Dynamics of immediate-early gene induction in hippocampal neural ensembles: Relationship to context memory formation and retrieval

Since their discovery, immediate-early genes (IEGs) have been integral to defining the molecular mechanisms involved in long-term memory (LTM) formation. Initial studies illustrated that transcription of IEGs was dependent on many of the same cellular pathways engaged during a learning event. In parallel, these experiments were complemented with loss-of-function studies confirming the necessity of IEG proteins for memory consolidation. In addition to elaborating the mechanisms of LTM formation, detection of IEGs has been adapted to visualize neuronal populations activated by a discrete event, such an exposure to an environmental context. Surprisingly, however, there is little data on the behavioral relevance of such ensemble specific activation of IEGs. This shortcoming mainly arises from previous gene imaging studies not measuring an animal's memory in tasks used to elicit IEG expression. To address this deficiency, we examined transcriptional activation of IEGs in hippocampi of rats exposed to an environmental context. The exposure parameters were strongly rooted in well defined memory tasks, which require hippocampal function and formation of an incidental context memory. In this way, the behavioral relevance of the cell imagining results was easily related to formation of a contextual representation. Incidental encoding was an important consideration because it allowed us to assess IEG expression that was strictly related to context exposure. Using this approach, the first 2 chapters revealed that IEG activation reached maximal levels in CA3 and CA1 ensembles with a 30 second exposure to context, which corresponded to the time required for rats to acquire context conditioning. Moreover, these experiments showed that hippocampal IEG activation was driven by exposure to the context and not an association between the context and shock. Findings from chapter 4 extended these results by demonstrating that hippocampal neural activity associated with rapid retrieval of context memory does not drive IEG expression. Results from chapter 5 determined that discriminatory context memory was associated with IEG expression in orthogonal CA1neuronal ensembles. Together, these findings provide a necessary link between IEG activation within specific neural ensembles and memory. In addition, these studies further our understanding on the mechanisms of LTM formation and the behavioral regulation of IEGs.