Every year, thousands of people suffer from spinal cord injuries, often resulting in paralysis and dependence on a ventilator. Unfortunately, respiratory complications are the most common cause of death among patients with such injuries.
The story of actor Christopher Reeve highlights the severity of this problem. The actor, famous for his role as Superman, was severely injured after a horse-riding incident, leaving him paralyzed and dependent on a ventilator. He and his wife, Dana Reeve, founded a foundation that funds spinal cord injury research and helps patients.
Scientists at the Case Western Reserve University School of Medicine have discovered that a special group of nerve cells, called interneurons, plays a significant role in regulating breathing, especially during physical exertion. The research, published in the journal “Cell Reports,” offers new opportunities for restoring respiratory function after a spinal cord injury.
Research Details
Although the brainstem controls the rhythm of breathing, the neural pathways that strengthen this process have been previously unknown. To study this, researchers examined the spinal cord neurons of genetically modified mice to determine their connections and activity during breathing.
They paid special attention to a specific type of nerve cell called Pitx2+ V0C interneurons. It was found that these neurons are directly connected to the motor neurons of the diaphragm, thus controlling the main respiratory muscle.
The study showed that these interneurons enhance the function of the respiratory system, which helps the body adapt breathing to an increase in carbon dioxide () in the blood. When the researchers blocked the signals of these neurons, the mice were no longer able to strengthen their breathing in response to high carbon dioxide levels. This suggests that these interneurons represent a breathing-enhancing system that regulates breathing intensity during physical exertion.
This discovery expands our knowledge of respiratory control. It shows that the nervous system regulates breathing intensity through spinal cord networks and doesn’t rely solely on brainstem control.
Currently, researchers are trying to find out how these neurons interact with other parts of the brainstem to safely control their activity.
Medscriptum interviewed Dr. Polyxeni Philippidou, an Associate Professor. She spoke about the connection of cholinergic neurons with other rhythmic functions and emotional states, and noted that this discovery offers new possibilities for creating future therapies.
Medscriptum: Have you had any unexpected discoveries related to spinal cord neurons or animal models that contradicted previous hypotheses or existing scientific literature?
Dr. Philippidou: Initially, we used the rabies virus to trace the neural network of the diaphragm muscle. Our goal was to study the neurons that have a direct connection to the diaphragm’s motor neurons. We assumed we would primarily find neurons located in the brainstem, as they control breathing rhythm and movement. It was unexpected for us that the spinal cord cholinergic interneurons provide significant information (~10%) to the diaphragm’s motor neurons. This was the first hint that this population could play a crucial role in breathing modulation.
Medscriptum: Your research is focused on interneurons and breathing, but do you see similarities with other rhythmic processes, such as heartbeat or digestion, which might be controlled by similar spinal cord mechanisms?
Dr. Philippidou: Our discovery suggests that these interneurons represent a special enhancing system for breathing. They help to increase the volume of inhaled air without changing the rhythm or frequency. These neurons have a similar function during movement: they increase the activity of motor neurons when performing complex tasks, such as swimming. Therefore, it’s an interesting hypothesis that these neurons can simultaneously enhance both breathing and movement, and perhaps also heartbeat, during exertion similar to exercise.
Medscriptum: It’s known that there’s a close connection between breathing and mood. Are you considering the possibility that these neurons are involved in anxiety or relaxation?
Dr. Philippidou: Neural connections that link breathing to emotional states are slowly emerging. Hypercapnia (high carbon dioxide levels) can cause anxiety and panic attacks. Since these interneurons are involved in the ventilatory response to high carbon dioxide levels, it’s likely that their dysfunction could be a cause of more intense anxiety.
Medscriptum: When preparing the publication, how did you select the most important results, and were there any findings you would have liked to give more attention to?
Dr. Philippidou: We initially focused on the role of spinal cord cholinergic interneurons in the hypercapnic ventilatory response, as this is a well-described reaction that requires an increase in the output of the diaphragm’s motor neurons. However, this may be only one process in which these neurons are involved. Additionally, we discovered other interneuron populations that connect to the diaphragm’s motor neurons, but we have not yet investigated their functions. In the future, we would like to determine the full repertoire of respiratory processes in which these interneurons are involved.
Medscriptum: Do you think that in the future, through optogenetics, portable stimulators, or gene therapy, we will be able to control these spinal cord networks and use them for rehabilitation in humans?
Dr. Philippidou: This is an exciting prospect for the future. It’s possible that by influencing these interneurons, breathing could be improved in cases where its function is impaired, for example, due to spinal cord injury, ALS, or changes caused by aging. The main step to achieving this will be finding ways to influence respiratory neurons without damaging other neurons. Therefore, fundamental research to study these neurons and respiratory networks is critically important for creating new therapies.
Medscriptum: How would you explain to Medscriptum’s readers why such a “fundamental discovery” is important, especially in an era where more attention is focused on technological medical innovations?
Dr. Philippidou: To be able to correct errors, we first need to understand how the system works. If we don’t know how the neural networks of the brain and spinal cord develop and function, it will be difficult for us to find treatment methods for neurodevelopmental diseases such as autism or neurodegenerative diseases like ALS. Sometimes unexpected discoveries happen during fundamental research. A great example of this is CRISPR, which was originally discovered as a bacterial defense system and is now used to create new therapies.
Medscriptum: Finally, can you tell us what your team is currently working on?
Dr. Philippidou: We are very interested in whether influencing these interneurons can help restore respiratory function in motor neuron diseases like ALS. We are also studying how these neurons manage to connect only to the diaphragm’s motor neurons during development and not to other motor neuron populations.
You can see the full study at the following link: https://www.cell.com/cell-reports/fulltext/
