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  4. Chemogenetic stimulation of phrenic motor output and diaphragm activity

Chemogenetic stimulation of phrenic motor output and diaphragm activity

bioRxiv preprint, 2024 · DOI: https://doi.org/10.1101/2024.04.12.589188 · Published: November 13, 2024

PhysiologyNeurology

Simple Explanation

This study explores a new method to improve breathing by stimulating the nerves that control the diaphragm, the main muscle for breathing. The researchers used a technique called chemogenetics, which involves using special receptors that can be activated by specific drugs, to stimulate phrenic motor neurons. The study found that activating these receptors in the spinal cord increased the activity of the diaphragm and improved breathing in mice and rats. This approach may have potential for treating conditions where breathing is impaired, such as after a spinal cord injury. The researchers also found that targeting these receptors specifically to the phrenic motor neurons was more effective than non-specific expression in the mid-cervical spinal cord, suggesting that precise targeting is important for this approach.

Study Duration
4-9 weeks post-AAV delivery in mice, 14-16 weeks in rats
Participants
Wild-type mice (n=11), ChAT-Cre mice (n=9), ChAT-Cre rats (n=9)
Evidence Level
Not specified

Key Findings

  • 1
    DREADD ligand JHU37160 (J60) caused a bilateral, sustained (>1 hour) increase in inspiratory EMG bursting in both wild-type and ChAT-Cre mice, with a greater relative increase in ChAT-Cre mice.
  • 2
    In ChAT-Cre rats, intravenous J60 resulted in a sustained (>30 min) increase in tidal volume (VT) during spontaneous breathing, assessed using whole-body plethysmography without anesthesia.
  • 3
    Phrenic nerve recordings in ChAT-Cre rats confirmed that J60 evoked a > 200% increase in inspiratory output under urethane anesthesia.

Research Summary

The study investigated whether expressing designer receptors exclusively activated by designer drugs (DREADDs) in the mid-cervical spinal cord could stimulate phrenic motor output to increase diaphragm activation. Experiments in mice showed that the DREADD ligand JHU37160 (J60) caused a sustained increase in inspiratory EMG bursting in both wild-type and ChAT-Cre mice, with a greater relative increase in ChAT-Cre mice. Experiments in ChAT-Cre rats demonstrated that spinal DREADD activation increased inspiratory tidal volume during spontaneous breathing and evoked a significant increase in inspiratory output in phrenic nerve recordings.

Practical Implications

Clinical application for restoring diaphragm activation

This technology may enable application to clinical conditions associated with impaired diaphragm activation and hypoventilation, such as cervical spinal cord injury.

Targeted gene delivery to the phrenic motor pool

The intrapleural or diaphragmatic injection delivery routes might ultimately prove better for selective phrenic motoneuron targeting. Using different AAV serotypes or viruses with better retrograde movement could optimize the targeting of phrenic motoneurons.

Spinal cord chemogenetics for incomplete cervical spinal cord injury

Focal expression of an excitatory DREADD in phrenic motoneurons could be used to increase the excitability of these cells, thereby improving the efficacy of spared bulbospinal synaptic inputs which convey “inspiratory drive”.

Study Limitations

  • 1
    Variability in the laterality of mCherry expression and physiological response to the DREADD ligand
  • 2
    Lack of unequivocal verification that the DREADD was expressed in phrenic motoneurons using retrograde labeling methods
  • 3
    Precision of the AAV delivery could be improved by further refining spinal injection surgical techniques.

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