The physical mechanisms behind memory formation and recall still need to be fully understood. At the cellular level, memory is thought to be encoded by ensembles of neurons known as engrams, which are activated during learning and control memory retrieval.
Astrocytes, glial cells located near neurons, support neurotransmission and promote circuit plasticity. Astrocytes also show experience-dependent plasticity, but whether specific groups of astrocytes are involved in memory recall remains unclear.
A new study by researchers at Baylor College of Medicine changes how we understand memory. The Baylor team expanded the traditional view of memory, which focused on neurons, by demonstrating that astrocytes—star-shaped, non-neuronal cells—also play a role in memory storage. They found that astrocytes work with neuronal ensembles called engrams to regulate both the storage and retrieval of memories.
Corresponding author Dr. Benjamin Deneen said, “The prevailing idea is that the formation and recall of memories only involve neuronal engrams that are activated by certain experiences and hold and retrieve a memory.”
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“Our lab has a long history of studying astrocytes and their interactions with neurons. We have found that these cells interact closely with each other, both physically and functionally, and that this is essential for proper brain function. However, the role of astrocytes in storage and retrieval of memories has not been investigated before.”
The researchers developed a novel set of laboratory tools to identify and study the activity of astrocytes involved in memory circuits in the brain. Their experiments conditioned mice to feel fear and freeze when exposed to a specific situation. Later, when the mice were returned to the same situation, they froze in response, demonstrating memory recall. However, if the mice were placed in a different situation, they did not freeze, indicating they did not remember the new context.
Co-first author Dr. Wookbong Kwon, a postdoctoral associate in the Deneen lab, said, “Working with these mice and our new lab tools, we were able to show that astrocytes play a role in memory recall.”
The researchers showed that during learning events like fear conditioning, a subset of astrocytes in the brain activates the c-Fos gene. Astrocytes expressing c-Fos then regulate the function of brain circuits in that specific region, influencing memory processing and recall.
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Co-first author Dr. Michael R. Williamson, a postdoctoral associate in the Deneen lab, said, “The c-Fos-expressing astrocytes are physically close to engram neurons. Furthermore, we found that engram neurons and the physically associated astrocyte ensemble are also functionally connected. Activating the astrocyte ensemble specifically stimulates synaptic activity or communication in the corresponding neuron engram. This astrocyte-neuron communication flows both ways; astrocytes and neurons depend on each other.”
When mice were placed in a non-fearful environment, they did not freeze. However, when the researchers activated the specific ensemble of astrocytes associated with memory, the mice froze, demonstrating that astrocyte activation can trigger memory recall.
To further understand how astrocyte ensembles mediate this process, the researchers focused on the gene NFIA. While their lab had previously shown that astrocytic NFIA regulates memory circuits, it was still determined whether it acts within ensembles of astrocytes to coordinate memory storage and recall.
The team discovered that astrocytes activated during learning events have higher levels of the NFIA protein. When they prevented NFIA production in these astrocytes, memory recall was suppressed. Importantly, this suppression was memory-specific. When the NFIA gene was deleted from astrocytes active during a learning event, the animals could not recall the specific memory associated with that event. However, they were still able to recall other memories.
Deneen said, “These findings speak to the nature of the role of astrocytes in memory. Ensembles of learning-associated astrocytes are specific to that learning event. The astrocyte ensembles regulating the recall of the fearful experience are different from those involved in recalling a different learning experience, and the ensemble of neurons is different as well.”
Journal Reference:
- Williamson, M.R., Kwon, W., Woo, J. et al. Learning-associated astrocyte ensembles regulate memory recall. Nature (2024). DOI: 10.1038/s41586-024-08170-w