Research How does the brain make some memories last a lifetime?

Why do we remember some moments forever—like our graduation—while others, like what we had for lunch last week, fade away? Memory persistence relies on a process called systems consolidation, where new memories, initially stored in the hippocampus, gradually become stabilized in the cortex for long-term storage. However, the molecular mechanisms driving this transition have remained elusive—until now.

A new study led by Prof. Dr. Ana M.M. Oliveira and colleagues at the Interdisciplinary Center for Neurosciences (IZN) has identified DNA methylation as a key regulator of memory persistence. Their findings, published in Biological Psychiatry, show that Dnmt3a2, an enzyme responsible for adding methylation marks to DNA, plays a crucial role in determining whether a memory lasts for days or a lifetime.

Using advanced genetic tools and behavioral experiments in mice, the researchers demonstrated that increasing Dnmt3a2 levels in the hippocampus transformed short-lived memories into persistent ones. This molecular switch facilitated stronger reactivation of cortical engrams—the groups of neurons that store a memory—showing that DNA methylation promotes memory transfer and stabilization in the cortex. Conversely, blocking hippocampal DNA methylation had the opposite effect: it weakened memory persistence and disrupted cortical engram maturation, without affecting the hippocampus itself.

These findings provide the first direct evidence that DNA methylation in the hippocampus does not just encode memory but actively dictates its duration by enabling cross-brain communication between the hippocampus and cortex. This research not only deepens our understanding of memory storage in healthy brains but could also open new therapeutic avenues for cognitive disorders affecting memory stability.

The study was funded by the German Research Foundation (DFG), the Chica and Heinz Schaller Foundation (CHS), and the Joachim Herz Foundation.