scholarly journals Key aspects of phrenic motoneuron and diaphragm muscle development during the perinatal period

2008 ◽  
Vol 104 (6) ◽  
pp. 1818-1827 ◽  
Author(s):  
Carlos B. Mantilla ◽  
Gary C. Sieck
Keyword(s):  
Muscle Development ◽  
Respiratory Muscles ◽  
Motor Units ◽  
Perinatal Period ◽  
Diaphragm Muscle ◽  
Postnatal Maturation ◽  
Motor Behaviors ◽  
Phrenic Motoneurons ◽  
Phrenic Motoneuron ◽  
Key Aspects

At the time of birth, respiratory muscles must be activated to sustain ventilation. The perinatal development of respiratory motor units (comprising an individual motoneuron and the muscle fibers it innervates) shows remarkable features that enable mammals to transition from in utero conditions to the air environment in which the remainder of their life will occur. In addition, significant postnatal maturation is necessary to provide for the range of motor behaviors necessary during breathing, swallowing, and speech. As the main inspiratory muscle, the diaphragm muscle (and the phrenic motoneurons that innervate it) plays a key role in accomplishing these behaviors. Considerable diversity exists across diaphragm motor units, but the determinant factors for this diversity are unknown. In recent years, the mechanisms underlying the development of respiratory motor units have received great attention, and this knowledge may provide the opportunity to design appropriate interventions for the treatment of respiratory disease not only in the perinatal period but likely also in the adult.

scholarly journals Diaphragm electromyographic activity following unilateral midcervical contusion injury in rats

2017 ◽  
Vol 117 (2) ◽  
pp. 545-555 ◽  
Author(s):  
Sabhya Rana ◽  
Gary C. Sieck ◽  
Carlos B. Mantilla
Keyword(s):  
Motor Units ◽  
Diaphragm Muscle ◽  
Emg Activity ◽  
High Threshold ◽  
Perineuronal Net ◽  
Neural Drive ◽  
Motor Behaviors ◽  
Neuromotor Control ◽  
Phrenic Motoneurons ◽  
Contusion Injury

Contusion-type injuries to the spinal cord are characterized by tissue loss and disruption of spinal pathways. Midcervical spinal cord injuries impair the function of respiratory muscles and may contribute to significant respiratory complications. This study systematically assessed the impact of a 100-kDy unilateral C4 contusion injury on diaphragm muscle activity across a range of motor behaviors in rats. Chronic diaphragm electromyography (EMG) was recorded before injury and at 1 and 7 days postinjury (DPI). Histological analyses assessed the extent of perineuronal net formation, white-matter sparing, and phrenic motoneuron loss. At 7 DPI, ∼45% of phrenic motoneurons were lost ipsilaterally. Relative diaphragm root mean square (RMS) EMG activity increased bilaterally across a range of motor behaviors by 7 DPI. The increase in diaphragm RMS EMG activity was associated with an increase in neural drive (RMS value at 75 ms after the onset of diaphragm activity) and was more pronounced during higher force, nonventilatory motor behaviors. Animals in the contusion group displayed a transient decrease in respiratory rate and an increase in burst duration at 1 DPI. By 7 days, following midcervical contusion, there was significant perineuronal net formation and white-matter loss that spanned 1 mm around the injury epicenter. Taken together, these findings are consistent with increased recruitment of remaining motor units, including more fatigable, high-threshold motor units, during higher force, nonventilatory behaviors. Changes in diaphragm EMG activity following midcervical contusion injury reflect complex adaptations in neuromotor control that may increase the risk of motor-unit fatigue and compromise the ability to sustain higher force diaphragm efforts. NEW & NOTEWORTHY The present study shows that unilateral contusion injury at C4 results in substantial loss of phrenic motoneurons but increased diaphragm muscle activity across a range of ventilatory and higher force, nonventilatory behaviors. Measures of neural drive indicate increased descending input to phrenic motoneurons that was more pronounced during higher force, nonventilatory behaviors. These findings reveal novel, complex adaptations in neuromotor control following injury, suggestive of increased recruitment of more fatigable, high-threshold motor units.

