Driving brain rhythm makes mice more sensitive to touch

By striking up the right rhythm in the right brain region at the right time, Brown University neuroscientists report in Nature Neuroscience that they managed to endow mice with greater touch sensitivity than other mice, making hard-to-perceive vibrations suddenly more vivid to them.

The findings offer the first direct evidence that “gamma” brainwaves in the cortex affect perception and attention. With only correlations and associations as evidence before, neuroscientists have argued for years about whether gamma has an important role or whether it’s merely a byproduct — an “exhaust fume” in the words of one — of such brain activity.

“There’s a lot of excitement about the importance of gamma rhythms in behavior, as well as a lot of skepticism,” said co-lead author Joshua Siegle, a former graduate student at Brown University and MIT, who is now at the Allen Institute for Neuroscience. “Rather than try to correlate changes in gamma rhythms with changes in behavior, which is what researchers have done in the past, we chose to directly control the cells that produce gamma.”

The result was a mouse with whiskers that were about 20 percent more sensitive.

“There were a lot of ways this experiment could have failed but instead to our surprise it was pretty decisive from the very first subject we looked at — that under certain conditions we can make a super-perceiving mouse,” said Christopher Moore, associate professor of neuroscience at Brown and senior author of the study. “We’re making a mouse do better than a mouse could have done otherwise.”

Specifically, Moore and co-first authors Siegle and Dominique Pritchett performed their experiments by using optogenetics — a technique of using light to control the firing patterns of neurons — to generate a gamma rhythm by manipulating inhibitory interneurons in the primary sensory neocortex of mice. That part of the brain controls a mouse’s ability to detect faint sensations via its whiskers.

A different part of the brain handles stronger, more imposing sensations, Moore said. The primary sensory neocortex, a particular feature of mammals, has the distinction of allowing an animal to purposely pay attention to more subtle sensations. It’s the difference between the feeling of gently brushing a fingertip along a wood board to assess if it needs a bit more sanding and the feeling of dropping the wood board on a foot.

Before anything else in the paper, the researchers confirmed that mice naturally produce a 40-hertz gamma rhythm in their sensory neocortex sometimes. Then they optogenetically generated that gamma rhythm with precise pulses of blue light. Mice with this rhythm could more often detect the fainter vibrations the researchers supplied to their whiskers than could mice who did not have the rhythm going in their brains.

Control and optogenetically stimulated mice alike had been conditioned to indicated their detection of a supplied stimulus by licking a water bottle. The vibrations provided to the mice to sense covered a span of 17 different levels of detectability.

The team’s hypothesis was that the gamma rhythm of the stimulated neurons, because they inhibit the transmission of sensation messages by pyramidal neurons in the neocortex with a structured periodicity, actually orders the pyramidal messages into a more coherent and therefore stronger train.

“It’s not surprising that these synchronized bursts of activity can benefit signal transmission, in the same way that synchronized clapping in a crowd of people is louder than random clapping,” Siegle said.

This idea suggested that the timing of the rhythm matters.

So in another experiment, Siegle, Pritchett, and Moore varied the onset of the gamma rhythm by increments of 5 milliseconds to see whether it made a difference to perception. It did. The mice showed their increased sensitivity only so long as the gamma rhythms were underway 20-25 milliseconds before the subtle sensations were presented. If they weren’t, the mice experienced on average no impact on sensitivity.

One of the key implications from the findings for neuroscience, Moore said, is that the way gamma rhythms appear to structure the processing of perception is more important than the mere firing rate of neurons in the sensory neocortex. Mice became better able to feel not because neurons became more active (they didn’t), but because they were entrained by a precisely timed rhythm.

Although the study provides causal evidence of a functional importance for gamma rhythms, Moore acknowledged, it still leaves open important questions. The exact mechanism by which gamma rhythms affect sensation processing and attention are not proved, only hypothesized.

And in one experiment, optogenetically stimulated mice appeared less able to detect the most obvious and imposing of the sensations, even as they became more sensitive to the more subtle ones. In other experiments, however, their detection of major sensations was not compromised.

But the possible loss of sensitivity to stimuli that are easier to feel could be consistent with a shifting of attention to fainter ones, said Pritchett, also a former Brown and MIT student now at the Champalimaud Centre for the Unknown in Lisbon, Portugal.

“What we are showing is that, paradoxically, the rhythmic inhibitory input works to amplify threshold stimuli, possibly at the expense of salient stimuli,” he said. “This is precisely what you would expect from a mechanism that might be responsible for selective attention in the brain.”

Therefore, Siegle, Pritchett, and Moore say they do have a better feel now for what’s going on in the brain.

Memory relies on astrocytes, the brain’s lesser known cells

When you’re expecting something—like the meal you’ve ordered at a restaurant—or when something captures your interest, unique electrical rhythms sweep through your brain.

These waves are called gamma oscillations and they reflect a symphony of cells—both excitatory and inhibitory—playing together in an orchestrated way. Though their role has been debated, gamma waves have been associated with higher-level brain function, and disturbances in the patterns have been tied to schizophrenia, Alzheimer’s disease, autism, epilepsy and other disorders.

