and long-term memory, a memory of events that occurred in the past. Hebb proposed that the reverberating circuit of neuronal activity underlies short-term memory and that stabilization of this activity produces long-term memory. This dual-trace theory of memory found further support in the finding that inhibition of protein synthesis with antibiotics did not prevent the animals from learning tasks but disrupted their long-term memory (for example, see ref.2). It is now widely accepted that there are at least two stages of memory: (i) short-term memory that temporarily stores information on the basis of changes in preexisting connections due to covalent modifications of preexisting proteins (3) and (ii) long-term memory that stores this information more permanently through the growth of new connections as a result of transcription and translation of certain genes, a process called consolidation (4, 5). A specialized form of short-term memory, called ''working memory,'' was introduced by the cognitive psychologists Baddeley and Hitch (6) to describe the memory that temporarily stores information provided by an environmental cue for the execution of an act in the near term. According to Baddeley and Hitch (6), working memory is the cognitive process that allows moment-to-moment perceptions across time to be integrated, rehearsed, and combined with simultaneous access to archival information about past experience, actions, or knowledge.In primates and rodents, working memory is usually tested in a variety of moment-to-moment tasks in which sensory information is held in memory until a decision is made and the appropriate behavior is produced. However, a hallmark of working memory is that there is improvement in the performance of tasks over days with practice.