‘Little Brain on the Heart’ Is Essential for Cardiac Function

Our hearts are embedded with their own neural network, which some neuroscientists have dubbed the “little brain on the heart.” A new study identifies the roles these cardiac neurons play in heart function and shows that they are crucial for our survival.

Scientists have known that the heart contains its own nervous system, called the intrinsic cardiac nervous system, for decades. And it was thought that neurons in the heart acted as part of the parasympathetic (“rest and digest”) nervous system, relaying signals from the vagus nerve to the cardiac cells that control heart rate. However, emerging research suggests that these neurons are not a unified group, but rather have distinct molecular identities.

Now, in a new Cell study, a team of researchers have identified two major populations of cardiac neurons—one that maintains cardiac function under normal conditions and another that maintains it under periods of stress. Without either type of neuron, the heart stops working, the researchers found.

A number of cardiovascular conditions—including atrial fibrillation, a common heart rhythm disorder—are linked to cardiac neurons. Understanding how the intrinsic cardiac nervous system controls heart function can help scientists develop new therapies for when it does not work properly.

“This group of neurons is very rare on the heart, but very important for it,” says principal investigator Rui Chang, PhD, associate professor of neuroscience and of cellular and molecular physiology. “They ensure that the heart is functional no matter the conditions.”

One of the challenges of studying cardiac neurons is that they make up only a tiny fraction—less than 0.01%—of the cells in heart tissue. They’re also sparsely distributed across the organ. For the new study, Chang’s team created specialized fluorescent animal models that enabled them to visualize and isolate all of the cardiac neurons on the heart. Then, they used single-cell sequencing to characterize the identity of each cell.

“So now, for the first time, we had a very high-resolution single-cell sequencing data set of these neurons,” Chang says.

Single-cell sequencing revealed two major types of cardiac neurons. To study their role in the heart, the researchers explored what happened in animal models when they either activated or removed each type of neuron. Activation of the first group of neurons, which the researchers called Npy+ neurons, led to a reduction in heart rate. When the researchers removed the neurons, the heart stopped functioning completely.

“They’re not only controlling the heart rate, but they’re required for keeping the heart functional,” Chang says.

The researchers then discovered that the second population of neurons, called Ddah1+ neurons, responded to stress. Mice with activated Ddah1+ neurons were more resilient than mice without the neurons when exposed to a drug that caused overactivation of the sympathetic nervous system.

“This other cell group ensures the heart to be functional under stressful conditions,” Chang says.

As one of the most important organs in the body, the heart needs to function properly under all circumstances, even during stressful situations such as imminent danger. The study highlights how these two groups of neurons work together to maintain cardiac function under both normal and stressful circumstances, the researchers say.

The heart is not the only organ with its own neural network. Growing evidence suggests that the gut also contains diverse populations of neurons with distinct roles. The new study highlights that cardiac neurons are similarly heterogenous and that the extent of their functions has yet to be uncovered.

Understanding how cardiac neurons function could lead to new therapies for a range of cardiovascular conditions, such as atrial fibrillation, heart failure, and myocardial infarctions.

“Our knowledge of the intrinsic cardiac nervous system is still minimal,” Chang says. “Understanding how this system works in controlling heart function under different disease conditions will certainly help us design new therapeutic strategies.”