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Mouse experiments reveal the brain–heart connections that cause us to lose consciousness rapidly — and wake up moments later.
The Effect of Melodrama (1830) by Louis Leopold Boilly. The precise mechanisms that control how and why people faint have long puzzled scientists. Credit: Leemage/Corbis via Getty
Whether as a result of heat, hunger, standing for too long or merely the sight of blood or needles, 40% of people faint at least once in their lives.
But exactly what causes these brief losses of consciousness — which researchers call syncope — has been a mystery..
Now, researchers have discovered a neural pathway that controls the process, involving a group of sensory neurons that connect the heart to the brainstem. A study published in Nature on 1 November1 reports that activating these neurons made mice stop moving and fall over almost immediately, then display symptoms observed during human syncope, such as rapid pupil dilation and rolling eyes.
The authors suggest that this pathway holds the key to understanding fainting, beyond the long-standing observation that it results from reduced blood flow in the brain. “There is blood-flow reduction, but, at the same time, there are dedicated circuits in the brain which manipulate this,” says study co-author Vineet Augustine, a neuroscientist at the University of California, San Diego.
“The study of these pathways could inspire new treatment approaches for cardiac causes of syncope,” says Kalyanam Shivkumar, a cardiologist at the University of California, Los Angeles.
The mechanisms that control how and why people faint have long been a puzzle, partly because researchers tend to focus on studying either the heart or the brain in isolation. But the authors of the study developed tools to show how these two systems interact.
Using single-cell RNA sequencing analysis of the nodose ganglion, part of the vagus nerve (which connects the brain to several organs, including the heart), the team identified sensory neurons that express a type of receptor involved in the contraction of small muscles in blood vessels.
These neurons, called NPY2R VSNs, are distinct from other branches of the vagus nerve that connect to the lungs or the gut. Instead, they form branches in the lower, muscular parts of the heart, called the ventricles, and connect to a distinct area of the brainstem called the area postrema.
By combining high-resolution ultrasound imaging with optogenetics — a way of controlling neuronal activity using light — the researchers stimulated the NPY2R VSNs in mice while monitoring the animals’ heart rate, blood pressure, respiration and eye movements. This allowed the team to manipulate specific neurons and visualize the heart in real time. “This was not possible before, because you needed to figure out the identity of these neurons,” says Augustine.
When the NPY2R VSNs were activated, mice that had been moving around freely fainted in a few seconds. As well as showing rapid pupil dilation and eyes rolling back in their sockets, the mice demonstrated other symptoms of syncope in humans, including reduced heart rate, blood pressure, breathing rate and blood flow to the brain.
“We now know that there are receptors in the heart that, when made to fire, will shut down the heart,” says Jan Gert van Dijk, a clinical neurologist at Leiden University Medical Centre in the Netherlands.
Humans usually recover rapidly from syncope. “Neurons in the brain are very much like extremely spoiled children. They need oxygen and they need sugar, and they need them now,” says van Dijk. “They stop working very quickly if you deprive them of oxygen or glucose.”
These nerve cells begin to die after about 2–5 minutes without oxygen, but syncope typically lasts less than 60 seconds. “If you add oxygen again, they’ll simply resume their work and do so just as quickly,” says van Dijk.
To better understand what happens inside the brain during syncope, the researchers used electrodes to record the activity of thousands of neurons from various brain regions in mice as the animals fainted. Activity decreased in all areas of the brain, except one specific region of the hypothalamus known as the periventricular zone (PVZ).
The authors then blocked the activity of the periventricular zone, and the mice experienced longer fainting episodes. Stimulating the region caused the animals to wake up and start moving again. The team suggests that a coordinated neural network that includes NPY2R VSNs and the PVZ regulates fainting and recovery.
“Coming from a clinical standpoint, this is all very exciting,” says Richard Sutton, a clinical cardiologist at Imperial College London. The discovery of NPY2R VSNs “doesn’t answer all questions immediately”, he adds, “but I think it could answer with future research almost everything”.
For “questions that cardiologists have been asking for decades, now you can bring in a neuroscience perspective and really see how the nervous system controls the heart”, says Augustine.
