TRANSCRIPTIONAL DAMPENING MAY GATE THE TEMPORAL WINDOW FOR MEMORY LINKING

The formation of long-term memories requires the orchestration of specific neuronal activity-induced patterns of gene expression. While most transcriptional changes return to baseline levels within hours of the initial neuronal activation, the associated epigenetic modifications persist long after. This has been proposed to constitute a memory priming mechanism, potentially facilitating the reactivation of engram neurons upon memory recall. However, direct functional evidence supporting this hypothesis remains lacking.
In the present work, we aimed at investigating this hypothesis by comparing the gene expression profiles of cultured cortical neurons with different activity history. Unexpectedly, we found that neuronal reactivation results in a dampened induction of activity-regulated genes. This attenuation was associated to the downregulation of the cAMP signalling pathway and of several key players in synaptic scaling, both at the transcriptional and epigenetic level.
Although these findings do not support the initial memory priming hypothesis, they align with the biology of memory linking. The reduced transcriptional response upon reactivation, along with its underlying molecular mechanisms, may contribute to explain how the temporal window for neuronal co-allocation of different memories in a given ensemble is closed. Current efforts aim at manipulating these candidate mechanisms in vivo to understand their role in memory linking.