During feelings of anxiety, the brain kicks the heart into overdrive. But as it races, does the heart, in turn, talk to the brain? For centuries, scientists have debated whether the heart holds sway over the mind, and now, research published today (March 1) in Nature suggests that physical states can influence emotional ones. The study found that an elevated heart rate can cause anxious behaviors in mice—but only in risky circumstances. This suggests that interventions that target the heart might be effective treatments for panic disorders, the authors suggest.
“I thought it was a very elegant demonstration of what we instinctively believe and have shown using piecemeal methods: that body states inform emotional feeling states,” says Sarah Garfinkel, a cognitive neuroscientist at University College London who was not involved in the work.
In his 1884 essay “What is an emotion?”, philosopher and psychologist William James, widely regarded as the founder of American psychology, makes the case that emotions are inextricably tied to bodily responses. Physiological changes, he writes, are the “raw material” of emotion, to which the brain assigns meaning, like fear, surprise, or excitement.
Since then, studies have suggested, albeit indirectly, that the heart is capable of sending fear-inducing signals to the brain, Garfinkel explains. But because the connection between the heart and brain is a two-way street, “it’very difficult to disentangle what drives the feeling states,” she adds. “Is the emotion what causes the heart rate to change or is [the emotion] a consequence of the changing heart rate?”
Karl Deisseroth, a neuroscientist and psychologist at Stanford who led the new study, has been interested in the heart’s role in emotional processing since the beginning of his career, when he learned as a psychiatry resident that an increased heart rate is a common symptom of panic disorders.
It’s now well-established that tachycardia, the term for an increased heart rate, is a hallmark of anxiety in both mice and humans. But Until now, there was no way to directly test whether an increased heart rate could induce an emotional response, he explains.
It would be decades before Deisseroth developed the tools to do so. Roughly fifteen years before the new study was published, he and his lab discovered light sensitive proteins called channelrhodopsins and developed optogenetics, a method to activate or silence neurons with light that has since revolutionized neuroscience. But these early light-sensitive proteins weren’t sensitive enough for researchers to noninvasively stimulate large organs like the heart. This is in part because most of the visual light spectrum doesn’t penetrate the skin well past a few millimeters. Red light gets through a bit better, but not enough to activate these early opsins.
Fluorescent image showing DAPI (blue) and ChRmine expression (red) in a mouse heart.
In 2019, as they continued to explore opsins with new properties, Deisseroth’s group discovered a new channelrhodopsin that’s highly sensitive to red light and conducts powerful electrical currents. With the newly engineered protein, which they called ChRmine, the researchers could finally manipulate cells deep within the body—including those within the heart.
In the new study, Deisseroth’s lab used a viral delivery strategy to create mice that expressed ChRmine in cardiomyocytes: electrically-active heart cells that kick-start contractions.
To induce tachycardia in these mice, Deisseroth and colleagues outfitted them with a small light-up vest of their own design, which acted as an optical pacemaker. When the vest lit up, it activated the ChRmine-expressing cells in the mice’s hearts, temporarily boosting their heart rate, which normally rests at around 600 beats per minute, up to 900 beats per minute.
Before this, “it was impossible to directly, causally, and precisely test,” the hypothesis that heart rate influences emotional states, Deisseroth tells The Scientist. “It was just exciting to even be able to do it.”
But just elevating the mice’s heart rates didn’t seem to affect their behavior—they didn’t show signs of anxiety, such as avoiding places where they consistently experienced an elevated heart rate. This finding initially surprised Deisseroth,” who explains that “when our heart rate goes up, it’s very often when things are aversive.”
Things changed when the researchers placed the mice into potentially risky situations, however. In one experiment, for example, the researchers replaced the enclosed cages mice are normally housed in with large, open environments that are known to stress them out. “An exposed environment is very aversive to mice because their main concern is being [preyed upon],” Deisseroth explains. In these environments, ChRmine-expressing mice exhibited more anxious behavior than normal mice following light stimulation. They avoided the center of the arena, opting to huddle at its edges. “If the brain perceives a potentially threatening environment, then [the heart going faster] causes anxiety-related behavior,” Deisseroth notes.
“This is showing very elegantly that the context is necessary to appraise signals or experience as anxiety,” says Garfinkel. In humans, an increase in heart rate could be due to excitement, agitation, or fear, depending on context. This is also true in mice: The brain needs to appraise the environment to assign an emotion to a physiological response, Garfinkel speculates.
Deisseroth and colleagues went on to identify the parts of the brain to which the heart talks. By fluorescently labeling a marker of brain activity, a gene called Fos, the researchers isolated two brain regions: the posterior insular cortex—a brain region that receives input from the body’s internal organs—and the prefrontal cortex that receive input from the heart.
Finally, the researchers wanted to establish a causal link between heart rate and brain activity, which meant doing optogenetics on the brain and heart simultaneously. “It was a pretty remarkable experiment,” says Deisseroth. Using optogenetics, the researchers turned off cells in the posterior insular cortex and the prefrontal cortex in some mice while stimulating the heart. When they silenced the posterior insular cortex (but not the prefrontal cortex) an elevated heart rate no longer increased anxious behaviors in stressful situations. “That doesn’t mean [the prefrontal cortex] isn’t involved in some way. It clearly receives the information that the heart is beating faster . . . but maybe it uses that information on longer timescales.”
Garfinkel says that the findings could potentially inform work in anxiety and post-traumatic stress disorder. “I would like to see what happens in animals that have PTSD,” she says, “because based on my human work, I would guess that traumatized animals don’t show the moderation of this effect as a function of their context.” She’d also like to know more about the individual differences between how different humans and animals react to an increased heart rate, which could also inform how anxiety disorders are treated.
Deisseroth says these findings show that targeting heart rate might be a good therapeutic avenue for panic disorders. “In people who have elevated heart rate and anxiety disorders, modulation of heart rate can and perhaps should be a treatment goal in itself,” he says. Many cardiac interventions, “are safe and well tolerated. It could help people quite a bit.”