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Memory encodes past experiences, thereby enabling future plans. The basolateral amygdala is a centre of salience networks that underlie emotional experiences and thus has a key role in long-term fear memory formation1. Here we used spatial and single-cell transcriptomics to illuminate the cellular and molecular architecture of the role of the basolateral amygdala in long-term memory. We identified transcriptional signatures in subpopulations of neurons and astrocytes that were memory-specific and persisted for weeks. These transcriptional signatures implicate neuropeptide and BDNF signalling, MAPK and CREB activation, ubiquitination pathways, and synaptic connectivity as key components of long-term memory. Notably, upon long-term memory formation, a neuronal subpopulation defined by increased Peak and decreased Tac expression constituted the most prominent component of the memory engram of the basolateral amygdala. These transcriptional changes were observed both with single-cell RNA sequencing and with single-molecule spatial transcriptomics in intact slices, thereby providing a rich spatial map of a memory engram. The spatial data enabled us to determine that this neuronal subpopulation interacts with adjacent astrocytes, and functional experiments show that neurons require interactions with astrocytes to encode long-term memory.
Consolidation of newly acquired memories into long-term memories and reconsolidation of long-term memory during recall requires transcription and translation, as shown by extensive studies of the role of gene expression during learning and memory2,3. Although key transcription factors in learning and short-term memory, such as CREB4, have been identified, the overall nature of long-term memories, which can persist for a lifetime, remains unknown. Gene-expression changes are known to be essential for long-term memory, but the cell types and the nature of the transcriptional programmes involved are incompletely understood. Moreover, multiple brain regions have been implicated in long-term memory formation and storage but it is unknown whether similar transcriptional processes are used in different regions of the brain.
Here, we performed high-resolution spatial and single-cell transcriptomics to comprehensively analyse the changes in the transcriptomic landscape during long-term memory formation in mice. We identified memory-specific gene-expression changes in the amygdala, a complex brain region within which the basolateral amygdala (BLA) is implicated in short- and long-term memories associated with salient experiences, such as fear. Lesions of the BLA abolish both short-term and long-term fear memory5. In fear learning paradigms, suppressing RNA transcription in the...