Astrocyte Ensembles are Involved in Memory Stabilization and Recall
Post by Amanda Engstrom
The takeaway
Engrams are the physical traces of memory in the neurons of the brain. This study reveals that astrocytes play a more direct role than previously thought, forming lasting ensembles that reactivate during memory recall. These astrocytic ensembles, driven by noradrenergic signaling, act as a multiday trace that helps stabilize and preserve memories over time.
What's the science?
Memory formation and stabilization involve specific neuronal ensembles, or groups of interconnected neurons that work together. Chemical and physical changes in these neurons then form memory traces – called engrams – to be activated during learning and recall. Remembering something transiently destabilizes memories, but the mechanism that subsequently re-stabilizes the memory is not completely understood and cannot be explained by neuronal engrams alone. Astrocytes are highly abundant non-neuronal cells within the central nervous system (CNS) that interact both structurally and functionally with neurons and other glial cells. They are known to be developmentally diverse and adaptive to physiological and pathological changes; however, the role of astrocytes in forming or stabilizing experience-dependent memories is not clear. This week in Nature, Dewa and colleagues investigated astrocytes that respond to memory formation and recall in order to assess their contribution to memory stabilization.
How did they do it?
The authors developed a tool to identify behaviorally relevant astrocyte ensembles in an unbiased manner by generating mice that allow them to label astrocytes that have been activated (marked by an increase in Fos gene expression) during a specific time window. For their studies, the authors “tagged” astrocytes either during a fear conditioning protocol or 24 hours later in a fear memory recall session. They then compared astrocyte activation with neuronal engram activity in the same fear conditioning paradigm. Once the authors identified the astrocyte ensembles, they performed a pharmacological screening for molecules that can activate astrocyte Fos expression and validated these target molecules through circuit analysis, imaging, and single-cell transcriptomics. Next, the authors determined the transcriptional response to memory formation and recall at different timepoints. Finally, they perturbed the astrocyte ensemble by using a peptide inhibitor to silence the target signaling cascade, as well as enhanced the ensemble signaling by overexpressing downstream signaling targets. Then they tested the efficiency of fear conditioning and recall using the same behavioral fear paradigm.
What did they find?
The density of activated (Fos+) astrocytes did not significantly increase immediately after fear conditioning. However, 24 hours later, during recall, there was a significant increase in the number of activated astrocytes across the entire brain, especially in the amygdala, compared to fear conditioning without recall. This is unique to astrocytes, as neurons are activated both during fear conditioning and recall. There was a significant regional correlation between neuronal and astrocyte activation at recall, suggesting that astrocyte ensembles are recruited in regions of active neuronal engrams. The authors identified noradrenaline (NA) as a strong inducer of Fos expression in astrocytes, and using fiber photometry, (an imaging technique to measure cellular activity) determined that during fear recall, NA signals are stronger and last longer than during fear conditioning.
The single-cell transcriptomics on astrocytes in the amygdala revealed that after fear conditioning, astrocytes upregulate adrenergic receptor genes (Adra1a and Adrb1), which increased in expression over 24 hours, indicating a “priming” state that develops over a day and then decreases over time. Disrupting the astrocyte ensemble disrupted memory stability and reduced the mouse’s response in the fear recall test. When the ensemble was enhanced through the overexpression of Adrb1 in astrocytes, the density of activated astrocytes increased, and improved memory retention and recall. Together, these results show that fear conditioning induces an astrocyte ensemble that is primed via NA signaling and persists for roughly one day. Upon recall, the astrocyte ensemble is activated and stabilizes the memory.
What's the impact?
This study is the first to show that astrocytes form their own experience-dependent ensembles that reactivate during memory recall and help stabilize memories over multiple days. This work expands the traditional neuron-centric view of memory consolidation and argues for the critical role of astrocytes in memory stabilization and recall.
