February 16, 2021
Written by: Marissa Maroni
Imagine you are on a road trip and stop at a gas station. You start to fill your car up with gas when you look around and begin to question, “Have I been here before?” You comb through your brain trying to connect the feeling with specific memories, like whether it could be the rest stop with the nice bathrooms. You shake your head and decide that since you can’t quite place it, you haven’t been here at all. Forgetting a place that you visited, or the specifics of a story is a common experience. But why does this happen and what causes it? Scientists have uncovered new evidence showing that immune cells called microglia in your brain may play a role in forgetting unused memories.
How are memories stored in the first place?
Your brain stores your memories in groups of neurons1. When you are studying for an exam, you often first read through the information you need to remember. This action activates a specific set of neurons. As you re-read your notes, you hopefully find yourself beginning to remember parts of the study material. This is because you are repeatedly activating the same set of neurons, strengthening this connection and creating a lasting memory of the material you are studying. These sets of neurons have to communicate with each other in order to represent the memory. This communication occurs at synapses, the spaces between neurons. When a group of neurons are repeatedly activated at the same time, such as when reading about cell biology for an exam, the synaptic connections between the neurons get stronger. Thus, memories are stored in these strengthened connections of synapses between these neurons. But how do we then lose memories after they’ve been created?
What did the researchers find?
A Model for Forgetting
Researchers from Zhejiang University School of Medicine in China were interested in microglia’s role in forgetting a memory2. But how can you test forgetting and what are microglia, anyway? Let’s dive in and begin to answer this! To test forgetting, researchers first had to create a memory that could be forgotten. Researchers used mice as an animal model to better manipulate microglia in the brain to determine their role in memory. To do this, they utilized a widely used method called contextual fear conditioning. This technique involves placing an animal, usually a rat or mouse, into an area where they receive a mild shock under their feet. After repeated training sessions, the animals remember that this location, or context, is generally paired with a foot shock3. When mice and rats experience fear, they exhibit a freezing behavior that researchers can measure. This behavior is similar to the way deer freeze in front of cars. Because the animal learns to associate a location with a foot shock, they freeze when placed back in that location, illustrating that they have developed a fear memory. Over time, though, mice begin to forget this memory. When mice are placed into the box a month after they make the memory, they freeze less than if they are placed into the box a week after they form the memory. Scientists interpret the decrease in freezing as forgetting. Utilizing this method, the researchers had a model to look at what happens in the brain when mice forget.
Microglia: The Immune Cells of the Brain
The researchers looked to a surprising type of cell in the brain to investigate forgetting. Microglia are the immune cells of the brain that respond to injury and disease. In this respect, microglia act like a combination of a nurse and a trash collector. They search for injury in the brain to heal, which often involves breaking down and disposing of harmful material. Microglia also play a role in synaptic remodeling. This means that microglia help alter connections in the brain that control your movements, thoughts, and memories. This interesting role led the researchers to wonder…could microglia be disposing of synapses and leading to the loss of memories?
Microglia’s Elimination of Synapses Mediates Forgetting
One way scientists determine a cell type’s role is to see what happens when it’s not there. To do this, researchers removed microglia from the brain using a drug that inhibits a receptor essential for microglia survival4. They found that after removing microglia, fewer mice forgot their fear memory, even over a month after training. This suggests that the removal of microglia can improve the retention of a fear memory.
To better understand how microglia could be causing memories to be forgotten, researchers hypothesized that microglia may be eliminating synapses between neurons, disbanding the group of neurons that was previously holding the memory. This elimination occurs by microglia targeting, engulfing, and digesting the synapse. Typically, synapses that are to be eliminated by microglia contain a certain marker, telling the microglia which cells to act on. Think of this mark like pus on a cut that signals when you have an infection. In order to test their hypothesis, researchers wanted to label the neurons that contained the fear memory and see if those specific synapses were being eliminated by microglia. Using genetic techniques, neurons were labeled using a system that “tags” neurons that were activated during the fear training. Then, in order to see if synapses between neurons that contain the fear memory have this marker, the researchers labeled them and analyzed their synapses. Indeed, neurons that held the fear memory did have marks on their synapses indicating that they were being targeted for removal by microglia. In addition, when microglia were depleted, there were a greater number of synapses remaining, suggesting that synapses were not being eliminated when microglia were no longer present.
Memories are typically forgotten when they’re not frequently recalled. Researchers were able to find evidence that microglia were eliminating synapses where the fear memory had been stored. But they still wondered if synapses were being eliminated by microglia because those groups of neurons were not being activated. To test this, researchers turned off the fear memory neurons using chemogenetics, a technique that allowed them to inhibit their activity. They found that there was more forgetting in mice with inactive fear memory neurons, which likely weakened their synapses. Interestingly, however, this increase in forgetting when memory neurons were inactive depended on the presence of microglia. In other words even when these fear memory neurons were inactivated, the mice did not forget when microglia were depleted! This suggests that microglia are targeting synapses where unused memories are stored.
The big question is, why is this important? This research suggests that microglia in your brain are eliminating synapses that store unused memories. Taking a step back, this makes a lot of sense! Although memories are important, not all of them need to be kept. Microglia are helping by removing memories that aren’t reused, ensuring that only the important, most useful memories are stored. Remember this after taking a test, because if you want to retain information you will have to continue to use it! If you don’t, the microglia in your brain could begin to break up the connections you worked hard to make!
Cover image from Unsplash User Yustinus Tjiuwanda
- Mayford, M., Siegelbaum, S. A., & Kandel, E. R. (2012). Synapses and memory storage. Cold Spring Harbor perspectives in biology, 4(6), a005751.
- Wang, C., Yue, H., Hu, Z., Shen, Y., Ma, J., Li, J., … & Wang, L. (2020). Microglia mediate forgetting via complement-dependent synaptic elimination. Science, 367(6478), 688-694.
- Buccafusco, J. J. (Ed.). (2000). Methods of behavior analysis in neuroscience. Crc Press.
- Elmore, M. R., Najafi, A. R., Koike, M. A., Dagher, N. N., Spangenberg, E. E., Rice, R. A., … & Green, K. N. (2014). Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron, 82(2), 380-397.