Invited Review: Mechanisms underlying motor unit plasticity in the respiratory system

2003 ◽  
Vol 94 (3) ◽  
pp. 1230-1241 ◽  
Author(s):  
Carlos B. Mantilla ◽  
Gary C. Sieck
Keyword(s):  
Motor Unit ◽  
Skeletal Muscles ◽  
Neuromuscular Junctions ◽  
Muscle Fibers ◽  
Respiratory Muscles ◽  
Motor Units ◽  
Diaphragm Muscle ◽  
Neuromotor Control ◽  
Phrenic Motoneurons

Neuromotor control of skeletal muscles, including respiratory muscles, is ultimately dependent on the function of the motor unit (comprising an individual motoneuron and the muscle fibers it innervates). Considerable diversity exists across diaphragm motor units, yet remarkable homogeneity is present (and maintained) within motor units. In recent years, the mechanisms underlying the development and adaptability of respiratory motor units have received great attention, leading to significant advances in our understanding of diaphragm motor unit plasticity. For example, following imposed inactivity of the diaphragm muscle, there are changes at phrenic motoneurons, neuromuscular junctions, and muscle fibers that tend to restore the ability of the diaphragm to sustain ventilation. The role of activity, neurotrophins, and other growth factors in modulating this adaptability is discussed.

scholarly journals Diaphragm muscle activity across respiratory motor behaviors in awake and lightly anesthetized rats

2018 ◽  
Vol 124 (4) ◽  
pp. 915-922 ◽  
Author(s):  
Federico Jimenez-Ruiz ◽  
Obaid U. Khurram ◽  
Wen-Zhi Zhan ◽  
Heather M. Gransee ◽  
Gary C. Sieck ◽  
...  
Keyword(s):  
Fixed Effects ◽  
Random Effect ◽  
Respiratory Muscles ◽  
Mixed Linear Model ◽  
Male Rats ◽  
Diaphragm Muscle ◽  
Emg Activity ◽  
Airway Patency ◽  
Motor Behaviors ◽  
Generating Capacity

Respiratory muscles such as the diaphragm are active across a range of behaviors including ventilation and higher-force behaviors necessary for maintenance of airway patency, and minimal information is available regarding anesthetic effects on the capacity of respiratory muscles to generate higher forces. The purpose of the present study was to determine whether diaphragm EMG activity during lower-force behaviors, such as eupnea and hypoxia-hypercapnia, is differentially affected compared with higher-force behaviors, such as a sigh, in lightly anesthetized animals. In adult male rats, chronically implanted diaphragm EMG electrodes were used to measure the effects of low-dose ketamine (30 mg/kg) and xylazine (3 mg/kg) on root mean square (RMS) EMG amplitude across a range of motor behaviors. A mixed linear model was used to evaluate the effects of ketamine-xylazine anesthesia on peak RMS EMG and ventilatory parameters, with condition (awake vs. anesthetized), behavior (eupnea, hypoxia-hypercapnia, sigh), side (left or right hemidiaphragm), and their interactions as fixed effects and animal as a random effect. Compared with the awake recordings, there was an overall reduction of peak diaphragm RMS EMG across behaviors during anesthesia, but this reduction was more pronounced during spontaneous sighs (which require ~60% of maximal diaphragm force). Respiratory rates and duty cycle during eupnea and hypoxia-hypercapnia were higher in awake compared with anesthetized conditions. These results highlight the importance of identifying anesthetic effects on a range of respiratory motor behaviors, including sighs necessary for maintaining airway patency. NEW & NOTEWORTHY Respiratory muscles accomplish a range of motor behaviors, with forces generated for ventilatory behaviors comprising only a small fraction of their maximal force generating capacity. Induction of anesthesia exerts more robust effects on the higher-force diaphragm motor behaviors such as sighs compared with eupnea. This novel information on effects of low, sedative doses of a commonly used anesthetic combination (ketamine-xylazine) highlights the importance of identifying anesthetic effects on a range of respiratory motor behaviors.

