Astrocytes are superstars in the game of long-term memory

(Press-News.org) Why are we able to recall only some of our past experiences? A new study led by Jun Nagai at the RIKEN Center for Brain Science in Japan has an answer. Surprisingly, it turns out that the brain cells responsible for stabilizing memories aren’t neurons. Rather, they are astrocytes, a type of glial cell that is usually thought of as a role player in the game of learning and memory. Published in the scientific journal Nature on Oct 15, the study shows how emotionally intense experiences like fear biologically tag small groups of astrocytes for several days so that they can re-engage when a mouse recalls the experience. It is this repeated astrocytic engagement that stabilizes memories.

Astrocytes have traditionally been thought to have a supporting role in the brain, literally. But when it became clear that engrams—the actual memory traces that exist in neurons—cannot alone account for stabilized, long-term memories, Nagai and his team turned to astrocytes for a solution. Neurons produce a protein called Fos when activated, and experiences can also trigger Fos production in some astrocytes. To monitor how astrocytes across the whole brain respond during learning and recall, the researchers developed a new system that can fluorescently label astrocytes with active Fos, but not neurons, and only if Fos is active during a specific time period, which is controlled by giving an animal a shot of 4-OHT.

With this system in place, they taught mice to associate a certain cage with an unpleasant experience. After learning the association, when mice were returned to the cage several days later, their reaction showed whether or not they remembered the past event. The key finding was that unlike in neurons, the researchers observed strong Fos activity in astrocytes only during recall, but not during the initial learning. Further experiments showed that Fos activity in these astrocytes requires input from the neurons in the amygdala that form the fear-memory engram in question, as well as simultaneous input from neurons that use the compound noradrenaline as a transmitter.

But engram activity and noradrenergic input happen during both learning and recall. So why does the Fos activity in astrocytes only happen during recall? Single-cell RNA sequencing of the astrocytes revealed that in the days following the emotional experience, the astrocytes began to produce alpha and beta adrenoreceptors, which are activated by noradrenaline. The extra adrenoreceptors can be thought of as a tag that identifies which astrocytes should be activated—produce Fos—the next time the animal recalls the experience and the neural engram is activated. To confirm their theories, when the researchers blocked Fos⁺ astrocyte signaling during recall, the mice had unstable memories and did not react as if they remembered anything during the recall test. On the flip-side, when the team forced the astrocytes to activate, animals were able to recall only mildly unpleasant experiences as if they were very unpleasant and even generalized their recalled experiences to other cages where they never experienced anything unpleasant.

Nagai says that in the short term, their discovery could help us understand PTSD and related conditions in which emotionally intense memories persist abnormally or are activated by overgeneralized objects in the environment. As he explains, “these findings could lead to new therapeutic approaches that target the astrocytic memory switch, leading to therapies that gently dampen traumatic memories while sparing others.”

“Beyond biology,” continues Nagai, “the astrocyte-tagging process might inspire AI models that mimic human memory filtering. Current AI systems are data-hungry and energy-intensive; by learning from astrocytes—which select memories efficiently based on emotional salience and recurrence—we may design more energy-efficient, context-aware AI systems that remember just enough.

The team’s next goal is to figure out how astrocytes become “eligible” to gate memory stabilization and to test whether specific types of memories can be suppressed or enhanced by manipulating them.

END