Last year, Ardem Patapoutian got a tattoo. An artist drew a tangled ribbon on his right arm, the diagram of a protein called Piezo. Dr. Patapoutian, a neuroscientist at Scripps Research in San Diego discovered Piezo in 2010, and in 2021 he won a Nobel Prize for the work. Three years later, he decided to memorialize the protein in ink.
Piezo, Dr. Patapoutian had found, allows nerve endings in the skin to sense pressure, helping to create the sense of touch. “It was surreal to feel the needle as it was etching the Piezo protein that I was using to feel it,” he recalled.
Dr. Patapoutian is no longer studying how Piezo informs us about the outside world. Instead, he has turned inward, to examine the flow of signals that travel from within the body to the brain. His research is part of a major new effort to map this sixth, internal sense, which is known as interoception.
Scientists are discovering that interoception supplies the brain with a remarkably rich picture of what is happening throughout the body — a picture that is mostly hidden from our consciousness. This inner sense shapes our emotions, our behavior, our decisions, and even the way we feel sick with a cold. And a growing amount of research suggests that many psychiatric conditions, ranging from anxiety disorders to depression, might be caused in part by errors in our perception of our internal environment.
Someday it may become possible to treat those conditions by retuning a person’s internal sense. But first, Dr. Patapoutian said, scientists need a firm understanding of how interoception works. “We’ve taken our body for granted,” he said.
‘Genuinely Overwhelming’
Everyone has a basic awareness of interoception, whether it’s a feeling of your heart racing, your bladder filling or a flock of butterflies fluttering in your stomach. And neuroscientists have long recognized interoception as one function of the nervous system. Dr. Charles Sherrington, a Nobel Prize-winning neuroscientist, first proposed the existence of “intero-ceptors,” in 1906.
But Dr. Sherrington believed that these interoceptors supplied the brain only with a meager trickle of signals. Most of the brain’s activity, he believed, involved making sense of touch and the other senses that relay information from our surroundings — “the full stream of the varied agencies forever pouring upon it from the outside world,” he wrote.
Dr. Sherrington made this error in part because he could not see how intimately our organs and nerves are wired together. Now scientists have powerful tools for studying interoception. “Just in the last five years, fundamental puzzles that have been around for 100 years have been solved,” said David Linden, a neuroscientist at Johns Hopkins University who is writing a book on interoception.
To study Piezo inside the body, for example, Dr. Patapoutian and his colleagues insert engineered viruses into the organ of a mouse; the viruses enter the nerve endings that infiltrate the organ and cause the neurons to glow. Close inspection has revealed that the nerve endings use Piezo proteins to detect changes in pressure in many organs.
“Pressure sensing is everywhere in the body,” Dr. Patapoutian said.
In the aorta, for instance, Piezo proteins sense blood pressure. In the lungs, they register every inhaled breath. They sense when the bladder stretches as it fills with urine.
Many of the Piezo-packed nerve endings belong to the vagus nerve, a cable of 100,000 neurons that infiltrates many organs. The vagus nerve detects pressure, but it also has receptors that register other changes, such as swings of temperature and acidity. In the intestines, the vagus nerve senses sugar molecules and fat in the food we eat — even specific nutrients, such as zinc. Some of its nerve endings can sense the microbes that live in our guts, tracing the rise and fall of their populations.
Other channels flood the brain with interoceptive signals, too. In the neck, the carotid artery houses a patch of cells that are sensitive to the levels of oxygen, carbon dioxide and other molecules. Those readings are relayed to another nerve that runs into the skull. The brain also directly monitors the blood through tiny windows in its lining.
These signals flow into the brainstem and from there spread to other brain regions for interpretation. Brain-scanning studies suggest that this network is constantly humming away, mostly beyond our conscious awareness. Our brains then use the information to make a steady stream of adjustments to our bodies. “The brain is constantly guided by these internal signals,” said Diego Bohórquez, a neuroscientist at Duke University.
When we breathe in, Piezo proteins sense the stretching of our lungs. The brain responds by stopping the inhalation from overstretching the delicate linings of the lungs. If the vagus nerve detects a toxin in our gut, it can send a signal to the brain that will swiftly cause us to vomit. In any moment, the brain is sifting and merging signals from all internal corners of the body. How it does so, and what it does with that information, remains largely mysterious.