Phrenic motoneuron morphology during rapid diaphragm muscle growth

2000 ◽  
Vol 89 (2) ◽  
pp. 563-572 ◽  
Author(s):  
Y. S. Prakash ◽  
Carlos B. Mantilla ◽  
Wen-Zhi Zhan ◽  
Kenneth G. Smithson ◽  
Gary C. Sieck
Keyword(s):  
Surface Area ◽  
Muscle Growth ◽  
Diaphragm Muscle ◽  
Type I ◽  
Cross Sectional ◽  
Early Postnatal Development ◽  
Adult Rat ◽  
Surface Areas ◽  
Phrenic Motoneurons ◽  
Phrenic Motoneuron

In the adult rat, there is a general correspondence between the sizes of motoneurons, motor units, and muscle fibers that has particular functional importance in motor control. During early postnatal development, after the establishment of singular innervation, there is rapid growth of diaphragm muscle (Diam) fibers. In the present study, the association between Diamfiber growth and changes in phrenic motoneuron size (both somal and dendritic) was evaluated from postnatal day 21 (D21) to adulthood. Phrenic motoneurons were retrogradely labeled with fluorescent tetramethylrhodamine dextran (3,000 MW), and motoneuron somal volumes and surface areas were measured using three-dimensional confocal microscopy. In separate animals, phrenic motoneurons retrogradely labeled with choleratoxin B-fragment were visualized using immunocytochemistry, and dendritic arborization was analyzed by camera lucida. Between D21 and adulthood, Diam fiber cross-sectional area increased by ∼164% overall, with the growth of type II fibers being disproportionate to that of type I fibers. There was also substantial growth of phrenic motoneurons (∼360% increase in total surface area), during this same period, that was primarily attributable to an expansion of dendritic surface area. Comparison of the distribution of phrenic motoneuron surface areas between D21 and adults suggests the establishment of a bimodal distribution that may have functional significance for motor unit recruitment in the adult rat.

scholarly journals Recruitment of rat diaphragm motor units across motor behaviors with different levels of diaphragm activation

2014 ◽  
Vol 117 (11) ◽  
pp. 1308-1316 ◽  
Author(s):  
Yasin B. Seven ◽  
Carlos B. Mantilla ◽  
Gary C. Sieck
Keyword(s):  
Motor Unit ◽  
Motor Neurons ◽  
Motor Units ◽  
Motor Unit Recruitment ◽  
Diaphragm Muscle ◽  
Emg Activity ◽  
Motor Behaviors ◽  
Airway Occlusion ◽  
Recruitment Order ◽  
Central Drive

Phrenic motor neurons are recruited across a range of motor behaviors to generate varying levels of diaphragm muscle (DIAm) force. We hypothesized that DIAm motor units are recruited in a fixed order across a range of motor behaviors of varying force levels, consistent with the Henneman Size Principle. Single motor unit action potentials and compound DIAm EMG activities were recorded in anesthetized, neurally intact rats across different motor behaviors, i.e., eupnea, hypoxia-hypercapnia (10% O2 and 5% CO2), deep breaths, sustained airway occlusion, and sneezing. Central drive [estimated by root-mean-squared (RMS) EMG value 75 ms after the onset of EMG activity (RMS75)], recruitment delay, and onset discharge frequencies were similar during eupnea and hypoxia-hypercapnia. Compared with eupnea, central drive increased (∼25%) during deep breaths, and motor units were recruited ∼12 ms earlier ( P < 0.01). During airway occlusion, central drive was ∼3 times greater, motor units were recruited ∼30 ms earlier ( P < 0.01), and motor unit onset discharge frequencies were significantly higher ( P < 0.01). Recruitment order of motor unit pairs observed during eupnea was maintained for 98%, 87%, and 84% of the same pairs recorded during hypoxia-hypercapnia, deep breaths, and airway occlusion, respectively. Reversals in motor unit recruitment order were observed primarily if motor unit pairs were recruited <20 ms apart. These results are consistent with DIAm motor unit recruitment order being determined primarily by the intrinsic size-dependent electrophysiological properties of phrenic motor neurons.

scholarly journals Inhibition of TrkB kinase activity impairs transdiaphragmatic pressure generation

