A study by researchers at Baylor College of Medicine may change the way we understand memory. Until now, memories have been explained by the activity of neurons that respond to learning events and control memory recall. The Baylor team has expanded this theory, with their research, including work in mice, showing that non-neuronal cell types called astrocytes—star-shaped cells—in the brain also store memories and that learning-associated astrocyte (LAA) ensembles work in concert with groups of neurons called engrams to regulate storage and retrieval of memories.
The study illuminates a more complete picture of the players that are involved and the activities that take place in the brain during memory formation and recall. In addition, it may offer a new perspective when studying human disorders associated with memory loss, such as Alzheimer’s disease, as well as conditions, such as post-traumatic stress disorder, in which memories occur repeatedly and are difficult to suppress.
“These findings speak to the nature of the role of astrocytes in memory,” said Benjamin Deneen, PhD, professor and Dr. Russell J. and Marian K. Blattner Chair in the department of neurosurgery, director of the Center for Cancer Neuroscience, a member of the Dan L Duncan Comprehensive Cancer Center at Baylor and a principal investigator at the Jan and Dan Duncan Neurological Research Institute.
Deneen is corresponding author of the team’s published paper in Nature, titled “Learning-associated astrocyte ensembles regulate memory recall,” in which they reported, “Collectively, our studies identify LAAs as key components of the adaptive response to learning experiences, regulating the flow of information during circuit plasticity and memory recall.”
The physical manifestations of memory formation and recall are fundamental questions that remain unresolved, the authors wrote. “At the cellular level, ensembles of neurons called engrams are activated by learning events and control memory recall.” Deneen further commented, “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.”
Astrocytes are found in close proximity to neurons and engage in a range of activities that support neurotransmission and circuit plasticity. “Moreover, astrocytes exhibit experience-dependent plasticity, in which their activation states, transcriptional responses and functional properties are tuned to environmental stimuli and internal states,” the scientists stated.
“Our lab has a long history of studying astrocytes and their interactions with neurons,” Deneen added. “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.”
For their newly reported study the researchers began by developing a completely new set of laboratory tools to identify and study the activity of astrocytes associated with memory brain circuits.
A typical experiment consisted of first, conditioning mice to feel fear and “freeze” after exposure to a certain situation. When mice were placed back in the same situation after some time, they would freeze because they remembered. If the same mice were placed in a different situation, they would not freeze because it was not the original context in which they were conditioned to feel fear.
“Working with these mice and with our new lab tools, we were able to show that astrocytes do play a role in memory recall,” said co-first author Wookbong Kwon, PhD, a postdoctoral associate in the Deneen lab.
The researchers showed that during learning events, such as fear conditioning, a subset of astrocytes in the brain expresses the gene c-Fos. Astrocytes expressing c-Fos subsequently regulate circuit function in that brain region.
“The c-Fos-expressing astrocytes are physically close with engram neurons,” said co-first author Michael R. Williamson, PhD, 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.”
When mice were in a situation not associated with fear, they did not freeze. However, Kwon said, “when the astrocyte ensemble in these mice in the non-fearful environment was activated, the animals froze, showing that astrocyte activation stimulates memory recall.” Commenting on their observations, the authors further noted, “Taken together, these results demonstrate that selective reactivation of hippocampal astrocyte ensembles that were previously activated during fear learning is sufficient to elicit memory recall.”
To better understand what mediates the activity of astrocyte ensembles in memory recall, the researchers investigated the gene NFIA. “Our lab has previously shown that astrocytic NFIA can regulate memory circuits, but whether it acts in ensembles of astrocytes to orchestrate memory storage and recall was unknown,” Williamson stated. To examine the role of NFIA in astrocyte ensembles after fear conditioning, the team developed a system that enables the selective deletion of NFIA in LAAs during fear conditioning. They found that astrocytes activated by learning events have elevated levels of the NFIA protein, and preventing NFIA production in these astrocytes suppresses memory recall. Importantly, this suppression was found to be memory specific.
“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. The authors added, “These findings demonstrate that memory impairment resulting from deletion of NFIA in LAAs is specific to memory recall associated with the original fear-conditioning event, whereas memory for other events remained intact…Therefore, these data indicate that a distinct ensemble of astrocytes selectively coordinates the consolidation and recall of a particular memory.”
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.”
In their report the authors concluded, “These findings expand on the notion that astrocytes exhibit experience-dependent plasticity, in which astrocyte function is tuned to sensory or social experiences, by illustrating new roles in memory consolidation and recall … Taken together, our data identify LAA ensembles as a form of plasticity that is sufficient to provoke memory recall and indicate that astrocytes are an active component of the engram.”