“It’s genuinely overwhelming, and right now our understanding is pretty weak,” Dr. Linden said.
Making Ourselves Sick
But progress has been made recently on at least one puzzle: how interoception makes us feel sick.
“When you feel ill, you lose energy, you lose your appetite, you don’t feel well, and you say, ‘Oh that’s a nasty bug making me fell ill,’” said Catherine Dulac, a neuroscientist at Harvard who studies sickness. “And it turns out that, no, it’s the brain that does that to you.”
As it happens, the brain is constantly monitoring the body for signs of infection. When a pathogen bumps into certain vagus nerve endings, they send signals to the brain. Other nerve endings can recognize the alarm signals that immune cells send to one another.
The brain then creates mental representations of such infections and uses them to fight back. It might raise the body’s temperature, which enables immune cells to fight germs more effectively. It might put the sleep-wake cycle on pause, keeping you in bed to conserve energy. It can even send signals that change the immune system’s assault against pathogens — ramping up an attack here, reining it in there — to minimize collateral damage.
The brain sometimes responds to illness by suppressing appetite. Hunger eventually returns, but it comes with the risk of suddenly overloading the body with protein, which can turn into toxic ammonia in the bloodstream.
In a recent study, however, researchers at Yale found that interoception helped mice avoid poisoning themselves. When a mouse is recovering from an infection, cells in the gut can sense certain amino acids and reduce the animal’s appetite.
But the brain does more than just react to interoception: It learns from this internal sense and then makes predictions that improve our survival. “You don’t just want to know when you’re running out of oxygen — you want to know when you’re going to run out of oxygen,” said Camilla Nord, a neuroscientist at the University of Cambridge. “You want to have a future sense.”
When you eat something new, for example, sensory cells in your gut tell your brain whether the food is a good source of nutrients. That information can create a desire for more of it in the future. Likewise, signals of internal sickness teach the brain to anticipate illnesses that have yet to start. Just the sight of a sick person can be enough to prompt a viewer’s brain to ramp up the immune system.
As vital as interoception is to our survival, Dr. Nord and other researchers suspect that it is also responsible for many disorders. If the brain misinterprets signals from the body, or if those signals are themselves faulty, the brain may send out commands that cause harm.
Increasingly, researchers think that some psychiatric disorders could be treated as disorders of interoception. Weight-loss drugs like Ozempic already hint at how potent this kind of treatment could be. These medications, known as GLP-1 drugs, mimic the signals that the gut sends to the brain when you’ve eaten, leading to a loss of appetite.
In addition to mimicking the body’s signals, treatment for an interoception disorder could also entail retuning regions of the brain to interpret signals differently. Dr. Nord and her colleagues have found that people with a range of psychiatric disorders, including bipolar disorder, anxiety, major depression, anorexia and schizophrenia, share unusual activity in a brain region known as the mid-insula, which is essential to interpreting signals from the body. Dr. Nord and her colleagues are currently running a trial in which they are delivering low-frequency ultrasonic waves to the mid-insula of patients with psychiatric disorders, to see if the region can be coaxed into responding to interoception in a healthier way.
But Dr. Patapoutian cautioned that interoception would be hard to harness until it was better understood. He and colleagues at Scripps Research hope to provide a foundation for such advances by creating an atlas of interoception throughout the entire body. In one recent discovery, they found that fat is infiltrated with nerve endings that sense pressure with Piezo proteins.
“Apparently it is important there, but we still don’t what it’s sensing,” Dr. Patapoutian said. “Is it that when your fat grows, it becomes denser and adds more pressure on the nerves? Is it, when fat grows, you have much more blood flow and this is what’s being sensed? We just don’t the answer.”
Dr. Patapoutian hopes his interoception atlas will help scientists get a firmer understanding of what our nerves are sensing not just in our fat, but throughout our bodies.
“In many, many of these organs, we have no idea what they do, or how they do it,” he said.
Carl Zimmer covers news about science for The Times and writes the Origins column.
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