Learning induces persistent chromatin loops underlying robust gene expression during memory recall.

Area of Science:

• Neuroscience
• Molecular Biology
• Genomics

Background:

• Long-term memories are stored in neuronal ensembles known as engrams.
• The molecular basis and persistence of engram cell traces within neuronal nuclei remain largely unknown.

Purpose of the Study:

• To investigate persistent molecular traces, specifically chromatin folding and DNA methylation, in hippocampal engram neurons after fear conditioning.
• To understand the enduring epigenetic and genomic changes associated with long-term memory storage and recall.

Main Methods:

• Employed activity-dependent nuclear tagging in vivo to profile single hippocampal neurons.
• Analyzed higher-order chromatin folding (3D genome architecture) and DNA methylation patterns.
• Examined these molecular features up to one month post-contextual fear conditioning (CFC).

Main Results:

• Identified significant, persistent, and genome-wide chromatin loop plasticity, including gained and lost loops, in engram neurons after CFC.
• Observed minimal persistence of DNA methylation changes at promoters and enhancers.
• Found that persistently altered loops connect regulatory elements to genes, correlating with robust gene expression changes during memory recall in specific neuronal subtypes.

Conclusions:

• Enduring chromatin traces, rather than DNA methylation, represent persistent molecular markers of engram cells storing long-term memories.
• These persistent genomic alterations are linked to specific gene expression patterns crucial for memory recall.
• The findings suggest a role for persistent chromatin structures in synaptic gene regulation relevant to neuropsychiatric disorders like PTSD and autism.