Electrical 'pulses' in resting brain mark memories for storage

New experiments show how the brain chooses which memories to keep, and support advice on the importance of rest

György Buzsáky first began studying waves when he was in high school. In his childhood home in Hungary, he built a radio receiver, tuned it to different electromagnetic frequencies, and used the transmitter to communicate with strangers from the Faroe Islands to Jordan.

He remembers some of these conversations better than others, just as you remember only some events from your past. Now a professor of neuroscience at New York University, Buzsaki has moved from radio waves to brain waves, asking: How does the brain decide what to remember?

By studying the brain’s electrical circuitry, Buzsaki seeks to understand how our experiences are represented and stored as memories. New research from his lab and others has shown that the brain marks experiences worth remembering by repeatedly sending out sudden, powerful, high-frequency brain waves. Known as “sharp wave pulsations,” these waves, caused by many thousands of neurons firing within milliseconds of each other, are “like fireworks in the brain,” says Vannan Yang, a doctoral student in Buzsaki’s lab who leads the new workswhich was published in the journal Science in March. They are triggered when mammals' brains are at rest — during breaks between tasks or during sleep.

Sharp wave pulsations were already known to be involved in the consolidation or storage of memories. The new study shows that they are also involved in their selection, indicating the importance of these waves in the formation of long-term memory.

It also provides a neurological basis for why rest and sleep are important for retaining information. The brain seems to run different programs when it’s awake and when it’s at rest. If you’re always asleep, you won’t form memories. If you’re always awake, you won’t form them either. “If you only do one thing, you’ll never learn anything,” Buzsaki says. “You have to have breaks.”

It is during these breaks that the fireworks begin.

Brain rehearsal

Buzsaki will never forget the first time he heard a sharp ripple. It was 1981, and he was a postdoc at the University of Western Ontario, listening to the brain activity of anesthetized rodents through a loudspeaker. Over nine years of research, he had become accustomed to the rhythmic, melodic oscillations that the awake animals made as they explored their environment. He was not prepared for the sudden “ping” that came from the speaker as the rodents slept.

For Buzsaki, the sound was as meaningful as the dramatic refrain of Beethoven's 5th Symphony. “Da-da-da-DA,” he sang, remembering his shock. And then another ringing: “Da-da-da-DA.”

What happened? When awake, the rodents' brains generated electrical activity that oscillated at a steady rate. But when they were anesthetized, their brains seemed to generate much faster waves irregularly.

Other researchers had observed rapid waves, too. Buzsáki’s postdoc Cornelius Vanderwolf described the irregular waves in 1969, and Nobel Prize-winning neuroscientist John O’Keefe coined the term “pulsation” to describe them in the 1970s. But it wasn’t until Buzsáki heard them himself that he became obsessed.

Over the next decade, he spent much of his lab time trying to characterize these electrical spikes. In the late 1980s, researchers discovered that they could coax neurons into making stronger connections associated with learning and memory by artificially stimulating them to fire rapidly. To Buzsáki, these spikes reminded him of his favorite waves. In 1989, he first hypothesized that sharp, wavelike pulsations might be part of the mechanism by which memories are formed and consolidated in the brain.

“He had the idea that this wasn’t just some noise, that this activity had meaning in the brain,” says Michael Zugaro, a neuroscientist at the Collège de France who worked as a postdoc in Buzsaki’s lab in 2002. “There was a lot of anticipation about what was going to happen, because very little was known at the time.”

In the 1990s and early 2000s, researchers took advantage of increased computing power and new tools that could record the electrical activity of more than 100 neurons at once to better characterize sharp waves. Buzsáki and others found that these pulses seemed to mimic animal brain activity, such as running a maze, except that the pulses oscillated 10 to 20 times faster than the original signals. One 2002 paper that “made sharp waves famous” found that sharp waves reactivated a pattern of neuronal activity, says Hiroaki Norimoto, a professor of neuroscience at Nagoya University in Japan.

In 2009 and 2010, two studies, including one led by Zugaro, showed that sharp wave pulses are involved in consolidating memories that last for a long time. When the researchers suppressed or disrupted these pulses, rats performed worse on memory tasks. “When you destroy them, the animal no longer remembers,” Zugaro says. Later studies found that lengthening or creating more pulses improved the rats’ memory.

It became clear that the pulsations were being played over and over again to solidify the memory. “The brain is rehearsing,” says Leela Davachi, a professor of psychology at Columbia University. “Even when you’re awake, your brain is still rehearsing and replaying the past.”

