Tuesday, June 2, 2026 · 3:00 PM
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Title: Memory Encoding Reprograms Neuronal Transcriptional Responses Via Durable Chromatin Remodeling
Abstract: The mammalian brain’s long-term memory circuits integrate information from prior and new experiences. The medial prefrontal cortex (mPFC) plays a crucial role in this process and can reliably store information for weeks to months in rodents and over years in humans. To maintain information over these extended timescales, the neural encoding of remote memories involves persistent synaptic, transcriptional, and epigenetic changes that outlast the more transient forms of molecular activation that occur in the initial minutes to hours of memory storage. However, whether these persistent effects include long-lasting changes to chromatin structureand whether chromatin states mainly reflect prior episodes of neural activation or retune transcriptional responses to future bouts of activation remain unknown. Here we show that mPFC neurons engaged during the initial formation of memory undergo progressive changes in chromatin accessibility over the first four weeks of memory storage, evincing long-lasting modifications to the genetic programs activated during subsequent memory retrieval.
In mice with contextual fear memory, we performed genetic trapping and single cell multiomic sequencing analyses of mouse mPFC engram neurons activated during fear conditioning. In the absence of subsequent memory recall, memory storage-related changes to chromatin structure were modestly reflected in gene expression patterns at 7 days and 28 days after fear conditioning. However, upon memory recall, the genetically labelled engram neurons executed distinct transcriptional programs than other neurons of the same genetic types, suggesting that chromatin rearrangements arising during remote memory storage alter the transcriptional control logic by which engram neurons respond to new experiences. These metaplastic changes to transcriptional programs preferentially affect gene-regulatory and post-transcriptional control mechanisms, show enrichment for genetic motifs related to development and cell-state regulation, and downregulate the neuron’s transcriptional responses to future excitation. Thus, rather than merely preserving a molecular record of prior learning, chromatin architectural changes in engram neurons occur over timescales of weeks and appear, in part, to repurpose conserved regulatory machinery to dampen the extent to which these neurons will be involved in further information storage. Based on these findings, we propose that chromatin structural changes provide a slow-timescale component of neural computation.
Please contact Sofia Rakicevic-More for the Zoom link.
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Munzer Auditorium 279 Campus Drive W, Stanford, CA 94305
When
Tuesday, June 2, 2026 · 3:00 PM