One set of neurons helps the heart (pictured, heart of a mouse) to keep beating steadily and another set buffers the heartbeat against acute stress.Credit: Steve Gschmeissner/Science Photo Library
Every heartbeat is choreographed not just by the brain but also by a mysterious nervous system embedded in the heart itself. Now, scientists studying mice have started to unravel how this complex system works to keep the heart beating steadily even at times of extreme stress — findings that challenge the classic view that all cardiac neurons are alike.
“The key is to keep the heart functional no matter what happens. 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 Cell1, could inform better treatments for heart disease.
Heart of the matter
Like the gut’s widely recognized ‘second brain’, 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 fat pad surrounding the heart. The system’s neurons exchange messages with the brain and with each other, and are the final players in a long chain of neurons that controls cardiac function. But because intrinsic cardiac neurons are exceedingly rare, making up only about 0.01% of the cells in a piece of heart tissue, their precise roles have been hard to pin down, says Chang.
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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 genetically distinct subtypes’ core functions and to map their locations.
Stimulating one population, called Npy+ neurons, lowered the animals’ heart rates; destroying it caused heart failure and death. These results suggest that Npy+ neurons can put the brakes on a racing heart, but are also necessary to keep it beating.
Stress protection
The second subtype, Ddah1+ neurons, proved more mysterious: neither stimulating nor eliminating them seemed to make a difference to the mice. “They didn’t seem to care,” says Chang. “They lived a long time. It was very puzzling.”
But one day, Qian Xu, a graduate student in the laboratory and study co-author, was taking the blood pressure of a mouse without Ddah1+ neurons. She watched it die mid-measurement. The team found that two-thirds of the mice without functional Ddah1+ neurons died while having their blood pressure taken. Control animals were unaffected. “Immediately before the animal dies, there’s a sudden drop in heart rate, and it never recovers,” says Chang.
The researchers suspected that stress was a trigger — each mouse had been restrained in a narrow tube with a cuff on its tail — and tried stressing the animals in a variety of ways. Again, most died. Removing Ddah1+ neurons seemed to leave the heart more vulnerable to stress. Conversely, stimulating the neurons improved survival in stressed mice.
