Chromatin plasticity contributes to neuronal selection during memory allocation

Memory allocation refers to the process by which neurons are recruited into the encoding ensemble to store learned information. This recruitment is regulated by neuronal selection based on differences in intrinsic excitability (IE) and the expression of the transcription factor CREB. However, whether other forms of plasticity influence memory allocation remains unknown. Here, we found that chromatin compaction and histone acetylation in the mouse lateral amygdala display a high degree of heterogeneity, a prerequisite for neuronal selection. Consequently, when we increased histone acetylation by overexpressing histone acetyl transferases (HATs), neurons with elevated histone acetylation were preferentially recruited into the encoding ensemble and memory retention was enhanced, while optogenetic silencing of the epigenetically altered neurons prevented memory expression. Mechanistically, using patch-clamp recordings and single-nucleus multi-ome sequencing, we observed that HAT overexpression increased IE and epitranscriptomic changes favoring synaptic plasticity. Lastly, by merging FRET-based epigenetic beacons with calcium indicators to simultaneously record histone acetylation and neuronal dynamics in real time, we found that epigenetic heterogeneity underlies IE in cell-autonomous manner. These results identify chromatin plasticity as a key factor catalyzing memory allocation. Overall design: Single-nuclear sequencing of mouse brain lateral amigdala.