Cervical Excitatory Neurons Rescue Breathing After Spinal Cord Injury

Peer Reviewed

Researchers discovered a novel neuronal circuit involving cervical excitatory interneurons that, when activated, rescue breathing after severe spinal cord injury. This circuit does not a play a role in normal breathing and is only activated in response to spinal cord trauma. The findings were reported in the October issue of Nature.

“This discovery could lead to a novel technique that could rescue breathing after spinal cord injury by either chemically, optically, or electrically activating these cervical interneurons to stimulate activation of the diaphragm and induce breathing,” said principal investigator Michael G. Fehlings, MD, PhD, FRCSC, FACS, Professor of Neurosurgery and Co-Director of the Spine Program at the University of Toronto in Ontario, Halbert Chair in Neural Repair and Regeneration and Chair of the AOSpine International Spinal Cord Injury Knowledge Forum.
anatomical illustration of the cervical spine including neck, nerves and brain. A novel technique could rescue breathing after spinal cord injury. Photo Credit: 123RF.com.Dr. Fehlings and colleagues used a gain-of-function/loss-of-function experiment to investigate the contribution of cervical excitatory interneurons to breathing in mouse models of spinal cord injury. These interneurons form synapses on phrenic motor neurons that control the diaphragm, as demonstrated in previous studies.1,2

“We used a viral vector to selectively express a chloride channel in this population of interneurons,” Dr. Fehlings explained. “When the chloride channels were activated, the neurons were inhibited and breathing was markedly impaired.”

Pharmacogenetic stimulation was then used to specifically stimulate the interneurons. This involved virally introducing receptors into the interneurons that were activated with designer drugs.

The researchers then found that these mid-cervical excitatory interneurons are recruited to maintain breathing in mice with non-traumatic cervical spinal cord injury (ie, severe progressive cervical cord compression) as well as promote respiratory recovery after traumatic spinal cord injury.

“The findings definitively prove the importance of this neuronal circuit,” Dr. Fehlings said. “The circuit is essentially dormant under normal circumstances because it does not function as efficiently as the normal circuitry responsible for breathing,” according to Dr. Fehlings.

“The efficiency of the normal circuitry responsible for breathing overrides any other circuits that are present,” Dr. Fehlings said. However, “in the setting of chronic non-traumatic spinal cord injury, which we modeled in this experiment with a slowly induced compression of the cervical cord that mimics a type of injury caused by cervical myelopathy, the damage to the descending circuits that normally control breathing activates these latent circuits to contribute to breathing.”

“We think this is a compensatory mechanism to facilitate recovery after injury to the central nervous system,” Dr. Fehlings said. “In other words, we have discovered a unique anatomical substrate for neuroplasticity in breathing.”

Next Steps in Research
The researchers next hope to examine this neuronal circuitry to rescue breathing after traumatic spinal cord injury in humans using electrical, optogenetic, and/or chemical stimulation, Dr. Fehlings told SpineUniverse.

“Potentially the simplest way to do this might be by applying either a magnetic field to induce electrical currents or directly stimulating the cervical excitatory interneurons with low levels of electrical current,” Dr. Fehlings explained “We would have to see whether this could be done effectively and safely, and I think that it could be.”

“A second approach is to use optogenetics, in which light sensitive receptors are introduced into the cervical interneurons,” Dr. Fehlings continue. “One can do this by introducing an attenuated viral vector (so the virus doesn’t damage the host) and then introduce optically sensitive receptors into the cervical interneurons and use light to stimulate the cervical interneurons.”

“A third approach is to introduce receptors that are sensitive to designer drugs,” as was done in the current animal study, Dr. Fehling said.

Applying Research to Brain Injury
“We think the novel mechanism that we have identified can be used to not only repair the injured spinal cord, but also unlock new mechanisms to recruit plasticity in other forms of brain injury such as traumatic brain injury or neurodegenerative disorders such as Alzheimer’s or Parkinson’s disease.

“In addition, we are thinking about potentially using stem cells as a means to activate these neuronal circuits to permanently rescue breathing,” Dr. Fehlings said.

Disclosure
Dr. Fehlings has no relevant disclosures.

Updated on: 12/03/18
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Michael G. Fehlings, MD, PhD, FRCSC, FACS
Professor of Neurosurgery
Co-Director, Spine Program
University of Toronto
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