Zebrafish provides keys to the heart’s ‘mini-brain’

The heart’s “mini-brain” is independent and highly localized, according to researchers at 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 distinct and smaller intracardiac nervous system (IcNS) embedded in the superficial layers of the heart wall. Dubbed the mini-brain by researchers decades ago, the IcNS was thought to be a simple structure capable only of relaying simple information from the brain to the heart.

The neurons of the mini-brain, however, have been understudied, said Konstantinos Ampatzis, lead researcher and assistant professor of neuroscience at Karolinska Institutet. “Cardiologists know that neurons exist but never study them because their primary concern is with the heart muscle cells, or cardiomyocytes, responsible for the heartbeat,” he explained. “Neuroscientists understand and decode neurons but do not know the neurons of the heart.”

Ampatzis’ team mapped the exact composition, organization and function of IcNS neurons using zebrafish as an animal model. “The zebrafish’s heart is closer to that of humans than that of the mouse,” 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 in New York helped identify their molecular signatures using single-cell RNA sequencing. 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 because they did not have additional funding.

Ampatzis expects 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. Most surprising was a subset of pacemaker neurons. “You can’t have a network that produces a rhythm without these neurons, and to be honest, we weren’t exactly expecting that,” he said.

Pacemaker neurons are typically associated with central pattern-generating networks within the central nervous system. These independent, highly localized neural networks generate and control complex rhythmic behaviors such as breathing, chewing, urination, and ejaculation. “More importantly, we found that this neural network operates in an isolated heart, without brain information, and can change heart rate and regularity itself,” Ampatzis said.

Other studies have confirmed that neurons do not produce the rhythm controlled by cardiomyocytes. The main function of neurons 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 over the heart’s rhythm. “From an evolutionary point of view, I think the system is like this because the heartbeat defines life,” Ampatzis added.

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 become the basis for further research. It might be possible to study cardiac arrhythmia by modulating pacemaker neurons, Ampatzis suggested. “You could even reuse or 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.

The arrhythmia affects millions of people, said Oliver Guttmann, MD, consultant cardiologist at 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 to burn or freeze certain areas of the heart to get rid of a rhythm because that 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, for example by creating increasingly smaller pacemakers.

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 the Burdon Sanderson Cardiac Science Center at the University of ‘Oxford, Oxford, England. . “If you can find the molecular roadmap to dysregulation, then this could be a potential target for gene therapy, cell therapy or neuromodulation therapy,” he explained. Interest in this field, sometimes called bioelectronic medicine, is growing. “It’s like the pharmacy, but there is no medicine. You’re tapping into the wiring of the nervous system,” he added.

More radical avenues of research could consider ways to combat neurodegenerative disorders ranging from dementia to Parkinson’s disease. “If neurons die in the brain, they die in the heart and can affect heart rhythm,” Ampatzis said. But we now know that zebrafish neurons produce substances that induce a proliferation of stem cells 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.

Ampatzis, Guttmann and Paterson said they have no relevant financial relationships.

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