The phrenic neuromuscular system

Fuller, David D.; Rana, Sabhya; Smuder, Ashley J.; Dale, Erica A.

doi:10.1016/b978-0-323-91534-2.00012-6

Cited by 20 publications

(19 citation statements)

References 143 publications

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“…Phrenic motoneurons receive a rhythmic, monosynaptic, glutamatergic synaptic input from medullary neurons. Acting via NMDA and AMPA receptors, this produces phrenic motoneuron depolarization and subsequent diaphragm muscle contraction 17 . Activating DREADD receptors on phrenic motoneurons should lower the threshold for activation via excitatory glutamatergic synaptic inputs, which would produce a greater output during the inspiratory phase.…”

Section: Discussionmentioning

confidence: 99%

“…The present study focused on chemogenetic activation of the phrenic neuromuscular system. Phrenic motoneurons provide motor innervation of the diaphragm muscle and are located in the mid-cervical (C3-5) spinal cord 17 . We tested the hypothesis that expressing DREADDs in the mid-cervical spinal cord would enable systemic (intravenous) delivery of a selective DREADD ligand to produce sustained increases in the respiratory-related activation of the diaphragm.…”

Section: Introductionmentioning

confidence: 99%

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Chemogenetic stimulation of phrenic motor output and diaphragm activity

Benevides,

Thakre,

Rana

et al. 2024

Preprint

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Impaired diaphragm activation contributes to morbidity and mortality in many neurodegenerative diseases and neurologic injuries. We conducted experiments to determine if expression of an excitatory DREADD (designer receptors exclusively activation by designer drugs) in the mid-cervical spinal cord would enable respiratory-related activation of phrenic motoneurons to increase diaphragm activation. Wild type (C57/bl6) and ChAT-Cre mice received bilateral intraspinal (C4) injections of an adeno-associated virus (AAV) encoding the hM3D(Gq) excitatory DREADD. In wild type mice, this produced non-specific DREADD expression throughout the mid-cervical ventral horn. In ChAT-Cre mice, a Cre-dependent viral construct was used to drive DREADD expression in C4 ventral horn motoneurons, targeting the phrenic motoneuron pool. Diaphragm EMG was recorded during spontaneous breathing at 6-8 weeks post-AAV delivery. The selective DREADD ligand JHU37160 (J60) caused a bilateral, sustained (>1 hr) increase in inspiratory EMG bursting in both groups; the relative increase was greater in ChAT-Cre mice. Additional experiments in a ChAT-Cre rat model were conducted to determine if spinal DREADD activation could increase inspiratory tidal volume (VT) during spontaneous breathing without anesthesia. Three to four months after intraspinal (C4) injection of AAV driving Cre-dependent hM3D(Gq) expression, intravenous J60 resulted in a sustained (>30 min) increase in VT assessed using whole-body plethysmography. Subsequently, direct nerve recordings confirmed that J60 evoked a >50% increase in inspiratory phrenic output. The data show that mid-cervical spinal DREADD expression targeting the phrenic motoneuron pool enables ligand-induced, sustained increases in the neural drive to the diaphragm. Further development of this technology may enable application to clinical conditions associated with impaired diaphragm activation and hypoventilation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chemogenetic stimulation of phrenic motor output and diaphragm activity

Benevides,

Thakre,

Rana

et al. 2024

Preprint

Self Cite

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“…Intermittent hypoxia also elicits plasticity in the output neurons of the respiratory control system—respiratory (phrenic) motor neurons 20,21 . The phrenic motor system is located at cervical spinal segments 3-6, which provides innervation of the major inspiratory pump muscle, the diaphragm 22,23,24 .…”

Section: Mainmentioning

confidence: 99%

Microglia regulate motor neuron plasticity via reciprocal fractalkine/adenosine signaling

Marciante,

Tadjalli,

Burrowes

et al. 2024

Preprint

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Microglia are innate CNS immune cells that play key roles in supporting key CNS functions including brain plasticity. We now report a previously unknown role for microglia in regulating neuroplasticity within spinal phrenic motor neurons, the neurons driving diaphragm contractions and breathing. We demonstrate that microglia regulate phrenic long-term facilitation (pLTF), a form of respiratory memory lasting hours after repetitive exposures to brief periods of low oxygen (acute intermittent hypoxia; AIH) via neuronal/microglial fractalkine signaling. AIH-induced pLTF is regulated by the balance between competing intracellular signaling cascades initiated by serotonin vs adenosine, respectively. Although brainstem raphe neurons release the relevant serotonin, the cellular source of adenosine is unknown. We tested a model in which hypoxia initiates fractalkine signaling between phrenic motor neurons and nearby microglia that triggers extracellular adenosine accumulation. With moderate AIH, phrenic motor neuron adenosine 2A receptor activation undermines serotonin-dominant pLTF; in contrast, severe AIH drives pLTF by a unique, adenosine-dominant mechanism. Phrenic motor neuron fractalkine knockdown, cervical spinal fractalkine receptor inhibition on nearby microglia, and microglial depletion enhance serotonin-dominant pLTF with moderate AIH but suppress adenosine-dominant pLTF with severe AIH. Thus, microglia play novel functions in the healthy spinal cord, regulating hypoxia-induced neuroplasticity within the motor neurons responsible for breathing.

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“…After high cervical SCI, diaphragm output is diminished, but systemically providing a low dose of ampakine can cause a rapid and sustained increase in diaphragm electromyogram output (Rana et al, 2021). Since depolarization of the phrenic motoneurons that innervate the diaphragm critically depends on AMPA receptor activation (Chitravanshi and Sapru, 1996; Fuller et al, 2022; Rana et al, 2019), ampakines are likely acting at least in part on spinal circuits to stimulate diaphragm output (Thakre et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Acute ampakines increase voiding function and coordination in a rat model of SCI

Rana

Alom

Martinez

et al. 2023

Preprint

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Neurogenic bladder dysfunction causes urological complications and reduces the quality of life in persons with spinal cord injury (SCI). Glutamatergic signaling via AMPA receptors is fundamentally important to the neural circuits controlling bladder voiding. Ampakines are positive allosteric modulators of AMPA receptors that can enhance the function of glutamatergic neural circuits after SCI. We hypothesized that ampakines can acutely stimulate bladder voiding that has been impaired due to thoracic contusion SCI. Adult female Sprague Dawley rats received a unilateral contusion of the T9 spinal cord (n=10). Bladder function (cystometry) and coordination with the external urethral sphincter (EUS) were assessed five days post-SCI under urethane anesthesia. Data were compared to responses in spinal intact rats (n=8). The low impact ampakine CX1739 (5, 10, or 15 mg/kg) or vehicle (HPCD) was administered intravenously. The HPCD vehicle had no discernable impact on voiding. In contrast, following CX1739, the pressure threshold for inducing bladder contraction, voided volume and the interval between bladder contractions were significantly reduced. These responses occurred in a dose-dependent manner. We conclude that modulating AMPA receptor function using ampakines can rapidly improve bladder voiding capability at sub-acute time points following contusion SCI. These results may provide a new and translatable method for therapeutic targeting of bladder dysfunction acutely after SCI.

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The phrenic neuromuscular system

Cited by 20 publications

References 143 publications

Chemogenetic stimulation of phrenic motor output and diaphragm activity

Chemogenetic stimulation of phrenic motor output and diaphragm activity

Microglia regulate motor neuron plasticity via reciprocal fractalkine/adenosine signaling

Acute ampakines increase voiding function and coordination in a rat model of SCI

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