Each heartbeat is choreographed not only by the brain but also by a mysterious nervous system embedded in the heart itself. Now, scientists studying mice have begun to unravel how this complex system works to keep the heart beating steadily even in times of extreme stress, findings that challenge the classic view that all cardiac neurons are the same.

“The key is to keep the heart functional no matter what, because if the pump function stops, you will die,” says Rui Chang, a neuroscientist at Yale University School of Medicine in New Haven, Connecticut, and co-author of the new paper.

The findings, published today in Cell¹could inform better treatments for heart disease.

The crux of the matter

Like the widely recognized “second brain” of the gut, the heart contains a mini-brain of its own, known, more formally, as the intrinsic cardiac nervous system. This network of neurons is embedded in the layer of fat that surrounds the heart. The system’s neurons exchange messages with the brain and with each other, and are the final actors in a long chain of neurons that control cardiac function. But because intrinsic cardiac neurons are extremely rare, representing only about 0.01% of the cells in a piece of cardiac tissue, their precise functions have been difficult to pin down, Chang says.

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To fill that gap, his team genetically engineered mice to label all of the animals’ cardiac neurons. The scientists sequenced genes isolated from these neurons and identified markers for two neuronal subtypes. They then used techniques such as high-resolution imaging to identify the core functions of the genetically distinct subtypes and map their locations.

Stimulate a population, called npy⁺ neurons, reduced the animals’ heart rate; destroying it caused heart failure and death. These results suggest that npy⁺ Neurons can slow down a racing heart, but they are also necessary to keep it beating.

Protection against stress

The second subtype, Ddah1⁺ neurons, was more mysterious: neither stimulating them nor eliminating them seemed to make a difference to the mice. “They didn’t seem to care,” Chang says. “They lived a long time. It was very disconcerting.”

But one day, Qian Xu, a graduate student in the lab and co-author of the study, was taking the blood pressure of a mouse without Ddah1⁺ neurons. He saw him die halfway. The team found that two-thirds of the mice without function Ddah1⁺ The neurons died while their blood pressure was taken. Control animals were not affected. “Immediately before the animal dies, there is a sudden drop in heart rate and it never recovers,” says Chang.

The researchers suspected stress was a trigger (each mouse had been restrained in a narrow tube with a tail cuff) and tried to stress the animals in a variety of ways. Once again, most died. removing Ddah1⁺ The neurons seemed to make the heart more vulnerable to stress. In contrast, stimulation of neurons improved survival in stressed mice.