Spatial transcriptomics reveal neuron–astrocyte synergy in long-term memory

Abstract

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 Penk 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.

Early-life stress alters postnatal chromatin development in the nucleus accumbens

“…However, adult ELS cells that were not initially activated had relatively greater ATAC peaks at promoters for Mog (marking oligodendrocytes) and Cx3cr1 (marking microglia) and lower peaks within Aqp4 (marking astrocytes) relative to Std-reared and juvenile samples (Supplemental Figure 1F-H). The finding that ELS alters chromatin in these cell populations that were not initially activated by ELS is consistent with research demonstrating dynamic cross-talk between neurons and glial cells, and that activity within nonneuronal cells adjacent to experience-activated neurons is required for long-term experience encoding (Badimon et al, 2020;Sun et al, 2024).…”

“…This hypothesis is supported by an enrichment of open chromatin in marker genes for oligodendrocytes, astrocytes, and microglia within non-activated cells after ELS ( Supplemental Figure 1 ). Indeed, activation of neurons stimulates surrounding “peri-engram” astrocytes and other glia, which likely induces chromatin remodeling within these cells (Sun et al, 2024). Additionally, microglia adjacent to stress-responsive cells in the hypothalamus are disrupted by ELS and fail to prune excitatory synapses (Bolton et al, 2022).…”

Functional states of prelimbic and related circuits during the acquisition of a GO/noGO task in rats

“…It has been shown recently that the acquisition of a cued fear conditioning in mice is dependent on the proper activity of bidirectional glutamatergic projections between mPFC and BLA circuits, and that presynaptic mPFC and postsynaptic BLA NMDARs are required for fear memory formation, although not for its expression (Bertocchi et al, 2023). Neuronal-astrocyte synergy has also been proposed to underlie long-term fear memory formation (Sun et al, 2024). Although only positive rewards were presented in this study, the BLA was preferentially active for noGO vs. GO correct responses, suggesting an important contribution of this brain center to the inhibitory component necessary for the generation of correct noGO responses.…”

Neuropeptide Y co-opts neuronal ensembles for memory lability and stability

“…Successful extinction suppresses the original fear memory to a dormant state with the potential for spontaneous relapse over time 23–25 . Taking advantage of fear memory and extinction as robust platforms to differentiate specific neuronal ensembles and their interconvertibility at different stages, we first profiled transcriptomic changes at the single-cell level to identify molecular signatures associated with two memory engrams 8,26,27 . To this end, we used unbiased high-throughput droplet-based single-cell RNA sequencing (scRNA-seq) combined with a single-cell preparation method designed to eliminate transcriptional perturbations during sample preparation, referred to as Act-seq 6 .…”