Retrograde amnesia observed following hippocampal lesions in humans and animals is typically temporally graded, with recent memory being impaired while remote memories remain intact, indicating that the hippocampal formation has a time-limited role in memory storage. However, this claim remains controversial because studies involving hippocampal lesions tell us nothing about the contribution of the hippocampus to memory storage if this region was present at the time of memory retrieval. We therefore used non-invasive functional brain imaging using (14C)2-deoxyglucose uptake to examine how the brain circuitry underlying long-term memory storage is reorganized over time in an intact brain. Regional metabolic activity in the brain was mapped in mice tested at different times for retention of a spatial discrimination task. Here we report that increasing the retention interval from 5 days to 25 days resulted in both decreased hippocampal metabolic activity during retention testing and a loss of correlation between hippocampal metabolic activity and memory performance. Concomitantly, a recruitment of certain cortical areas was observed. These results indicate that there is a time-dependent reorganization of the neuronal circuitry underlying long-term memory storage, in which a transitory interaction between the hippocampal formation and the neocortex would mediate the establishment of long-lived cortical memory representations.

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The present study analysed the effects of the stage of learning of an appetitive operant conditioning task on the spatial and temporal patterns of c-Fos protein levels in the brain of BALB/c mice. c-Fos levels were assessed by immunohistochemistry at either 60, 120 or 180 min after either the first, the second or the fifth daily training session and compared to sham animals. The results show an increase of c-Fos-positive nuclei in several subcortical and cortical brain regions, 60-min post-acquisition. Because these activations were a function of task mastery, the data indicate that they were specifically related to learning. Following the first acquisition session, significant increases in c-Fos-positive neurons were observed in the dorsal hippocampus (CA3), anterior cingulate, occipital and parietal cortices. Following the second daily training session, c-Fos was highly expressed in some subcortical regions, the hippocampus, the subiculum, the entorhinal, and posterior cingulate areas. Moreover, a significant correlation was found between the progression of performance from day 1 to day 2 and c-Fos expression on the hippocampal CA1 subfield. Following complete acquisition, no further task-dependent increases in c-Fos-labelled nuclei was observed in any brain region sampled, suggesting that the intervention of c-Fos-induced mechanisms in the consolidation process were terminated. The training stage-dependent changes in regional post-training c-Fos expression in the hippocampus and the connected limbic regions suggest that this neuronal network is actively engaged in memory consolidation processes.