2020 ◽  
Vol 128 (2) ◽  
pp. 338-344
Author(s):  
Miguel Pareja-Cajiao ◽  
Heather M. Gransee ◽  
Naomi A. Cole ◽  
Gary C. Sieck ◽  
Carlos B. Mantilla
Keyword(s):  
Neuromuscular Transmission ◽  
Kinase Activity ◽  
Motor Units ◽  
Diaphragm Muscle ◽  
Receptor Subtype ◽  
Transdiaphragmatic Pressure ◽  
Tracheal Occlusion ◽  
Motor Behaviors ◽  
Subtype B ◽  
Maximal Stimulation

Signaling via the tropomyosin-related kinase receptor subtype B (TrkB) regulates neuromuscular transmission, and inhibition of TrkB kinase activity by 1NMPP1 in TrkBF616A mice worsens neuromuscular transmission failure (NMTF). We hypothesized that acute inhibition of TrkB kinase activity will impair the ability of the diaphragm muscle to produce maximal transdiaphragmatic pressure (Pdi) without impacting the ability to generate forces associated with ventilation, consistent with the greater susceptibility to NMTF in motor units responsible for higher-force nonventilatory behaviors. Adult male and female TrkBF616A mice were injected with 1NMPP1 ( n = 8) or vehicle (DMSO; n = 8) 1 h before Pdi measurements during eupneic breathing, hypoxia/hypercapnia (10% O2/5% CO2), tracheal occlusion, spontaneous deep breaths (“sighs”) and during maximal activation elicited by bilateral phrenic nerve stimulation. In the vehicle-treated group, Pdi increased from ~10 cmH2O during eupnea and hypoxia/hypercapnia, to ~35 cmH2O during sighs and tracheal occlusion, and to ~65 cm H2O during maximal stimulation. There was no effect of acute 1NMPP1 treatment on Pdi generated during most behaviors, except during maximal stimulation (~30% reduction; P < 0.05). This reduction in maximal Pdi is generally similar to the worsening of NMTF previously reported with TrkB kinase inhibition in rodents. Accordingly, impaired TrkB signaling limits the range of motor behaviors accomplished by the diaphragm muscle and may contribute to neuromuscular dysfunction, primarily by impacting fatigable, higher force-generating motor units. NEW & NOTEWORTHY TrkB signaling plays an important role in maintaining neuromuscular function in the diaphragm muscle and may be necessary to accomplish the various motor behaviors ranging from ventilation to expulsive, behaviors requiring near-maximal forces. This study shows that inhibition of TrkB kinase activity impairs maximal pressure generation by the diaphragm muscle, but the ability to generate the lower pressures required for ventilatory behaviors is not impacted.

scholarly journals Diaphragm muscle function following midcervical contusion injury in rats

2019 ◽  
Vol 126 (1) ◽  
pp. 221-230 ◽  
Author(s):  
Obaid U. Khurram ◽  
Matthew J. Fogarty ◽  
Sabhya Rana ◽  
Pangdra Vang ◽  
Gary C. Sieck ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Force Generation ◽  
Diaphragm Muscle ◽  
Neuron Loss ◽  
Motor Behaviors ◽  
Contusion Injury ◽  
Motor Neuron Loss ◽  
The Impact ◽  
Over Time

