By Bronwyn Thompson
November 10, 2024
Memory storage and retrieval may be able to be targeted thanks to new discovery
Baylor College of Medicine
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Fascinating new findings into how clusters of ‘brain stars’ retain memories has changed what we know about how they’re held in our minds.
Baylor College of Medicine researchers have been investigating the star-shaped cells in our brains known as astrocytes, which act as microscopic storage boxes that hold our memories. This unique filing system is then accessed by a specific set of neurons known as engrams, which manage the ‘brain stars’ by regulating and retrieving those memories on demand.
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Previously, it’s been thought that neuronal networks were solely responsible for learning and memory.
“The prevailing idea is that the formation and recall of memories only involves neuronal engrams that are activated by certain experiences, and hold and retrieve a memory,” said corresponding author Dr Benjamin Deneen, a professor at Baylor and principal investigator at the Jan and Dan Duncan Neurological Research Institute. “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.”
Because of the incredibly complex nature of the brain, it remains the least understood organ in the human body. Back in 2016, Stanford University researchers highlighted the immense challenges that face neuroscientists – and eight years on, while there has been some progress in understanding various mechanisms, pathways and genetic influence on neurological conditions and diseases, much of it still remains a mystery.
It’s also really hard to study. In this latest work, the Baylor team used a mouse model to investigate the role of astrocytes on memory. In the experiment, the mice were conditioned to be fearful and then put in a situation that made them freeze up with fear. When the exposure was repeated in the same context, the mice again froze up. But when they were in a completely different setting, they didn’t have the same fear response.
The researchers found that this fear conditioning – a learning process – triggered a subset of astrocytes that express the c-Fos gene, which plays a key role in circuitry in that region of the brain.
“The c-Fos-expressing astrocytes are physically close with engram neurons,” said co-first author Michael R Williamson, a postdoctoral associate in the Deneen lab. “Furthermore, we found that engram neurons and the physically associated astrocyte ensemble also are 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.”
Essentially, it was only when the mice were in an environment that they associated with fear that the c-Foss-expressing astrocytes were activated – and the mice, consequently, reacted with the same freezing behavior.
“However, when the astrocyte ensemble in these mice in the non-fearful environment was activated, the animals froze, showing that astrocyte activation stimulates memory recall,” said co-first author Wookbong Kwon, another postdoctoral associate in the Deneen lab.
Previously, the researchers had found that the gene Nuclear factor I-A (NFIA) was important in astrocytic regulation of memory circuits, but whether it played a role in storing and retrieving memories from these brain stars was unknown. So, in light of the results of the mouse study, the team returned to this area of investigation.
They found that activated astrocytes had elevated NFIA protein levels, and when it was suppressed, the neurons failed to retrieve memories from storage. And it only blocked the memory specific to the event the mice had previously experienced.
“When we deleted the NFIA gene in astrocytes that were active during a learning event, the animals were not able to recall the specific memory associated with the learning event, but they could recall other memories,” Kwon said.
Naturally, the implications of this discovery provide interesting avenues of research for conditions in which memory retrieval is compromised, such as in Alzheimer’s disease, or when specific memories are harmful, like in post-traumatic stress disorder (PTSD).
“These findings speak to the nature of the role of astrocytes in memory,” Deneen added. “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.”
While understanding the brain remains a work in progress, we imagine that future treatments to target memories will be a little more sophisticated than those used by Lacuna Incorporated, in the 2004 film Eternal Sunshine of the Spotless Mind …
Lacuna Inc.
The study was published in the journal Nature.
Source: Baylor College of Medicine
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