Research into the nature of memory reveals how cells that store information stabilize over time

Think about a time when you had two different but similar experiences in a short period of time. Maybe you attended two holiday parties in the same week or gave two presentations at work. Soon after, you might find yourself confusing the two, but over time this confusion fades and you are better able to differentiate between these different experiences.

New research published in Natural neuroscience reveals that this process occurs at the cellular level, discoveries essential to the understanding and treatment of memory disorders, such as Alzheimer’s disease.

Dynamic engrams store memories

The research focuses on engrams, which are neuronal cells in the brain that store memory-related information. “Engrams are the neurons that are reactivated to support memory recall,” explains Dheeraj S. Roy, Ph.D., one of the senior authors of the paper and an assistant professor in the Department of Physiology and Biophysics at the Jacobs School of Medicine and Biomedical. Science at the University at Buffalo. “When engrams are disrupted, you suffer from amnesia.”

In the minutes and hours immediately following an experience, he explains, the brain needs to consolidate the engram for storage. “We wanted to know: What happens during this consolidation process? What happens between the time an engram is formed and the time you have to recall that memory later?”

The researchers developed a computational model for learning and memory formation that begins with sensory information, which constitutes the stimulus. Once this information reaches the hippocampus, the part of the brain where memories are formed, different neurons are activated, some of which are excitatory and others inhibitory.

When neurons are activated in the hippocampus, they do not all work at the same time. As memories are formed, neurons that are activated over time become part of the engram and strengthen their connectivity to support future recall.

“Activation of engram cells during memory recall is not an all-or-nothing process but must generally reach a threshold (i.e., a percentage of the original engram) for recall effective,” explains Roy. “Our model is the first to demonstrate that the engram population is not stable: the number of engram cells activated during recall decreases over time, meaning that they are dynamic in nature. The crucial question The next step was to find out if this had a behavioral consequence.

Dynamic engrams are necessary for memory discrimination

“During the consolidation period after learning, the brain actively works to separate the two experiences and this may be one of the reasons why the number of activated engram cells decreases over time for a single memory “, he said. “If true, this would explain why memory discrimination improves over time. It’s as if your memory of the experience was initially a major highway, but over time, as the consolidation period on the order of minutes to hours, your brain divides them into two pathways so you can distinguish between the two.”

Roy and the team’s experimentalists now had a testable hypothesis, which they carried out using a well-established behavioral experiment with mice. Mice were briefly exposed to two different boxes with unique odors and lighting conditions; one was a neutral environment, but in the second box they received a mild foot shock.

A few hours after this experiment, the mice, which are usually constantly in motion, demonstrated a fear memory by freezing when exposed to either box. “This demonstrates that they could not distinguish between the two,” says Roy. “But at twelve o’clock, all of a sudden, they only showed fear when they were exposed to the box they felt uncomfortable in during their very first experience. They were able to distinguish between the two. The animal tells us it knows. The box is the scary one, but five hours earlier they couldn’t do that.”

Using a light-sensitive technique, the team was able to detect active neurons in the mouse’s hippocampus as the animal explored the boxes. The researchers used this technique to mark active neurons and later measure how many of them were reactivated by the brain for recall. They also conducted experiments that tracked a single engram cell through experiments and time. “So I can literally tell you how an engram cell or a subset of them responded to each environment over time and correlate that to their memory discrimination,” says Roy.

The team’s early computational studies predicted that the number of engram cells involved in a single memory would decrease over time, and animal experiments confirmed this.

“When the brain first learns something, it doesn’t know how many neurons are needed and so intentionally a larger subset of neurons is recruited,” he explains. “As the brain stabilizes neurons, consolidating memory, it removes unnecessary neurons so fewer are needed and, in doing so, helps separate engrams for different memories.”

What happens with memory problems?

The findings are directly relevant to understanding what goes wrong in memory disorders, such as Alzheimer’s disease. Roy explains that to develop treatments for such disorders, it is essential to know what happens during initial memory formation, consolidation, and activation of engrams for recall.

“This research tells us that a very likely cause of memory dysfunction is that there is something wrong with the first window after memory formation where the engrams have to change,” says Roy.

He is currently studying mouse models of early Alzheimer’s disease to discover if engrams form but are not properly stabilized. Now that more is known about how engrams work to form and stabilize memories, researchers can examine which genes change in the animal model when the engram population decreases.

“We can look at mouse models and ask, are there specific genes that are changed? And if so, then we finally have something to test for, we can modulate the gene for these processes.” “refinement” or “consolidation” of engrams to see if that plays a role in improving memory performance,” he says.

Now at the Jacobs School, Roy conducted the research while he was a McGovern Fellow at the Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University. Roy is one of three neuroscientists recruited to the Jacobs School this year to launch a new specialization in systems neuroscience within the school’s Department of Physiology and Biophysics.

The paper’s co-authors are from Imperial College London; the Austrian Institute of Science and Technology; the McGovern Institute for Brain Research at MIT; and the Life Sciences Center and IDG/McGovern Institute for Brain Research at Tsinghua University in China.