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Long-Term Memory-Related Cell Types, Expression Features Found in Mouse Transcriptome Study

NEW YORK – A team led by investigators at Stanford University has tracked down cell subpopulations and gene expression features associated with long-term memory in mice in a brain region known as the basolateral amygdala (BLA).

"We identified memory-specific gene expression changes in the amygdala, which is a complex brain region whose basolateral area is implicated in short- and long-term memories associated with salient experiences, such as fear," co-senior and co-corresponding authors Stephen Quake of Stanford University and the Chan Zuckerberg Initiative and Thomas Südhof, a researcher at Stanford University School of Medicine, and their colleagues reported in Nature on Wednesday.

For their study, Quake, Südhof, and colleagues performed spatial transcriptomic, single-cell transcriptomic, and bioinformatic analyses on BLA cells from mouse models with reporter genes that are expressed when the animals are both exposed to the drug tamoxifen and experiencing memory recall. Their analyses on cells from exposed and control mice in fear training and recall conditioning experiments led to transcriptional signatures in a subset of neurons and astrocytes that appeared to be memory specific.

"Gene expression changes are known to be essential for long-term memory, but the cell types and the nature of the transcriptional programs involved are incompletely understood," the authors wrote, adding that an analysis of the current results in combination with published long-term fear memory data focused on the medial prefrontal cortex "enabled us to examine region-specific versus general gene expression changes."

Based on single-cell RNA-seq profiles for nearly 6,400 BLA cells, for example, the team highlighted shifts involving components of synaptic connectivity, MAP kinase, ubiquitination, CREB activation, and neuropeptide and brain-derived neurotrophic factor (BDNF) signaling.

The investigators also flagged a subpopulation of neurons in the BLA region that was marked by enhanced expression of the proenkephalin neuropeptide-coding gene PENK and reduced levels of a TAC gene encoding the tachykinin neuropeptide precursor during the process of long-term memory formation.

Based on these and other findings, the authors suggested that "neuropeptides, including neurotensin, secretogranin, tachykinin, proenkephalin, [the neuroendocrine precursor peptidase ProSAAS], and [the cocaine- and amphetamine-regulated transcript protein neuropeptide CART], are involved in memory consolidation in BLA engram cells."

These "P+T-" neurons "constitute the most prominent part of the long-term memory engram," the researchers reported, referring to the concept of the "engram," a unit of cognitive information that is physically stored as a memory. They noted that spatial transcriptomic analyses on mouse brain slice samples highlighted a nearby astrocyte cell population needed to consolidate the formation of these long-term memories.

Together, data from their current study "help dissect the network of engram cells that consolidate short-term memory to long-term memory and characterize the persistent gene expression program that mediates this consolidation," the authors explained, noting that their findings "show that neurons and astrocytes in the BLA exhibit memory-specific persistent transcriptional signatures that correspond to multiple signaling pathways but are highly specific to a small subset of cells representing engram cells."