Sleep deprivation screws your memory by messing with the neuronal connectivity

The hippocampus (sea horse) area has been a known structure of our brain since the ancient Greeks.

But don’t worry, recovery sleep reverses them back to normal.

Humans need to spend a significant time of their lives asleep. In modern society, where demands are high, insufficient sleep is a common byproduct for millions of people. It is a well reported phenomenon that sleep deprivation (=loss of sleep) is associated with learning and memory impairment and that forced long-term loss of sleep has caused death in lab animals.

For many decades, researchers have been investigating the hippocampus, a walnut sized structure of the brain, and its importance for memory and spatial orientation. In fact, the hippocampus is often one of the first regions that suffer damage from onset of Alzheimer’s disease, which is characterized by short-term memory loss and disorientation.

A few years ago, researchers also identified the hippocampus as the most prominent brain region being affected during sleep deprivation. However, until recently, the molecular mechanisms of memory impairment during extended wakefulness have been unclear.

In a recent paper, researchers affiliated with the University of Pennsylvania together with collaborators all over the Netherlands, UK, US and Poland, showed that the protein cofilin acted differently in a specific part of the hippocampus, called CA1, upon sleep deprivation. Cofilin works in the brain by breaking down actin filaments which shape the connections between neurons.

Imagine connections between neurons as bridges between two parts of a city; the actin filaments are the steel bars of those bridges, and Cofilin is a “bulldozer“ tearing those bridges down to free up space.

When we sleep, our brain builds new bridges between neurons according to traffic demands; neurons that communicated a lot with each other get more bridges, neurons that did not communicate get no or very few bridges. The architecture and strength of the connections between neurons define how well we learn new things and how good we can remember them. Have you ever experienced that you memorize things better if you can put them into context?

For example, it is damn hard for anybody to memorize a random date in history for a long period of time, but when it comes to the birthday of a loved one, it’s astonishingly easy to keep several of them in mind. It is easier because we remember not only the abstract date, but also the persons and circumstances; maybe the last party with them, which was in winter, because you remember being cold. That’s why you had tee with schnapps, together with your wife, and she promised her birthday will be on the beach next year, since you already booked the trip to Hawaii in March. That’s how your brain remembers these birthday dates easily.
Simply put, memory is an effect of neuronal connectivity; the more different facts we can group together, the easier we will remember.

Neurons that fire together, wire together.

One of the “evangelical” rules of thump in neuroscience.

Now, researchers found out some time ago that we need sleep to build those bridges (wires, connections) between neurons in order for our memory and learning to work properly. The scientific term is memory consolidation, and sleep is absolutely necessary for it.

In contrast, during wakefulness, the Cofilin “bulldozer” is active and destroys all the unnecessary ancient bridges that had been built in our sleep. It is basically the cleaning up/maintaince service after a night of work building connections. Both, building and destroying neuronal connections is absolutely necessary to ensure synaptic plasticity (=dynamic formability of connections), without it learning or memories would be impossible.

The question Havekes and colleagues addressed was not only how the “bulldozer”-protein Cofilin functions, but also why the “bulldozer” is switched on during the day and who turns it off during sleep.

In their investigation, they also found that a signal protein called PDE4A5, which is highly produced in the hippocampus and acts as an inhibitor to cAMP signaling, is overly activated by sleep deprivation.

In our “bulldozer” analogy, PDE4A5 would be the “supervisor” telling the bulldozer driver to take some extra shifts. These extra shifts upset the balance of creating new bridges and cleaning away the old ones; we need both processes to work properly for our memory to function. By refusing to give our body enough sleep, we are similar to the employer who demands from his employees to work overtime without compensation. This is not healthy.

The good news: Once we’ve been exposed to sleep deprivation, the damage done to our neuronal bridges can be reversed by getting recovery sleep. In Havekes study, even as little as 3 hours of recovery sleep allowed his mice to bounce back to normal neuronal structure.

A little advice for people who do not sleep enough: Just try be a good employer, go to sleep and allow your inner bulldozer to rest and to consume his overtime compensation.
Sleep deprivation increases PDE4A5 protein levels that cause a reduction in cAMP levels and attenuation of the PKA-LIMK signaling pathway, which results in a reduction in the phosphorylation of cofilin. Dephosphorylated cofilin can lead to spine loss. Suppressing PDE4A5 function or attenuating cofilin activity through viral expression of a catalytically inactive forms prevents the loss of dendritic spines, impairments in synaptic plasticity, and memory deficits associated with sleep loss. Proteins whose function is reduced after sleep deprivation are shown in blue. Proteins whose function is promoted by sleep deprivation are shown in red.

Finally, as a proof of principle, once Havekes and collagues exchanged the “supervisor” protein PDE4A5 with an inactive “dummy” version, they could let the “bulldozer” rest even during prolonged wakeness and thus were able to prevent exzessive loss of neuronal “bridges” in mice brains.

However, do not be fooled into believing that replacing the “supervisor” or “bulldozer” proteins permanently is a good option. As in real life, eventually morning comes and somebody will have to clean up the mess we made during the night.



This story is part of advances in biological sciences, a science communication plattform that aims to explain ground-breaking science in the field of biology, medicine, biotechnology, neuroscience and genetics to literally everyone. Scientific understanding has too much barriers, let’s break them down!

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