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Monday, September 20, 2021

Glowing brain cell reactivation

The basic assumption of researchers dealing with memory, including Brian Wiltgen, an assistant professor of UC Davis’s department of psychology and the Center for Neuroscience, is that memory retrieval involves the activation of the same neurons that were engaged during learning. He is in charge of a neuroscience laboratory focused on various topics such as memory circuit activation and memory consolidation. Recently, using genetically modified mice, Wiltgen and his group tested this assumption.

In the past, psychologists would study various cases such as humans with their hippocampuses removed, or animal tests.

“In humans, several patients have had the hippocampus removed and it produced dense amnesia,” Wiltgen said. “In animals, the hippocampus is important for learning about places. If this structure is removed, the animals will not recognize a familiar place.”

In humans, the hippocampus serves a similar role. Researchers call the role of the hippocampus a storage center for “trace” memories. This means that if we smell, taste, hear or feel something similar to the stored trace in the hippocampus, the entire associated memory will be reactivated.

“By studying patients with brain damage produced by medical conditions such as strokes, and brain damage induced in experimental animals, [psychologists detected where memories are stored],” said Arne Ekstrom, an assistant professor of the department of psychology and UC-Davis Human Spatial Cognition Lab.

Researchers have identified the importance of the hippocampus by doing brain scans of test subjects, and recording which areas of the brain were most active during memory retrieval.

“Other information has come from functional brain imaging (fMRI) studies that identify areas of the brain that are active when people retrieve memories of past events,” said Charan Ranganath, a professor of the department of psychology at UC Davis and the Dynamic Memory Lab.

In other cases, electrodes were used in place of an fMRI to help track learning and memory locations in the brain.

“Researchers sometimes insert electrodes into the brain of epileptic patients to find the foci [focus] of their seizures,” Wiltgen said. “It’s been found that some neurons in the hippocampus are activated when a specific video clip is watched and then reactivated when the person recalls that same clip.”

To further cement psychologists’ basic assumption and add more data to the evidence already backing the assumption, Wiltgen conducted his study on mice.

“In our experiment, we use genetically modified mice to permanently label neurons that are activated during learning,” he said.

Out of the many types of mice generated from the various scientific research interests, Wiltgen picked mice with green fluorescent nerve cells.

“In our mice, cellular activity leads to the expression of a protein called tTA. This protein [produces] a fluorescent marker, called green fluorescent protein (GFP), which allows us to identify the activated neurons,” Wiltgen said. “Mice were essential for our experiments because they are the only animal with the genetic changes that allowed us to tag neurons.”

Wiltgen and his colleagues could track what neurons were active while mice learned. In particular, the mice learned about the danger of electrical shock. When they sensed that they were in the same cage where the initial electrical shock originated, they tensed up in fear, and the neurons during the learning process reactivated. However, in a new environment, there was no reactivation. The results were similar to what was found in the prior research with epileptic patients.

The hippocampus is not by any means the only part of the brain associated with memory storage and retrieval. Other areas assist in learning and memory storage.

“It appears that there is a division of labor, with different areas supporting different kinds of memories. So, for instance, the amygdala seems to be responsible for learning about the salience (importance) of objects or places, such as whether they are associated with danger or reward,” Ranganath said.

According to Ekstrom, cortical areas such as the parietal cortex and prefrontal cortex are also important.

“Parts of the thalamus are also involved, but their exact functions in memory are unclear,” Ekstrom said.

Researchers have differentiated between areas that are responsible for forming memories and areas responsible for recalling memories. In mice, reactivation of memories decreased over time in brain regions such as the amygdala, which is responsible for forming memories.

The study has opened many new possibilities and has greatly added to researchers’ understanding of how memory works.

“Prior to Wiltgen’s study, we thought that when a memory is retrieved, most of the cells representing the original memory trace are reactivated. Wiltgen’s study shows that while many of the cells active during encoding are active during retrieval, many are not,” Ekstrom said. “This begs the question of what these additional neurons are doing and opens the door to better understanding the role of individual neurons in representing memories, at least in [animal] models,” Ekstrom said.

According to Ranganath, Wiltgen’s research has provided the strongest evidence to date showing that the hippocampus is involved in storing memories and the context of those memories.

In the future, this research could help current and future researchers investigate ways to reactivate neurons in patients with Alzheimer’s disease or other memory-degenerative disorders.

VICTORIA TRANG can be reached at science@theaggie.org.

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