Think of your experience as “a melody on a piano,” says Daniel Bendor, a neuroscientist at University College London. A specific pattern of neurons fires to record your experience, like a pianist tapping out a specific sequence of keys. Then, during sleep, the hippocampus plays back that pattern — but faster, and potentially hundreds or thousands of times. Wild, sharp waves spread from the hippocampus, which is the brain’s gateway for “episodic memories” of a particular experience, to the cerebral cortex, which is involved in storing long-term memory.

However, no one could explain why the pulsations spread when the animal was awake and resting. “[Они] must serve some other purpose,” Bendor recalls. Scientists had many ideas. Some suggested that the pulsations during wakefulness helped with planning or decision-making. Others suggested that they somehow altered or reordered memories.

Another idea proposed by several groups was that waking recall and sleep recall are closely linked and may be the mechanism by which the brain chooses which experiences to remember.

Memory tests

At New York University, a room with infrared lighting contained boxes of resting and sleeping mice. In the next room were mazes made of plastic and tape. One by one, the mice were placed in the mazes. They ran around wearing electrodes that recorded the activity of about 500 neurons in the hippocampus and learned that completing certain routes would reward them with water. As they explored the maze, the mice took short breaks to rest or clean themselves. After the tests were over, they were returned to their home cages for a nap. The researchers continued to record their brain activity while they slept.

Young analyzed the data, mapping which neurons fired during different trials. She saw a wide range: Some neurons fired during early trials, others during later trials. Sometimes they fired at different rates. This suggests that the brain was registering the animal’s experience differently during individual trials. Notably, some trials were followed by bursts of sharp wavelike pulsations, while others were not.

She then compared the brain activity recorded while the mice were running the maze with the corresponding pulsations that appeared later. The trials that were repeated more frequently when the mice were resting were the same trials that were repeated when they were sleeping. And the trials that weren't repeated when the mice were awake weren't repeated when they were sleeping.

The team concluded that resting-state ripples may be a mechanism by which the brain prioritizes experiences for remembering. “It’s possible that ripples during wakefulness are memory markers that consolidate certain experiences for long-term storage,” says Young. “In contrast, those that aren’t marked are not recalled during sleep and are forgotten.”

“There must be some sorting to remember what’s important and forget the rest,” Zugaro says. “Understanding how specific memories are selected for storage has been missing until now. … Now we have a good lead.”

Last December, a team led by Bendor at University College London published results in Nature Communications that anticipated Yang and Buzsaki’s. They, too, found that the sharp wavelike pulsations that rats experience while awake and asleep seem to mark experiences for memory. But their analysis averaged across different experiences, an approach that is less precise than Yang and Buzsaki’s.

The key innovation of the NYU team was to include the element of time, which distinguishes similar memories from one another. The mice ran the same mazes, but the researchers were able to distinguish between blocks of trials at the neuronal level, something that had never been achieved before.

The brain patterns mark “something that’s more intimate with the event and less like general knowledge,” says Lauren Frank, a neuroscientist at the University of California, San Francisco, who was not involved in the study. “I think that’s a really interesting finding.”

“They show that the brain may be creating some kind of temporal code to distinguish between different memories that occur in the same place,” says Freya Olafsdottir, a neuroscientist at Radboud University who was not involved in the work.

Shantanu Jadhav, a neuroscientist at Brandeis University, praised the study. “It’s a good start,” he said. But he hopes to see a follow-up study that includes a behavioral test. Demonstrating that an animal forgets or remembers certain trial blocks would be “real proof that this is a cueing mechanism.”

The study leaves a burning question unanswered: Why are some experiences chosen over others? The new work suggests how the brain flags certain experiences for remembering. But it can’t tell us how the brain decides what’s worth remembering.

Sometimes what we remember seems random or unimportant, and certainly different from what we would choose if given the choice. It seems that the brain prioritizes based on “importance,” Frank says. Since research shows that emotional or novel experiences are remembered better, it’s possible that internal fluctuations in arousal or levels of neuromodulators like dopamine or adrenaline and other chemicals that affect neurons ultimately select experiences, he suggests.

Jadhav echoed that idea, saying, “The internal state of the organism may influence whether an experience is encoded and stored more effectively.” But it’s not known what makes one experience more likely to be stored than another, he added. And in the case of Yang and Buzsaki’s study, it’s not clear why the mouse remembers one trial better than another.

Buzsáki continues to study the role of sharp waves in the hippocampus, though he and his team are also interested in the potential applications that might arise from these observations. For example, it’s possible that scientists could disrupt the waves as a treatment for conditions like post-traumatic stress disorder, in which people remember certain experiences too vividly, he said. “The simple result here is that you can erase the sharp waves and forget what you experienced.”

But for now, Buzsaki will continue to monitor these powerful brain waves to learn more about why we remember what we remember.