Posts Tagged ‘Carl Zimmer’

A mouse exploring one of the custom hologram generators used in the experiments at Stanford. By stimulating particular neurons, scientists were able to make engineered mice see visual patterns that weren’t there.

By Carl Zimmer

In a laboratory at the Stanford University School of Medicine, the mice are seeing things. And it’s not because they’ve been given drugs.

With new laser technology, scientists have triggered specific hallucinations in mice by switching on a few neurons with beams of light. The researchers reported the results on Thursday in the journal Science.

The technique promises to provide clues to how the billions of neurons in the brain make sense of the environment. Eventually the research also may lead to new treatments for psychological disorders, including uncontrollable hallucinations.

“This is spectacular — this is the dream,” said Lindsey Glickfeld, a neuroscientist at Duke University, who was not involved in the new study.

In the early 2000s, Dr. Karl Deisseroth, a psychiatrist and neuroscientist at Stanford, and other scientists engineered neurons in the brains of living mouse mice to switch on when exposed to a flash of light. The technique is known as optogenetics.

In the first wave of these experiments, researchers used light to learn how various types of neurons worked. But Dr. Deisseroth wanted to be able to pick out any individual cell in the brain and turn it on and off with light.

So he and his colleagues designed a new device: Instead of just bathing a mouse’s brain in light, it allowed the researchers to deliver tiny beams of red light that could strike dozens of individual brain neurons at once.

To try out this new system, Dr. Deisseroth and his colleagues focused on the brain’s perception of the visual world. When light enters the eyes — of a mouse or a human — it triggers nerve endings in the retina that send electrical impulses to the rear of the brain.

There, in a region called the visual cortex, neurons quickly detect edges and other patterns, which the brain then assembles into a picture of reality.

The scientists inserted two genes into neurons in the visual cortices of mice. One gene made the neurons sensitive to the red laser light. The other caused neurons to produce a green flash when turned on, letting the researchers track their activity in response to stimuli.

The engineered mice were shown pictures on a monitor. Some were of vertical stripes, others of horizontal stripes. Sometimes the stripes were bright, sometimes fuzzy. The researchers trained the mice to lick a pipe only if they saw vertical stripes. If they performed the test correctly, they were rewarded with a drop of water.

As the mice were shown images, thousands of neurons in their visual cortices flashed green. One population of cells switched on in response to vertical stripes; other neurons flipped on when the mice were shown horizontal ones.

The researchers picked a few dozen neurons from each group to target. They again showed the stripes to the mice, and this time they also fired light at the neurons from the corresponding group. Switching on the correct neurons helped the mice do better at recognizing stripes.

Then the researchers turned off the monitor, leaving the mice in darkness. Now the scientists switched on the neurons for horizontal and vertical stripes, without anything for the rodents to see. The mice responded by licking the pipe, as if they were actually seeing vertical stripes.

Anne Churchland, a neuroscientist at Cold Spring Harbor Laboratory who was not involved in the study, cautioned that this kind of experiment can’t reveal much about a mouse’s inner experience.

“It’s not like a creature can tell you, ‘Oh, wow, I saw a horizontal bar,’” she said.

Dr. Churchland said that it would take more research to better understand why the mice behaved as they did in response to the flashes of red light. Did they see the horizontal stripes more clearly, or were they less distracted by misleading signals?

One of the most remarkable results from the study came about when Dr. Deisseroth and his colleagues narrowed their beams of red light to fewer and fewer neurons. They kept getting the mice to lick the pipe as if they were seeing the vertical stripes.

In the end, the scientists found they could trigger the hallucinations by stimulating as few as two neurons. Thousands of other neurons in the visual cortex would follow the lead of those two cells, flashing green as they became active.

Clusters of neurons in the brain may be tuned so that they’re ready to fire at even a slight stimulus, Dr. Deisseroth and his colleagues concluded — like a snowbank poised to become an avalanche.

But it doesn’t take a fancy optogenetic device to make a few neurons fire. Even when they’re not receiving a stimulus, neurons sometimes just fire at random.

That raises a puzzle: If all it takes is two neurons, why are we not hallucinating all the time?

Maybe our brain wiring prevents it, Dr. Deisseroth said. When a neuron randomly fires, others may send signal it to quiet down.

Dr. Glickfeld speculated that attention may be crucial to triggering the avalanche of neuronal action only at the right times. “Attention allows you to ignore a lot of the background activity,” she said.

Dr. Deisseroth hopes to see what other hallucinations he can trigger with light. In other parts of the brain, he might be able to cause mice to perceive more complex images, such as the face of a cat. He might be able to coax neurons to create phantom sounds, or even phantom smells.

As a psychiatrist, Dr. Deisseroth has treated patients who have suffered from visual hallucinations. In his role as a neuroscientist, he’d like to find out more about how individual neurons give rise to these images — and how to stop them.

“Now we know where those cells are, what they look like, what their shape is,” he said. “In future work, we can get to know them in much more detail.”


By Carl Zimmer

In 2014 John Cryan, a professor at University College Cork in Ireland, attended a meeting in California about Alzheimer’s disease. He wasn’t an expert on dementia. Instead, he studied the microbiome, the trillions of microbes inside the healthy human body.

