We examined whether increasing retrieval difficulty in a spatial memory task would promote the recruitment of the anterior cingulate cortex (ACC) similar to what is typically observed during remote memory retrieval. Rats were trained on the hidden platform version of the Morris Water Task and tested three or 30 d later. Retrieval difficulty was manipulated by removing several prominent extra-pool cues from the testing room. Immediate early gene expression (c-Fos) in the ACC was greater following the cue removal and comparable to remote memory retrieval (30-d retention interval) levels, supporting the view of increased ACC contribution during high cognitive-demand memory processes.[Supplemental material is available for this article.]Long-term systems consolidation suggests that memories that are initially dependent on the hippocampus (HPC) become increasingly represented in other cortical structures over time, such that they can eventually survive complete HPC damage (Squire and Alvarez 1995;Frankland and Bontempi 2005). The anterior cingulate cortex (ACC) is one structure that is thought to come to support these HPC-independent memories. This is based largely on findings suggesting that inactivation or damage to the ACC impairs the recall of remote memories while sparing recent ones Teixeira et al. 2006;Ding et al. 2008) and that the ACC shows greater activation during recall of a remote memory than a recent one. For example, Teixeira et al. (2006) found that the retrieval of a remote (1 mo old) spatial memory in mice elicited greater expression of the immediate-early genes c-Fos and zif268 in the ACC than retrieval of a recent (1 d old) memory, concluding that spatial memory becomes consolidated and dependent on the ACC over a protracted period of time.Although these previous findings suggest that the ACC contributes to the recall of remote memories, these observations could be alternatively explained by the increased cognitive demand that would follow the retrieval of older and temporally degraded memories (Rudy et al. 2005). Specifically, Rudy et al. (2005) proposed that memories, through either forgetting or interference, become weaker with the passage of time, which in turn requires greater cognitive effort for successful retrieval. This increase in cognitive demand would also cause the recruitment of additional cortical structures, including the ACC, in order to overcome the retrieval difficulty. According to this view, the ACC would not be directly involved in long-term systems consolidation and the storage of remote memories per se, but would play a key role in additional cognitive processes associated with the retrieval of remote memories. The aim of this study was to assess whether the ACC is indeed recruited under retrieval conditions that require greater cognitive processing.If the role of the ACC in remote memory is due to an increase in cognitive processing to compensate for the retrieval difficulty of a degraded memory, then it should be possible to increase ACC activation for a recent memory b...