Molecular Mechanisms of Memory Formation and Persistence in the Adult and Aged Brain

Abstract

Memory formation relies on an orchestrated activation of cellular and molecular mechanisms that drive acquisition and consolidation of memories into a stable form. Research of the past decades has begun to elucidate how activation at the synapse promotes communication to the nucleus, where learning-induced gene expression takes place. This genomic response, that also includes post-transcriptional alterations in the newly-synthetized transcripts, is required for long-term memory formation. In in the first sections of this work, we uncovered a role for the Growth Arrest and DNA Damage γ (Gadd45γ) in memory formation and age-related cognitive decline. We showed that Gadd45γ mediates synapse-to-nucleus communication required for induction of activity-dependent gene expression and memory formation. We further identified that the expression of this protein is tightly regulated in hippocampal neurons. Decreasing or increasing Gadd45γ expression compromised activity-dependent gene expression and memory formation. We further discovered that during murine and human aging the hippocampal expression of this protein is dysregulated, suggesting that it may be involved in age-related cognitive decline. In the next section, we identified the alternative splicing program associated with spatial memory formation. We showed that the DNA methylation reader methyl-CpG-binding protein 2 (MeCP2) is required for the accurate induction of alternative splicing in baseline conditions and after learning. These findings place MeCP2 as a key regulator of adult brain function, particularly cognitive abilities. Lastly, we investigated molecular mechanisms underlying memory persistence. We showed that neuronal PAS domain protein 4 (Npas4) expression is induced several hours after persistent memory learning, but not when mice form short-lasting memories. This delayed expression is dependent on N-Methyl-D-aspartic acid (NMDA) receptor activation several hours after learning. Interestingly, artificially inducing Npas4 expression in a short-lasting memory protocol, further accelerated memory decay. These findings suggest that late Npas4 expression might be a mechanism associated with forgetting. Altogether, in this work we discovered new molecular mechanisms of memory formation and persistence in the adult and aged brain.