The human heart beats 60-100 times a minute, without you needing to pay any attention to it. Heart function is controlled by the brain’s autonomic nervous system (the parasympathetic and sympathetic branches), responding to signals from these branches to speed up or slow down. Or so we thought.

Somewhere within the heart, there may be a “mini brain” — a dedicated, small nervous system that focuses specifically on the heart.

The intracardiac nervous system (IcNS) has been known for decades. Traditionally, this network was believed to be a simple relay, passing along signals from the brain. However, research published by a team from the Karolinska Institutet and Columbia University shows that the IcNS is far from simple. Using the zebrafish, a model species for heart studies, scientists decoded the IcNS’s molecular, cellular, and functional diversity.

“This ‘little brain’ has a key role in maintaining and controlling the heartbeat, similar to how the brain regulates rhythmic functions such as locomotion and breathing,” explains Konstantinos Ampatzis, principal researcher and docent at the Department of Neuroscience, Karolinska Institutet, Sweden, who led the study.

Their study employed advanced techniques like single-cell RNA sequencing, neuroanatomical mapping, and electrophysiology to create a comprehensive picture of this cardiac “little brain.” The team found several types of neurons in the heart that have different functions. Specifically, some neurons have pacemaker properties, essentially controlling the rhythm of the heart.

The finding goes against the current view that it’s only the parasympathetic and sympathetic branches that control the heartbeat.

“We were surprised to see how complex the nervous system within the heart is,” says Ampatzis. Understanding this system better could lead to new insights into heart diseases and help develop new treatments for diseases such as arrhythmias.

But is a zebrafish heart like a human heart?

The notion of a “little brain” in the heart isn’t entirely new. The idea dates back to early 20th-century studies, but it’s very difficult to test on humans. That’s why zebrafish have become a go-to model for heart research.

Their hearts are structurally similar to those of humans, with a predictable rhythm and comparable electrical activity. Importantly, zebrafish hearts are transparent, allowing scientists to watch them in action. These fish also share key genetic pathways with humans, making discoveries in zebrafish highly relevant to human health.

The zebrafish heart comprises four chambers, like humans (though the chambers are very different). Neurons in the IcNS are concentrated near the valves between these chambers, particularly in an area called the sinoatrial plexus (SAP). The SAP is a hub of nerve cells that help regulate heart rhythms, making it a prime target for understanding how the IcNS functions.

Of course, there are major differences between a zebrafish heart and a human one, but it’s a good model that can offer clues to what’s going on in the human heart as well.

A two-layer control system

To decode the IcNS, the researchers focused on a technique called single-cell RNA sequencing. This technique allows scientists to examine the genetic activity of individual cells, providing a detailed molecular profile. The team analyzed nearly 10,000 cells from zebrafish hearts, identifying 22 distinct clusters of cells. Among these, they found a small but significant group of neurons — around 1.5% of all heart cells.

These neurons were far more diverse than previously thought. They included cells that use different neurotransmitters to communicate — sending excitatory or inhibitory signals. This suggests the IcNS is capable of complex regulation, finely tuning the heart’s performance.

This doesn’t mean that the parasympathetic and sympathetic branches don’t control the heart, there’s substantial evidence for that. Rather these findings support the idea of a two-layer system for heart rhythm control. The first layer consists of the traditional pacemaker cells in described before, and the second layer is the IcNS, which can fine-tune and potentially override this rhythm based on the body’s needs.

For instance, during exercise, the heart needs to beat faster. While the brain sends signals to increase heart rate, the IcNS can make quick adjustments on the fly, ensuring the heart keeps up with the body’s demands.

Journal Reference: Andrea Pedroni et al, Decoding the molecular, cellular, and functional heterogeneity of zebrafish intracardiac nervous system, Nature Communications (2024). DOI: 10.1038/s41467-024-54830-w