Dr. Cryan and other scientists were beginning to find hints that these microbes could influence the brain and behavior. Perhaps, he told the scientific gathering, the microbiome has a role in the development of Alzheimer’s disease.

The idea was not well received. “I’ve never given a talk to so many people who didn’t believe what I was saying,” Dr. Cryan recalled.

A lot has changed since then: Research continues to turn up remarkable links between the microbiome and the brain. Scientists are finding evidence that microbiome may play a role not just in Alzheimer’s disease, but Parkinson’s disease, depression, schizophrenia, autism and other conditions.

For some neuroscientists, new studies have changed the way they think about the brain.

One of the skeptics at that Alzheimer’s meeting was Sangram Sisodia, a neurobiologist at the University of Chicago. He wasn’t swayed by Dr. Cryan’s talk, but later he decided to put the idea to a simple test.

“It was just on a lark,” said Dr. Sisodia. “We had no idea how it would turn out.”

He and his colleagues gave antibiotics to mice prone to develop a version of Alzheimer’s disease, in order to kill off much of the gut bacteria in the mice. Later, when the scientists inspected the animals’ brains, they found far fewer of the protein clumps linked to dementia.

Just a little disruption of the microbiome was enough to produce this effect. Young mice given antibiotics for a week had fewer clumps in their brains when they grew old, too.

“I never imagined it would be such a striking result,” Dr. Sisodia said. “For someone with a background in molecular biology and neuroscience, this is like going into outer space.”

Following a string of similar experiments, he now suspects that just a few species in the gut — perhaps even one — influence the course of Alzheimer’s disease, perhaps by releasing chemical that alters how immune cells work in the brain.

He hasn’t found those microbes, let alone that chemical. But “there’s something’s in there,” he said. “And we have to figure out what it is.”

‘It was considered crazy’

Scientists have long known that microbes live inside us. In 1683, the Dutch scientist Antonie van Leeuwenhoek put plaque from his teeth under a microscope and discovered tiny creatures swimming about.

But the microbiome has stubbornly resisted scientific discovery. For generations, microbiologists only studied the species that they could grow in the lab. Most of our interior occupants can’t survive in petri dishes.

In the early 2000s, however, the science of the microbiome took a sudden leap forward when researchers figured out how to sequence DNA from these microbes. Researchers initially used this new technology to examine how the microbiome influences parts of our bodies rife with bacteria, such as the gut and the skin.

Few of them gave much thought to the brain — there didn’t seem to be much point. The brain is shielded from microbial invasion by the so-called blood-brain barrier. Normally, only small molecules pass through.

“As recently as 2011, it was considered crazy to look for associations between the microbiome and behavior,” said Rob Knight, a microbiologist at the University of California, San Diego.

He and his colleagues discovered some of the earliest hints of these links. Investigators took stool from mice with a genetic mutation that caused them to eat a lot and put on weight. They transferred the stool to mice that had been raised germ-free — that is, entirely without gut microbiomes — since birth.

After receiving this so-called fecal transplant, the germ-free mice got hungry, too, and put on weight.

Altering appetite isn’t the only thing that the microbiome can do to the brain, it turns out. Dr. Cryan and his colleagues, for example, have found that mice without microbiomes become loners, preferring to stay away from fellow rodents.

The scientists eventually discovered changes in the brains of these antisocial mice. One region, called the amygdala, is important for processing social emotions. In germ-free mice, the neurons in the amygdala make unusual sets of proteins, changing the connections they make with other cells.

Studies of humans revealed some surprising patterns, too. Children with autism have unusual patterns of microbial species in their stool. Differences in the gut bacteria of people with a host of other brain-based conditions also have been reported.

But none of these associations proves cause and effect. Finding an unusual microbiome in people with Alzheimer’s doesn’t mean that the bacteria drive the disease. It could be the reverse: People with Alzheimer’s disease often change their eating habits, for example, and that switch might favor different species of gut microbes.

Fecal transplants can help pin down these links. In his research on Alzheimer’s, Dr. Sisodia and his colleagues transferred stool from ordinary mice into the mice they had treated with antibiotics. Once their microbiomes were restored, the antibiotic-treated mice started developing protein clumps again.

“We’re extremely confident that it’s the bacteria that’s driving this,” he said. Other researchers have taken these experiments a step further by using human fecal transplants.

If you hold a mouse by its tail, it normally wriggles in an effort to escape. If you give it a fecal transplant from humans with major depression, you get a completely different result: The mice give up sooner, simply hanging motionless.

As intriguing as this sort of research can be, it has a major limitation. Because researchers are transferring hundreds of bacterial species at once, the experiments can’t reveal which in particular are responsible for changing the brain.

Now researchers are pinpointing individual strains that seem to have an effect.

To study autism, Dr. Mauro Costa-Mattioli and his colleagues at the Baylor College of Medicine in Houston investigated different kinds of mice, each of which display some symptoms of autism. A mutation in a gene called SHANK3 can cause mice to groom themselves repetitively and avoid contact with other mice, for example.

In another mouse strain, Dr. Costa-Mattioli found that feeding mothers a high-fat diet makes it more likely their pups will behave this way.