Our memories may persist even when half of the brain connections that store them are wiped out, according to a study in dormant mice. The “remarkable” discovery tells us more about how memory works and could one day reveal ways to improve it.

“Memories may be harder to break than we thought,” says at Boston University, who wasn’t involved in the study. “This absolutely, substantially advances our understanding of how memory works.”

When we experience a stimulus, neurons in our sensory organs, like our eyes, transmit electrical signals to our brain. Neurons then process this information by firing electrical signals to each other via junctions called synapses.

These neurons, called engram neurons, encode information into a memory by forming new synapses and strengthening existing ones. Recalling a memory .

Many scientists think a memory persists as long as the specific pattern of synapses on the engram neurons encoding that memory is maintained. This is partly based on experiments that have used drugs or genetic tools to , says at the Okinawa Institute of Science and Technology in Japan.

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But recent studies suggest a memory persists in location or number. This has called into question “what’s necessary and sufficient to have a memory preserved”, says at Yale University.

To address this, Tanaka and his colleagues took inspiration from hibernating animals. “Under hibernation, brain activity seems to drop significantly,” he says. “But studies in natural hibernators show that somehow those animals, after arousal in the spring, seem to remember their friends and the location of food they hid before hibernation.”

By examining how memory is retained during hibernation, a situation in which the brain changes dramatically, the researchers hoped to unpick basic principles by which the mammalian brain stores memories long term. “The [researchers] very cleverly and creatively get at the question of memory by using hibernation as a way to poke and prod at the brain,” says Ramirez.

They applied weak electric shocks to the feet of mice – which don’t naturally hibernate – while they were in a chamber that smelled of alcohol, creating a fearful memory associated with that scent. The next day, the mice froze in fear upon being placed in the same chamber, without receiving shocks.

The researchers induced an artificial state of hibernation in about half the mice for two days. This was done by injecting them with drugs that slow metabolism and placing them in a dark chamber.

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Five days later, mice that had artificially hibernated still froze when placed in the alcohol-smelling chamber. This was despite brain scans revealing that more than half of the synapses within the engram neurons in their hippocampus – a brain region crucial for memory – disappeared during hibernation. “Despite massive brain remodelling during hibernation, the memories were retained,” says Tanaka.

Dragoi says the findings are relevant to people, since prior research has shown that our brains store information very similarly to mice. “It tells us something about how our mammalian brains may work,” says Ramirez.

The team also found that the hibernating rodents’ brains retained synapses that clustered closely together on the surface of engram neurons, while those outside these clusters disappeared. This suggests that clustered synapses specifically are crucial for retaining memory in the brain, says Tanaka.

Non-clustered synapses that were wiped out by hibernation reappeared within a day post-hibernation, indicating that, while clustered engram synapses are necessary to retain the information within memories, the non-clustered synapses may be important for accessing memories, he says.

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“This study is a remarkable step forward because it addresses a long-standing puzzle in memory research: how the brain retains long-term memories,” says at Vrije University Amsterdam in the Netherlands.

The team is exploring the molecular pathways through which clustered engram synapses store information and plans to dig into how non-clustered ones reappear, says Tanaka.

Targeting such pathways with drugs could even reveal ways to prevent or slow memory impairment, says Ramirez. “It gives hope that even in instances where information seems to be lost in the brain, whether it’s amnesia or Alzheimer’s disease, memory may nonetheless persist.”

In most of the body, histamine triggers an immune response, as people with hay fever know only too well. But in the brain, it seems to have a completely different role, with a small experiment demonstrating that boosting histamine levels improves the accuracy of our memory by around 10 per cent.

“We think it’s changing something called novelty-linked arousal,” says at the University of Oxford. “So, how alert we feel when we see new things in the environment.”

It’s long been known that there are receptors in the brain for detecting histamine. “They are densely packed around areas of the brain which are involved in learning and memory,” says Colwell. Animal studies support the idea that .

This might explain some of the , says Colwell. “A lot of those older ones got into the brain,” he says. “They would have made people less able to remember things, which you often see when people were taking those antihistamines for a long time.”

But what happens if the levels of histamine in the brain increase? There hadn’t been a way of testing this in people, but Colwell and his colleagues realised an existing drug used to treat narcolepsy, called pitolisant, has this effect. It binds to what are known as histamine 3 receptors and raises the molecule’s levels throughout the brain, he says.

To put it to the test, his team recruited 60 volunteers and gave half of them pitolisant and half a placebo. They then imaged their brains in an MRI scanner while they did various memory tests. The scans showed that in those given pitolisant, there was greater connectivity between the parts of the brain where histamine is made and the hippocampus, an area involved in memory. These people were also 11 per cent more accurate in retrieving information learned while they were in the scanner.

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But it would be a mistake to try to use pitolisant as a “smart drug”, says Colwell. “I would imagine it’s going to really affect sleep, and that’s going to make your memory much worse in the long term.”

at Hannover Medical School in Germany says there’s little danger of pistolisant being abused as a smart drug, as it should be very difficult for people to get hold of. He adds that the findings confirm that the results in non-human animals apply to people, too, and that this may boost interest in treating various brain conditions by targeting histamine receptors.

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People who take pitolisant to help treat narcolepsy or a genetic condition called Prader-Willi syndrome have previously reported improved attention and alertness, says at Heinrich Heine University in Düsseldorf, Germany, who helped create the drug. “A recurring finding has been that pitolisant can help restore impaired cognitive function and improve attention when these are compromised by disease,” he says. “In most cases, however, the effect has been to normalise impaired function rather than to enhance cognition beyond normal levels.”

The fact that histamine has two such different effects in the body also shows how evolution repurposes things. “I think the bigger picture is that this shows how economical the human body is,” says Colwell.