The Science of Memory Extinction
Microglia and memory pruning
Posted Feb 17, 2020
In “Funes the Memorious,” a short story by Argentinian writer Jorge Luis Borges, the narrator describes his relationship with the fictional character Ireneo Funes, who has suffered an accident that has left his body partially paralyzed. His memory, however, has been awoken to its full potential; Funes can remember everything that has ever happened to him down to the most minute detail.
For many of us, such an ability would appear to be a great gift. One would never forget a birthday or anniversary. One could learn new languages with ease. One could also go back and relive entire days with a level of detail that would border on the surreal.
All these gifts Funes most certainly had. He learned Latin, English, Portuguese, and French. Furthermore, his memory was so precise that he could very easily recreate complex images. As Borges wrote, “A circle drawn on a blackboard, a right triangle, a lozenge—all these are forms we can fully and intuitively grasp; Ireneo could do the same with the stormy mane of a pony, with a herd of cattle on a hill, with the changing fire and its innumerable ashes…”
As the story progresses, the reader begins to realize that the ability does have a dark side. On the one hand, such an enormous magnitude of information would be simply too much to process—one would have to be immortal to fully appreciate the wealth of memories available to them. On the other, Funes’ tremendous capacity to discern even minor differences between similar objects made language exceedingly frustrating. “Not only was it difficult for him to comprehend that the generic symbol dog embraces so many unlike individuals of diverse size and form,” Borges wrote, “It bothered him that the dog at three-fourteen (seen from the side) should have the same name as the dog at three-fifteen (seen from the front).”
The narrator later muses that this need to focus on what we would consider minutia had robbed Funes of the ability to truly think. “To think is to forget differences, generalize, make abstractions. In the teeming world of Funes, there were only details, almost immediate in their presence.”
While there are many lessons to learn from this story, the most germane to this post is that forgetting isn’t always a curse. In fact, the pruning of unnecessary memories is an integral part of brain health. Even more interesting, researchers in China may have recently found one of the primary mechanisms within the brain that allows us to forget.
How Memories Are Created and Maintained
The hippocampus plays an integral role in memory, particularly in the processing of negative or stressful information. When a person experiences something stressful, the memory of the event is encoded and stored in a specific population of neurons known as an engram. These individual engrams become part of a larger network reliant upon synaptic connections. Memory retrieval relies on the reactivation of engram cells via these connections.
The brain consists of more than just these neural networks. It is also home to billions of glial cells that are believed to be the most abundant types of cells in the central nervous system (though there is some debate about the ratio of neurons to glial cells). Glial cells (or glia) are responsible for providing support and nutrients to neurons. A subset of glia, microglia, is in charge of removing dead neurons from the brain, repairing and protecting the CNS, and destroying pathogens. Microglia have also been shown to maintain the health of synapses and to be particularly active while we sleep.
How We Forget
Forgetting, one would think, would be a kind of decay, something that happens gradually due to the failure to utilize the synaptic connections that allow for engram reactivation. The act of forgetting is envisioned as something akin to athletes falling out of shape during the offseason because they are not constantly exercising or honing their skills.
Put another way, we tend to think of forgetting as a negative phenomenon, like the crumbling of a public road that is not properly maintained. In this simile, the engrams are the towns, while the synapses are the highways connecting them. The workers responsible for ensuring the integrity of these “roads,” meanwhile, are the microglia.
However, a paper recently published in Science suggests that microglia may play an even more significant role. The paper’s findings suggest that microglia are not just the figurative maintenance crews; they are also responsible for determining when a synaptic road is no longer valuable and then eliminating it. In this scenario, the act of forgetting does not arise because of synaptic disuse, but because microglia are taking active measures to prune away unnecessary synaptic connections.
The team behind the paper tested this hypothesis by subjecting mice to contextual fear conditioning (or CFC, which is a kind of Pavlovian conditioning that involves placing the rodent in a novel environment (a specific cage), and then administering a weak shock to the rodent’s foot). This shock results in what is known as “freezing,” which, as the name suggests, is a fear-induced response by the mouse that involves stopping any movement except for respiration. The team then tested for freezing behavior in the novel cage five days and 35 days after the CFC training. After five days, most of the mice still froze when placed in this environment. After 35 days, most had forgotten their fears and demonstrated far less freezing behavior when placed in the novel cage.
The team then administering minocycline, which has demonstrated an inhibitory effect on microglial function, to a separate group of mice, and then repeated the same experiment. What they found was that the minocycline-treated group exhibited significantly longer freezing times than the control group 35 days following CFC training. According to the paper’s lead author, Dr. Chao Wang of the Zhejiang University School of Medicine, this suggests that “synapse elimination by microglia leads to dissociation of engrams and the forgetting of previously learned contextual fear memory.”
While these findings are significant, it’s currently unclear if microglia play a similar role in maintaining and eliminating memories that are not related to fear. Still, the study does advance our understanding of memory, which could have major implications for the treatment of diseases that affect memory, particularly Alzheimer’s disease.
Dr. Ahmad reports no conflict of interest. He is not a speaker, advisor, or consultant and has no financial or commercial relationship with any biopharmaceutical entity whose product/device may have been mentioned in this article.