Nearly seven years ago, Sheena Josselyn and her husband Paul Frankland were talking with their two-year-old daughter and started to wonder why she could easily remember what happened over the last day or two but couldn’t recall events that had happened a few months before. Josselyn and Frankland, both neuroscientists at the Hospital for Sick Children Research Institute in Toronto, suspected that maybe neurogenesis, the creation of new neurons, could be involved in this sort of forgetfulness.
In humans and other mammals, neurogenesis happens in the hippocampus, a region of the brain involved in learning and memory, tying the generation of new neurons to the process of making memories. Josselyn and Frankland knew that in infancy, the brain makes a lot of new neurons, but that neurogenesis slows with age. Yet youngsters have more trouble making long-term memories than adults do, a notion that doesn’t quite jibe with the idea that the principal function of neurogenesis is memory formation.
To test the connection between neurogenesis and forgetting, the researchers put mice in a box and shocked their feet with an electric current, then returned the animals to their home cages and either let them stay sedentary or had them run on a wheel, an activity that boosts neurogenesis. Six weeks later, the researchers put the mice back in the box where they had received the shocks. There, the sedentary mice froze in fear, anticipating a shock, but the mice that had run on a wheel didn’t show signs of anxiety. It was as if the wheel-running mice had forgotten they’d been shocked before.
Frankland says that this sort of active erasure of memories makes sense, because remembering everything that happens can overload the brain; some memories, such as what exactly we did last week, need to be cleared out to make room for new information. While scientists don’t know yet exactly how the brain maintains memories, some suggest that neuronal connections play a role. Neurogenesis may help erase memories, then, if new neurons make their way into established brain circuits and tweak the existing network of synapses.
But neurogenesis might not be the only way memories are removed from the brain, notes Yan Gu, a neuroscientist at Zhejiang University School of Medicine in Hangzhou, China. Research that he and others have carried out since Josselyn and Frankland’s study shows that immune cells called microglia also aid in forgetting, eating away at the connections among nerve cells where memories may reside.
Gu and colleagues made this finding in 2019 in a series of experiments in which they manipulated the numbers of microglia and new neurons in the brains of mice. From past studies, the team knew that microglia remove extra synapses early in life. Given synapses’ suspected role in memory storage, the team wondered whether there was a connection between microglia and memory. To test the idea, the team repeated the experiment Josselyn and Frankland had run, putting adult mice in an unfamiliar cage, then shocking their feet with electricity.
The work provides solid evidence for microglia’s role in forgetting.
The team then returned the mice to their home cages and used a drug to wipe out microglia in some of the animals’ brains, particularly in the dentate gyrus, the specific region of the hippocampus where new neurons are made. When put back into the cage where they’d been shocked, the drug-treated mice froze while the untreated mice didn’t, suggesting that mice with reduced microglia had held onto their memory of the foot shocks better than mice with normal levels of the immune cells.
“After we found depleting microglia prevented forgetting, we then started to investigate why and how microglia regulate forgetting in the brain,” Gu writes in an email to The Scientist. One of the first tests the team did was to determine how mice behaved if they had normal levels of microglia but the immune cells weren’t able to consume synapses as they normally do. Mice given a drug to block microglia’s eating behaviors remembered the foot shock better than mice not given the drug, the team found, confirming that their propensity for forgetting had to do with the immune cells’ ability to manipulate connections among nerve cells.
The team then gave another set of mice a drug to boost hippocampal neurogenesis, followed by the drug that blocked microglia from manipulating synapses. Again, the mice froze in the shock box more than untreated mice did, showing that even boosting neurogenesis—which Josselyn and Frankland had found promotes forgetting—couldn’t counteract the memory-protecting effects of knocking out the microglia.
“This connection between microglia and forgetting is fascinating,” says Jorge Valero, a neuroscientist at the Achucarro Basque Center for Neuroscience in Leioa, Spain, who wasn’t involved in Gu’s work but also studies microglia’s role in this phenomenon. Valero and his colleagues recently reported in the Journal of Neuroscience that the immune cells gobble down newly made neurons tagged for cell death. When they ingest those new neurons, the microglia begin to secrete chemicals that reduce neurogenesis.
Curious whether microglia’s memory-destroying activity is dependent on neurogenesis, or whether it can still occur even when neurogenesis is absent, Gu’s team tried their experiments again, this time wiping out microglia in a region of the hippocampus where there’s no neurogenesis. Again, the mice without microglia froze longer when put back into the box where they’d been shocked than mice who still had normal numbers of microglia, indicating that microglia aid in the forgetting of memories that are not tied to newly made neurons at all, the team reported in Science in February.
“It looks like a very careful study,” says the Stony Brook University School of Medicine’s Stella Tsirka, who was not involved in the research. She’s studied microglia for several decades and has long suspected that the cells have a function not only in immune responses during disease but in the normal, healthy brain. Gu’s work provides solid evidence for microglia’s role in forgetting in the hippocampus, she says, though it’s not yet clear if the immune cells also munch on memories in other regions of the brain.