Zebrafish Provide the Keys to the Heart’s ‘Mini-Brain’

The heart’s “mini-brain” is independent and highly localized, according to researchers at the Karolinska Institutet in Stockholm, Sweden. The findings could lead to new research into arrhythmia, dementia, and Parkinson’s disease.

Although controlled by the brain, the heart has a separate, smaller intracardiac nervous system (IcNS) embedded within the superficial layers of the heart wall. Nicknamed the mini-brain by researchers decades ago, the IcNS was assumed to be a simple structure capable only of relaying simple information from the brain to the heart.

The neurons in the mini-brain, however, have been under-researched, said Konstantinos Ampatzis, principal researcher and assistant professor of neuroscience at the Karolinska Institutet. “Cardiologists know that neurons exist but never study them because their first concern is the cardiac muscle cells, or cardiomyocytes, that are responsible for the heartbeat,” he explained. “Neuroscientists understand and decode neurons but don’t know about neurons in the heart.”

Ampatzis’s team mapped the exact composition, organization, and function of neurons in the IcNS using zebrafish as an animal model. “The heart of the zebrafish is closer to that of humans than the mouse heart is,” he explained. “The heart rate of a zebrafish is exactly the same.”

Several techniques were used to characterize these neurons. Electrophysiology determined their function, and researchers at Columbia University in New York City helped identify their molecular signatures using single-cell RNA sequencing. Ampatzis and his team also analyzed neurotransmitters that the neurons release to communicate with each other. Researchers in Sweden and New York worked on this project in their spare time because they had no additional funding.

Ampatzis expected to see ganglions 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. Most surprising was a subset of pacemaker neurons. “You cannot have a network that produces a rhythm without these neurons, and we didn’t expect exactly that, to be honest,” he said.

Pacemaker neurons are usually associated with so-called central pattern generator networks within the central nervous system. These independent, highly localized neuronal networks generate and control complex rhythmic behaviors such as respiration, mastication, urination, and ejaculation. “Most importantly, we found that this neuronal network works in an isolated heart, without brain information, and can change the rhythm of the heart and the regularity by itself,” said Ampatzis.

Further studies confirmed that neurons do not produce the rhythm, which is controlled by the cardiomyocytes. The neurons’ main function is to regulate the speed of the heartbeat. In other words, this smaller localized network acts as a kind of insurance system to safeguard the brain’s control of the heartbeat. “From an evolutionary perspective, I think that the system is like this because the heartbeat defines life,” Ampatzis added.

With the neurons of the heart mapped, medical researchers now have a toolbox of molecular markers, neurotransmitters, and other information on how such neurons function. These findings could become the basis of new research. It might be possible to investigate heart arrythmia by modulating pacemaker neurons, Ampatzis suggested. “You could even repurpose or find specific drugs that can interfere with this local network of the heart,” he said, adding that this might be a less invasive option than is possible today.

Arrhythmia affects millions of people, said Oliver Guttmann, MD, a consultant cardiologist at The Wellington Hospital and honorary associate professor of cardiology at University College London, both in London, England. Beta-blockers remain the drug of choice for arrhythmia, but other options can be invasive. “We do ablations to try and burn or freeze certain areas of the heart to get rid of a rhythm because often this comes from hyperactive cells somewhere,” he said. Pacemakers and defibrillators are also needed to modulate dangerous rhythms. Innovation is focusing on making interventions far 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 Paterson, DPhil, head of the Department of Physiology, Anatomy, and Genetics and honorary director of Burdon Sanderson Cardiac Science Centre at the University of Oxford, Oxford, England. “If you can find the molecular road map of dysregulation, then that could be a potential target for a gene therapy or cell therapy or for neuromodulation therapy,” he explained. Interest in this field, which is sometimes called bioelectronic medicine, is mounting. “It’s like pharmaceutics, but there’s no drug. You’re tapping into the wiring of the nervous system,” he added.

More radical research pathways might look at ways to tackle neurodegenerative disorders from dementia to Parkinson’s disease. “If neurons die in the brain, then they die in the heart and can affect the rhythm of the heart,” said Ampatzis. But zebrafish neurons are now known to produce substances that induce a proliferation of stem cells in bones, skin, and even the nervous system. “We think those neurons of the heart could perhaps contribute to the regeneration of the heart,” he said.

Ampatzis, Guttmann, and Paterson reported having no relevant financial relationships.

Tatum Anderson is a global health and medical journalist. For over 20 years, she has placed articles in publications from the Bulletin of the World Health Organization to The Lancet, BMJ, BBC News, and the Economist.