Scientists from the University of Buffalo, Imperial College London, Massachusetts Institute of Technology, and elsewhere have published new research that demonstrates how brain cells get better at distinguishing between similar experiences. The insights could be useful for making sense of Alzheimer’s disease and other memory disorders and could help with drug research and development.
The paper, titled “Dynamic and selective engrams emerge with memory consolidation,” was published in Nature Neuroscience. The study focuses on engrams, neurons that are involved in episodic memory consolidation and storage. They are “reactivated to support memory recall,” explained Dheeraj Roy, PhD, a senior author on the paper and an assistant professor at the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo. “When engrams are disrupted, you get amnesia.”
Under normal circumstances, people with healthy brains can remember the differences between similar experiences thanks to engrams that do the work of consolidating memories. Roy and his colleagues were especially interested in what happens from the time an engram is formed to when the individual needs to recall the memory.
To answer this question, they built a neural network for learning and memory formation that takes in sensory information as input. Typically, in the brain that information goes to the hippocampus and activates excitatory and inhibitory neurons as memories form. Neurons that happen to be activated closely in time are included in the engram and involved in future recall.
“Activation of engram cells during memory recall is not an all or none process but rather typically needs to reach a threshold (i.e., a percentage of the original engram) for efficient recall,” Roy explained. “Our model is the first to demonstrate that the engram population is not stable: The number of engram cells that are activated during recall decreases with time, meaning they are dynamic in nature.”
When brain cells consolidate memories, they are “actively working to separate the two experiences and that’s possibly one reason why the numbers of activated engram cells decrease over time for a single memory,” Roy said. “If true, this would explain why memory discrimination gets better as time goes on. It’s like your memory of the experience was one big highway initially but over time, over the course of the consolidation period on the order of minutes to hours, your brain divides them into two lanes so you can discriminate between the two.”
The next step was determining the behavioral consequences that result from engram dynamics.
The researchers performed an experiment that exposed mice to environments in two boxes: one with a neutral environment and one that delivered a mild shock. A few hours after exposure, the mice froze when presented with either box, suggesting that they couldn’t yet discriminate between the two. Twelve hours after their initial exposure, the mice only showed fear when they were exposed to the shock box. The mice were essentially “telling us that they know this box is the scary one but five hours earlier they couldn’t do that.”
Using a light-sensitive technique, the team observed which neurons were active in the mice hippocampus and tagged them. Later on, they measured how many neurons were reactivated during recall. Their results showed that the number of engrams involved in a single memory decreased over time. They can also explain how a single engram or a subset of engrams respond to each box environment over time and link it to how the mice discriminate between memories.
“When the brain learns something for the first time, it doesn’t know how many neurons are needed and so on purpose a larger subset of neurons is recruited,” Roy said. “As the brain stabilizes neurons, consolidating the memory, it cuts away the unnecessary neurons, so fewer are required and in doing so helps separate engrams for different memories.”
So how can these findings help with research into brain diseases and disorders? Understanding what happens at the cellular level when memories are formed and consolidated is critical for drug discovery and development. “This research tells us that a very likely candidate for why memory dysfunction occurs is that there is something wrong with the early window after memory formation where engrams must be changing,” Roy explained. Currently, Roy is studying engrams in mouse models of early Alzheimer’s disease to discover if they are formed but not correctly stabilized.
“We can look at mouse models and ask, are there specific genes that are altered? And if so, then we finally have something to test, we can modulate the gene for these ‘refinement’ or ‘consolidation’ processes of engrams to see if that has a role in improving memory performance,” he said.