Now, new research from the Salk Institute shows that little known supportive cells in the brain known as astrocytes may in fact be major players that control these waves.

In a study published July 28 in the Proceedings of the National Academy of Sciences, Salk researchers report a new, unexpected strategy to turn down gamma oscillations, by disabling not neurons but astrocytes—cells type traditionally thought to provide more of a support role in the brain. In the process, the team showed that astrocytes, and the gamma oscillations they help shape, are critical for some forms of memory.

"This is what could be called a smoking gun," says co-author Terrence Sejnowski, head of the Computational Neurobiology Laboratory at the Salk Institute for Biological Sciences and a Howard Hughes Medical Institute investigator. "There are hundreds of papers linking gamma oscillations with attention and memory, but they are all correlational. This is the first time we have been able to do a causal experiment, where we selectively block gamma oscillations and show that it has a highly specific impact on how the brain interacts with the world."

A collaboration among the labs of Salk professors Sejnowski, Inder Verma and Stephen Heinemann found that activity in the form of calcium signaling in astrocytes immediately preceded gamma oscillations in the brains of mice. This suggested that astrocytes, which use many of the same chemical signals as neurons, could be influencing these oscillations.

To test their theory, the group used a virus carrying tetanus toxin to disable the release of chemicals released selectively from astrocytes, effectively eliminating the cells’ ability to communicate with neighboring cells. Neurons were unaffected by the toxin.

After adding a chemical to trigger gamma waves in the animals’ brains, the researchers found that brain tissue with disabled astrocytes produced shorter gamma waves than in tissue containing healthy cells. And after adding three genes that would allow the researchers to selectively turn on and off the tetanus toxin in astrocytes at will, they found that gamma waves were dampened in mice whose astrocytes were blocked from signaling. Turning off the toxin reversed this effect.

The mice with the modified astrocytes seemed perfectly healthy. But after several cognitive tests, the researchers found that they failed in one major area: novel object recognition. A healthy mouse spent more time with a new item placed in its environment than it did with familiar items, as expected.

In contrast, the group’s new mutant mouse treated all objects the same. “That turned out to be a spectacular result in the sense that novel object recognition memory was not just impaired, it was gone—as if we were deleting this one form of memory, leaving others intact,” Sejnowski says.

The results were surprising, in part because astrocytes operate on a seconds- or longer timescale whereas neurons signal far faster, on the millisecond scale. Because of that slower speed, no one suspected astrocytes were involved in the high-speed brain activity needed to make quick decisions.

"What I thought quite unique was the idea that astrocytes, traditionally considered only guardians and supporters of neurons and other cells, are also involved in the processing of information and in other cognitive behavior," says Verma, a professor in the Laboratory of Genetics and American Cancer Society Professor.

It’s not that astrocytes are quick—they’re still slower than neurons. But the new evidence suggests that astrocytes are actively supplying the right environment for gamma waves to occur, which in turn makes the brain more likely to learn and change the strength of its neuronal connections.

Sejnowski says that the behavioral result is just the tip of the iceberg. “The recognition system is hugely important,” he says, adding that it includes recognizing other people, places, facts and things that happened in the past. With this new discovery, scientists can begin to better understand the role of gamma waves in recognition memory, he adds.

Laughter May Work Like Meditation in the Brain

Laughter triggers brain waves similar to those associated with meditation, according to a small new study.

It also found that other forms of stimulation produce different types of brain waves.

The study included 31 people whose brain waves were monitored while they watched humorous, spiritual or distressing video clips. While watching the humorous videos, the volunteers’ brains had high levels of gamma waves, which are the same ones produced during meditation, researchers found.

During the spiritual videos, the participants’ brains showed higher levels of alpha brain waves, similar to when a person is at rest. The distressing videos caused flat brain wave bands, similar to when a person feels detached, nonresponsive or doesn’t want to be in a certain situation.

Researchers were led by Lee Berk, an associate professor in the School of Allied Health Professions, and an associate research professor of pathology and human anatomy in the School of Medicine, at Loma Linda University, in California.

The study was scheduled to be presented Sunday at the Experimental Biology meeting held in San Diego. The data and conclusions should be viewed as preliminary until published in a peer-reviewed journal.

“What we have found in our study is that humor associated with mirthful laughter sustains high-amplitude gamma-band oscillations. Gamma is the only frequency found in every part of the brain,” Berk said in a university news release.

“What this means is that humor actually engages the entire brain — it is a whole brain experience with the gamma wave band frequency and humor, similar to meditation, holds it there; we call this being ‘in the zone,’” Berk explained.

He said that with laughter, “it’s as if the brain gets a workout.” This effect is important because it “allows for the subjective feeling states of being able to think more clearly and have more integrative thoughts,” Berk said. “This is of great value to individuals who need or want to revisit, reorganize or rearrange various aspects of their lives or experiences, to make them feel whole or more focused.”

Oops! Researchers find neural signature for mistake correction

Culminating an 8 year search, scientists at the RIKEN-MIT Center for Neural Circuit Genetics captured an elusive brain signal underlying memory transfer and, in doing so, pinpointed the first neural circuit for “oops”—the precise moment when one becomes consciously aware of a self-made mistake and takes corrective action.