Summary: Scientists have discovered a specialized group of spinal cord interneurons that help regulate breathing when the body faces challenges like high carbon dioxide levels. Blocking these neurons impaired the body’s ability to adapt its breathing, suggesting they play a key role in respiratory control.
This breakthrough could lead to new treatments for people with spinal cord injuries or neurodegenerative diseases who struggle to breathe independently. The researchers believe the neurons could be an accessible and promising therapeutic target for improving respiratory health.
Key Facts
- New Target: Identified spinal cord interneurons that regulate breathing in response to physiological stress.
- Therapeutic Potential: Could lead to treatments for breathing problems in spinal cord injury and neurodegenerative disease.
- Critical Function: Blocking these neurons reduced the body’s ability to respond to high CO₂ levels, a potentially life-threatening condition.
Source: Case Western Reserve
Late actor Christopher Reeve, best known for his role as Superman in the 1970s and ’80s, became an activist for spinal cord injury research after being paralyzed in a horseback-riding accident—making him a lifelong wheelchair user and on a ventilator.
Reeve, who died in 2004, was among about 300,000 people nationally living with a spinal cord injury, with respiratory complications being the most common cause of illness and death, according to the Christopher & Dana Reeve Foundation, which he and his late wife created to support the research.
But the results of a new study, led by researchers at Case Western Reserve University’s School of Medicine, show promise that a group of nerve cells in the brain and spinal cord—called interneurons—can boost breathing when the body faces certain physiological challenges, such as exercise and environmental conditions associated with altitude.
The researchers believe their discovery could lead to therapeutic treatments for patients with spinal cord injuries who struggle to breathe on their own.
Their findings were recently published in the journal Cell Reports.
“While we know the brainstem sets the rhythm for breathing,” said Polyxeni Philippidou, an associate professor in the Department of Neurosciences at Case Western Reserve University School of Medicine and lead researcher, “the exact pathways that increase respiratory motor neuron output, have been unclear—until now.”
The research team included collaborators from the University of St. Andrews in the United Kingdom, the University of Calgary in Canada and the Biomedical Research Foundation Academy of Athens in Greece.
Legacy of spinal cord research at CWRU
The School of Medicine’s Department of Neurosciences has been studying motor circuits and spinal cord injury for more than 30 years, beginning with the late Jerry Silver, a founding faculty member of the department who was recognized by the Reeve Foundation for his work.
Silver, who died in January, was a member of the Scientific Advisory Council of the Reeve Foundation and the Scientific Board of the International Spinal Research Trust in England. He was awarded the Christopher Reeve-Joan Irvine Research Medal for critical contributions to the promotion of repair of the damaged spinal cord; the Reeve Foundation also posted a tribute after his passing.
In addition, former department Chair Lynn Landmesser, who died in late 2024, was a pioneering neuroscientist and helped develop the Cleveland Brain Health Initiative at the School of Medicine. She made pivotal contributions to the study of motor circuit development and was a member of the National Academy of Sciences.
The study
By identifying a subset of interneurons as a new and potentially easy-to-reach point for treatment in spinal cord injuries and breathing-related diseases, the researchers believe doctors may be able to develop therapies to help improve breathing in people with such conditions.
The study showed that blocking signals from these spinal cord cells made it harder for the body to breathe properly when there was too much carbon dioxide (CO2) in the blood, a condition known as hypercapnia.
CO2 is created in the body when cells make energy. Red blood cells carry CO2 from organs and tissues to the lungs, where it is exhaled. If the body can’t shed CO2, it can build up in the blood, making it hard to breathe and leading to respiratory failure.
“These spinal cord cells are important for helping the body adjust its breathing in response to changes like high CO2 levels,” Philippidou said.
In this study, the team used genetically modified mouse models to explore the pathways involved in breathing. The researchers mapped neuron connections, measured neuron electrical activity, observed the models’ behavior and used microscopy to visualize neuron structure and function—all focused on spinal cord nerve cells involved in breathing.
“We were able to define the genetic identity, activity patterns and role of a specialized subset of spinal cord neurons involved in controlling breathing,” Philippidou said.
The team is now testing whether targeting these neurons in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, and Alzheimer’s disease can help restore breathing.
About this spinal cord injury and neurology research news
Author: Polyxeni Philippidou
Source: Case Western Reserve
Contact: Polyxeni Philippidou – Case Western Reserve
Image: The image is credited to Neuroscience News
Original Research: Open access.
“A cholinergic spinal pathway for the adaptive control of breathing” by Polyxeni Philippidou et al. Cell Reports
Abstract
A cholinergic spinal pathway for the adaptive control of breathing
The ability to amplify motor neuron (MN) output is essential for generating high-intensity motor actions. This is critical for breathing that must be rapidly adjusted to accommodate changing metabolic demands.
While brainstem circuits generate the breathing rhythm, the pathways that directly augment respiratory MN output are not well understood.
Here, we map first-order inputs to phrenic motor neurons (PMNs), a key respiratory MN population that initiates diaphragm contraction to drive breathing.
We identify a predominant spinal input from a distinct subset of genetically defined V0C cholinergic interneurons.
We find that these interneurons receive phasic excitation from brainstem respiratory centers, augment phrenic output through M2 muscarinic receptors, and are highly activated under a hypercapnia challenge.
Specifically silencing cholinergic interneuron neurotransmission impairs the breathing response to hypercapnia.
Collectively, our findings identify a spinal pathway that amplifies breathing, presenting a potential target for promoting recovery of breathing following spinal cord injury.
