Human-approved drugs bring back ‘lost’ memories in mice

Summary: Roflumilast, a drug commonly prescribed for the treatment of COPD and asthma, helps regain learning memories after a period of sleep deprivation in mice.

Source: University of Groningen

Students sometimes spend an all-nighter to prepare for an exam. However, research has shown that sleep deprivation is bad for memory.

Now University of Groningen neuroscientist Robbert Havekes has discovered that what you learn while being sleep deprived isn’t necessarily lost, it’s just hard to remember.

He and his team found a way to make this “hidden knowledge” accessible again within days of studying sleep deprivation using optogenetic approaches and the human-approved asthma drug roflumilast.

These results were published on December 27 in the journal Current biology.

Havekes, associate professor of memory and sleep neuroscience at the University of Groningen, the Netherlands, and his team have studied extensively how sleep deprivation affects memory processes.

“We previously focused on finding ways to support memory processes during an episode of sleep deprivation,” says Havekes. However, in their latest study, their team examined whether amnesia resulting from sleep deprivation was a direct result of information loss or simply caused by difficulties retrieving information.

“Sleep deprivation undermines memory processes, but every student knows that an answer that eluded them during the exam can surface hours later.” In this case, the information was actually stored in the brain, but difficult to retrieve.

Seahorse

To answer this question, Havekes and his team used an optogenetic approach: Using genetic techniques, they induced a light-sensitive protein (channelrhodopsin) to be produced selectively in neurons that are activated during a learning experience. This helped to remember a particular experience by shedding light on these cells.

“In our sleep deprivation studies, we applied this approach to neurons in the hippocampus, the area of ​​the brain where spatial information and factual knowledge is stored,” says Havekes.

First, the genetically modified mice were given a spatial learning task in which they had to learn the location of individual objects, a process that relies heavily on neurons in the hippocampus. The mice then had to perform this same task a few days later, but this time with an object moved to a new location. Mice that were sleep-deprived for a few hours before the first session failed to detect this spatial change, suggesting that they cannot remember the original locations of objects.

“However, when we reintroduced them to the task after reactivating the hippocampal neurons that initially stored this information with light, they were able to remember the original locations,” says Havekes.

“This shows that information was stored in the hippocampus during sleep deprivation, but could not be retrieved without the stimulation.”

Memory issues

The molecular pathway triggered during reactivation is also targeted by the drug roflumilast, used by patients with asthma or COPD.

Havekes: “When we gave trained mice roflumilast while they were sleep deprived just before the second test, they remembered, just as it did with direct stimulation of neurons. »

As roflumilast is already clinically approved for use in humans and known to enter the brain, these findings open avenues to test whether it can be applied to restore access to “lost” memories in humans. the man.

This shows neurons in the hippocampus
High magnification image showing a portion of the mouse hippocampus in which a sparse population of neurons coding for a specific learning event is labeled in red. Neurons that are not activated by the learning event are displayed in blue. Credit: Havekes l\Lab / University of Groningen

The discovery that more information is present in the brain than we previously expected and that these “hidden” memories can be accessed again – at least in mice – opens up all sorts of exciting possibilities.

“It might be possible to boost memory accessibility in people with age-related memory problems or early-stage Alzheimer’s disease with roflumilast,” says Havekes.

“And perhaps we could reactivate specific memories to make them permanently retrievable again, as we have successfully done in mice.”

If a subject’s neurons are stimulated by the drug as they try to “relive” a memory or revise information for an exam, that information might be reconsolidated more firmly in the brain. “At the moment this is all speculation of course, but time will tell.”

At present, Havekes is not directly involved in such studies in humans. “My interest lies in uncovering the molecular mechanisms that underlie all these processes,” he explains.

See also

It shows a woman running

‘What makes memories accessible or inaccessible? How does roflumilast restore access to these “hidden” memories? As always with science, by tackling a question you get many new questions for free.

About this neuropharmacology and memory research news

Author: Rene Fransen
Source: University of Groningen
Contact: René Fransen – University of Groningen
Picture: Image is credited to Havekes l\Lab / University of Groningen

Original research: Free access.
“Recovery of object location memories after sleep deprivation-induced amnesia” by Robbert Havekes et al. Current biology


Summary

Recovery of object location memories after sleep deprivation-induced amnesia

Strong points

  • Sleep deprivation-induced amnesia is a memory retrieval problem
  • Activation of memory engrams after sleep deprivation restores memory retrieval ability
  • Amnesia due to sleep loss can be permanently reversed days after learning
  • Roflumilast and optogenetics can be used to restore memory access

Summary

It is well established that sleep deprivation after learning impairs hippocampal memory processes and can cause amnesia. It is unclear, however, whether sleep deprivation results in the loss of information or simply the suboptimal storage of hard-to-retrieve information.

Here, we show that location memories of hippocampal objects formed under sleep deprivation conditions can be successfully retrieved several days post-training, using optogenetic activation of the dentate gyrus memory engram ( DG) or treatment with roflumilast, a clinically approved phosphodiesterase 4 (PDE4) inhibitor.

Moreover, the combination of optogenetic activation of the DG memory engram and roflumilast treatment, 2 days after training and sleep deprivation, made memory more persistently accessible for recovery even for several days. later (i.e. without further optogenetic or pharmacological manipulation).

Overall, our studies in mice demonstrate that sleep deprivation does not necessarily cause memory loss, but rather leads to suboptimal storage of information that cannot be retrieved without drug treatment or optogenetic stimulation.

Moreover, our results suggest that object location memories, consolidated under sleep deprivation conditions and previously thought to be lost, can be made accessible again several days after the learning and deprivation episode. sleep, using roflumilast, a clinically approved PDE4 inhibitor.

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