Revelations about the “mini-brain” of the heart thanks to zebrafish

Although controlled by the brain, the heart has a distinct and smaller intracardiac nervous system (ICNS) embedded in the superficial layers of the heart wall.

Nicknamed the mini-brain by researchers several decades ago, the SNiC was until then considered as a structure only capable of relaying simple information from the brain to the heart.

Thanks to new work on the intracardiac neurons of adult zebrafish, researchers from the Karolinska Institutet in Stockholm, Sweden have challenged this dogma and shown that its role is much broader.

This mini-brain has several types of neurons, including sympathetic and parasympathetic neurons and sensory neurons with apparent neurochemical and functional diversity. It has an action independent of the central nervous system (CNS) and plays a key role in controlling the heart rate.

These data, published in Nature Communications , could lead to new research on arrhythmia, dementia or even Parkinson's disease.

Little work on the intracardiac nervous system

Mini-brain neurons have been insufficiently researched, said Konstantinos Ampatzisprincipal investigator of the study and assistant professor of neuroscience at Karolinska Institutet.

“Cardiologists know that neurons exist, but never study them, because they are primarily interested in the heart muscle cells, or cardiomyocytes, which are responsible for the heartbeat,” he explained. And at the same time, “neuroscientists understand and decode neurons, but do not know the neurons of the heart. »

An innovative study using zebrafish

Dr. Ampatzis' team mapped the exact composition, organization and function of neurons in the SNiC using zebrafish as an animal model.

“The zebrafish heart is closer to that of humans than that of mice,” he explained. “The heart rate of a zebrafish is exactly the same. »

Several techniques have been used to characterize these neurons. Electrophysiology determined their function, and researchers at Columbia University (New York, USA) helped identify their molecular signatures using single-cell RNA sequencing.

Dr. Ampatzis and his team also analyzed the neurotransmitters that neurons release to communicate with each other. Researchers from Sweden and New York worked on this project in their spare time, as they had no additional funding.

Dr. Ampatzis expected to see ganglia or relay neurons capable only of receiving or sending information.

“But we found a very diverse set of neurons in a small network,” he said.

Their findings included sympathetic, parasympathetic, and sensory neurons with apparent neurochemical and functional diversity.

Essential pacemaker neurons

Most surprising was a subset of pacemaker neurons.

“It's impossible to have a network producing a rhythm without these neurons, and to be honest, we didn't expect this,” Dr. Ampatzis said.

Cardiac pacemaker neurons are generally associated with what are called central pattern generator networks within the central nervous system.

“However, we found that this neural network works in an isolated heart, without brain information, and that it can modify the rhythm of the heart and its regularity by itself,” said Dr. Ampatzis.

Other studies have confirmed that neurons do not produce the rhythm, which is controlled by cardiomyocytes. The main function of neurons is to regulate the speed of the heartbeat. In other words, this small, localized network acts as a kind of system to protect the brain's control of the heartbeat. “From an evolutionary point of view, I think the system is set up this way because the heartbeat defines life,” he adds.

Towards less invasive therapies

Once the neurons of the heart are mapped, medical researchers now have a toolbox of molecular markers, neurotransmitters and other information about how these neurons work. These results could serve as a basis for further research.

It might be possible to study cardiac arrhythmia by modulating pacemaker neurons, Dr. Ampatzis suggests. “We could even find specific drugs that can interfere with this local network of the heart,” he said, adding that this could be a less invasive option than today.

Arrhythmia affects millions of people, recalled the Dr. Oliver Guttmannconsultant cardiologist at Wellington Hospital and honorary lecturer in cardiology at University College London, both in London, England. And some treatment options can be invasive.

“We do ablations to try to burn or freeze certain areas of the heart to eliminate the rhythm, because it often comes from overactive cells somewhere,” he said.

Pacemakers and defibrillators are also needed to modulate dangerous rhythms. Innovation aims to make interventions much less invasive than they are today by creating smaller and smaller pacemakers, for example.

Moving from zebrafish to more complex mammalian systems will be the next big step, said David PatersonHead of the Department of Physiology, Anatomy and Genetics and Honorary Director of the Burdon Sanderson Cardiac Science Center at the University of Oxford (Oxford, England). “If you can find the molecular pathway of dysregulation, that could be a potential target for gene therapy, cell therapy or neuromodulation therapy,” he explained. This field, sometimes called bioelectronic medicine, is attracting growing interest. “It’s like pharmacology, but there is no medicine. It’s about harnessing the wiring of the nervous system,” he added.

More radical avenues of research could help tackle neurodegenerative disorders, from dementia to Parkinson's disease. “If neurons die in the brain, they die in the heart and can affect heart rhythm,” Dr. Ampatzis said. However, zebrafish neurons are now known to produce substances that induce stem cell proliferation in bones, skin and even the nervous system. “We think that these neurons in the heart could perhaps contribute to the regeneration of the heart,” he said.

This article was translated from the Portuguese edition of Medscape.com part of the Medscape professional network, using several editorial tools, including AI, in the process. The content was reviewed by the editorial staff before publication.