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NEUROSCIENCE

What our memories retain

New connections form between brain cells during REM sleep – the dream stage

Sono_fapesp_sandrajavera_ilustraSandra JaveraIt has been common knowledge for a while now that during sleep, the brain consolidates memories of recent important events. One has to be awake and aware to register new information. But the changes in brain circuits that will capture that information and allow it to be recorded at a later time occur only later, during sleep. Specialists in sleep and memory formation appear to be in agreement up to this point. They part company, however, when it comes to how memories are consolidated and in what stage of sleep this occurs. A recent study conducted by Brazilian researchers has put to rest some doubts and challenged the prevailing explanation to date about what causes memories to be solidified during sleep.

In a series of experiments conducted on rats, the animal models used for sleep and memory studies, researchers in São Paulo and Rio Grande do Norte showed that during sleep, the weakest connections (synapses) between brain cells are pruned or eliminated, as two Italian researchers had proposed in 2003. But the Brazilian scientists confirmed that, when the animal is asleep, synapses are also strengthened. “The model proposed by Giulio Tononi and Chiara Cirelli is not incorrect, but it is incomplete because it accounts for only part of what is really happening,” says neuroscientist Sidarta Ribeiro, a researcher at the Federal University of Rio Grande do Norte (UFRN) and coordinator of the new study.

In the study, published in the journal Neurobiology of Learning and Memory, Ribeiro and his collaborators recreated a situation in the laboratory that simulates learning and then monitored what happened in the animals’ brains. In the experiment, biologist Julien Calais placed rats (one at a time) in a box they were already familiar with and let them freely explore their surroundings. He then added four objects, which he had made himself with shoeshine brushes, pieces of tubing and nails and which were new to the animals. Since rats are curious creatures with nocturnal habits, Calais used an infrared camera that allowed him to film in the dark to confirm that the rat he was observing wanted to explore the new toys.

Calais waited for the rat to take some time to poke the objects with his vibrissae (whiskers) after which he kept the animal awake for the 90 minutes following the exercise. He then let the animal sleep for three hours, during which time he monitored his sleep with devices that register changes in the brain’s electrical activity. With the assistance of geneticist Elida Ojopi and neurologist Koishi Sameshima, Calais observed that during REM sleep – the shortest of the four sleep stages, during which dreaming occurs – certain protein-coding genes that form synapses are activated in the hippocampus, the region of the brain that functions as the memory’s front door.

This result was a surprise to some observers. Several years ago, Tononi and Cirelli had demonstrated that, in general, these genes gradually turn off as the rats begin to nod off and then fall into a deeper sleep. Based on this data and data from other studies, they proposed the so-called theory of synaptic homeostasis. According to this idea, any new piece of information – a piece of music that has never been heard before, for example – is transformed into a memory through a series of chemical changes initiated during the wakefulness stage dedicated to creating new connections between neurons. During sleep, the weakest connections, based on events that will be forgotten, are undone. It is as if sleep prunes away less important information, like a gardener trimming away memories from a tree.

Sidarta Ribeiro was still not convinced however. He believed the Italian researchers had based their findings on experiments that were not robust enough to support the theory of synaptic homeostasis. Ribeiro began to study sleep during his dissertation work under the supervision of Claudio Vianna de Mello and Constantine Pavlides at Rockefeller University in the United States. In 1999, he showed that during REM sleep, there was an increased expression in some genes, although this did not always happen. Gene activation occurred only if the animal had been exposed to new information – in other words, if it had learned something new – before falling asleep.

Etched in memory
This result led Ribeiro to plan the experiments, carried out by Calais, which showed that genes linked to synapse formation were deactivated during slow wave sleep and some of them were reactivated in a subsequent stage, REM sleep – also known as paradoxical sleep, because the brain is as active in this phase as during the wakefulness phase. These results matched the studies run by Ribeiro over the course of the last 15 years and bolstered the theory he formulated in 2004, when he was still working with Miguel Nicolelis at Duke University.

According to this theory, consolidating memories involves both the activation of some genes and strengthening of connections as well as deactivation of other genes and the elimination of synapses during sleep. Ribeiro compares this process, which begins in the hippocampus and then reaches the cortex, to the engraving of an image on a piece of wood. “The new information that is recorded is like the high-relief carving on a figurine,” he says.

Débora Hipólide, a biologist and professor at the Federal University of São Paulo (Unifesp) who studies the effects of sleep deprivation on memory and learning says that these data contain important information that explains the molecular basis of memory consolidation. They still do not establish which of the two theories describes the phenomenon better though.

“We have to investigate both the electrophysiological and the molecular parameters to get the range of information needed to corroborate either of the theories,” she says. According to Hipólide, the new study contributes an important finding, which reinforces the idea that REM sleep is critical for memory consolidation. “The genes that were active during the wakefulness stage are reactivated during REM sleep. It’s as if the brain revisits the information in this stage,” she says.

Project
Gene expression during sleep after exposure to an enriched environment (2006/05436-8); Grant Mechanism: Master’s degree scholarship (Julien Braga Calais Correia Pinto); Principal Investigator: Elida Paula Benquique Ojopi (FM-USP); Investment R$32,864.04 (FAPESP).

Scientific article
CALAIS, J. B. et al. Experience-dependent upregulation of multiple plasticity factors in the hippocampus during early REM sleep. Neurobiology of Learning and Memory. 2015.

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