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Abstract

Memory formation is a complex process regulated by various molecular mechanisms, including unique transcriptional signatures and epigenetic factors. In addition, the brain is equipped with mechanisms that not only promote, but actively constrict memory formation. While the role of epigenetic modifications, such as DNA methylation, in cognition has been established, there are still significant gaps in our understanding of the specific functions of individual DNA methyltransferases (Dnmts) and how their downstream effectors orchestrate memory. Moreover, the molecular mechanisms underlying memory persistence and memory suppression remain largely unexplored. I investigated the role of specific Dnmts in long-term memory formation, highlighting their unique functions and downstream effects. Additionally, I explored how DNA methylation contributes to the transfer of information from the hippocampus to the cortex for long-term storage and the stabilisation of cortical engrams to drive memory persistence. First, I examined the involvement of Dnmt3a1, the predominant Dnmt3a isoform in the adult brain, in hippocampus-dependent long-term memory formation. I identified an activity-regulated Dnmt3a1-dependent gene expression program and found a downstream effector gene (Neuropilin-1) with a previously undescribed function in memory formation. Intriguingly, I found that despite a common requirement for memory formation, Dnmt3a1 and Dnmt3a2 regulate this process via distinct mechanisms - Nrp1 overexpression rescued Dnmt3a1, but not Dnmt3a2, knockdown-driven impairments in memory formation. Next, I investigated the molecular mechanisms underlying memory persistence and systems consolidation, the gradual transfer of information from the hippocampus to the cortex. By modulating DNA methylation processes in the dorsal hippocampus, a short-lasting memory could be converted into a long-lasting one. The applied manipulation resulted in improved reactivation of cortical engrams and increased fear generalisation, mimicking the characteristics of remote memory. These findings provide compelling evidence for the facilitatory role of DNA methylation in memory information transfer to the cortex for long-term storage. Furthermore, I examined the temporal expression patterns of immediate early genes (IEGs), specifically neuronal PAS domain protein 4 (Npas4), and its potential role in memory suppression. My investigation revealed that highly salient stimuli induced a biphasic expression of Npas4 in the hippocampus, with the later phase dependent on NMDA receptor activity. Notably, this later phase of Npas4 expression restricted memory consolidation, suggesting a role in balancing the formation of highly salient memories and preventing the development of maladaptive behaviours. These findings highlighted the intricate regulatory network by which experience salience modulates IEG expression and thereby fine-tunes memory consolidation. Overall, this study uncovered the unique functions of distinct Dnmts in memory formation and persistence and shed light on the associated mechanisms that are responsible to facilitate the transfer of information required for long-term storage. This comprehensive understanding of the molecular processes underlying memory formation contributes to our broader knowledge of memory consolidation and may have implications for therapeutic interventions targeting memory-related disorders.