Temporally-graded Retrograde Amnesia for Cocaine Place Preference Memories following Hippocampal Lesions

Memory is thought to be a dynamic process, as its strength, quality and anatomical organization change as a function of time. The systems consolidation hypothesis of memory postulates that while some memories are initially dependent on hippocampus, they gradually become immune to hippocampal disruptions over time. Although this temporal gradient has been observed in many types of memories, such as contextual fear memories, little is known about the reorganization of contextual drug-associated memory. In the present study, we examined the role of hippocampus in cocaine conditioned place preference (CPP) memory at different time points after conditioning. First, we found that excitotoxic hippocampal lesions impaired recent (1 day), but not remote (30 days) cocaine CPP memory in mice, suggesting that contextual drug-associated memory reorganizes over time, and becomes independent of the hippocampus. However, this remote hippocampus independent memory was disrupted if a reminder (drug+context) was administered one day before surgery, suggesting that a reminder rendered this older memory dependent on the hippocampus. Third, overexpressing myocyte enhancer factor 2 (MEF2), a transcription factor that disrupts structural plasticity, in hippocampus blocked cocaine CPP association, suggesting that structural changes in hippocampus is required to form a contextual drug-associated memory. Together, these studies are a first step in examining whether and how context-drug memories reorganized over time. These results may be particularly important as context-drug associations are implicated in drug relapse.Ph.D