Midcervical spinal cord contusion injury results in tissue damage, disruption of spinal pathways, and motor neuron loss. Unilateral C4 contusion results in loss of 40%–50% of phrenic motor neurons ipsilateral to the injury (~25% of the total phrenic motor neuron pool). Over time after unilateral C4 contusion injury, diaphragm muscle (DIAm) electromyogram activity increases both contralateral and ipsilateral to the side of injury in rats, suggesting compensation because of increased activation of the surviving motor neurons. However, the impact of contusion injury on DIAm force generation is less clear. Transdiaphragmatic pressure (Pdi) was measured across motor behaviors over time after unilateral C4 contusion injury in adult male Sprague-Dawley rats. Maximum Pdi (Pdimax) was elicited by bilateral phrenic nerve stimulation at 7 days postinjury. We hypothesized that Pdimax is reduced following unilateral C4 contusion injury, whereas ventilatory behaviors of the DIAm are unimpaired. In support of our hypothesis, Pdimax was reduced by ~25% after unilateral C4 contusion, consistent with the extent of phrenic motor neuron loss following contusion injury. One day after contusion injury, the Pdi amplitude during airway occlusion was reduced from ~30 to ~20 cmH2O, but this reduction was completely reversed by 7 days postinjury. Ventilatory behaviors (~10 cmH2O), DIAm-specific force, and muscle fiber cross-sectional area did not differ between the laminectomy and contusion groups. These results indicate that the large reserve capacity for DIAm force generation allows for higher-force motor behaviors to be accomplished despite motor neuron loss, likely reflecting changes in motor unit recruitment. NEW & NOTEWORTHY Respiratory muscles such as the diaphragm generate the pressures necessary to accomplish a variety of motor behaviors ranging from ventilation to near-maximal expulsive behaviors. However, the impact of contusion injury on diaphragm pressure generation across behaviors is not clear. The present study shows that contusion injury impairs maximal pressure generation while preserving the ability of the diaphragm to accomplish lower-force motor behaviors, likely reflecting changes in diaphragm motor unit recruitment.

scholarly journals Diaphragm neuromuscular transmission failure in aged rats

2019 ◽  
Vol 122 (1) ◽  
pp. 93-104 ◽  
Author(s):  
Matthew J. Fogarty ◽  
Maria A. Gonzalez Porras ◽  
Carlos B. Mantilla ◽  
Gary C. Sieck
Keyword(s):  
Nerve Stimulation ◽  
Phrenic Nerve ◽  
Neuromuscular Transmission ◽  
Motor Units ◽  
Diaphragm Muscle ◽  
Muscle Stimulation ◽  
Transmission Failure ◽  
Old Rats ◽  
Motor Neuron Loss ◽  
Fast Twitch

In aging Fischer 344 rats, phrenic motor neuron loss, neuromuscular junction abnormalities, and diaphragm muscle (DIAm) sarcopenia are present by 24 mo of age, with larger fast-twitch fatigue-intermediate (type FInt) and fast-twitch fatigable (type FF) motor units particularly vulnerable. We hypothesize that in old rats, DIAm neuromuscular transmission deficits are specific to type FInt and/or FF units. In phrenic nerve/DIAm preparations from rats at 6 and 24 mo of age, the phrenic nerve was supramaximally stimulated at 10, 40, or 75 Hz. Every 15 s, the DIAm was directly stimulated, and the difference in forces evoked by nerve and muscle stimulation was used to estimate neuromuscular transmission failure. Neuromuscular transmission failure in the DIAm was observed at each stimulation frequency. In the initial stimulus trains, the forces evoked by phrenic nerve stimulation at 40 and 75 Hz were significantly less than those evoked by direct muscle stimulation, and this difference was markedly greater in 24-mo-old rats. During repetitive nerve stimulation, neuromuscular transmission failure at 40 and 75 Hz worsened to a greater extent in 24-mo-old rats compared with younger animals. Because type IIx and/or IIb DIAm fibers (type FInt and/or FF motor units) display greater susceptibility to neuromuscular transmission failure at higher frequencies of stimulation, these data suggest that the age-related loss of larger phrenic motor neurons impacts nerve conduction to muscle at higher frequencies and may contribute to DIAm sarcopenia in old rats. NEW & NOTEWORTHY Diaphragm muscle (DIAm) sarcopenia, phrenic motor neuron loss, and perturbations of neuromuscular junctions (NMJs) are well described in aged rodents and selectively affect FInt and FF motor units. Less attention has been paid to the motor unit-specific aspects of nerve-muscle conduction. In old rats, increased neuromuscular transmission failure occurred at stimulation frequencies where FInt and FF motor units exhibit conduction failures, along with decreased apposition of pre- and postsynaptic domains of DIAm NMJs of these units.

Excitatory connections between upper cervical inspiratory neurons and phrenic motoneurons in cats

1994 ◽  
Vol 77 (2) ◽  
pp. 679-683 ◽  
Author(s):  
Y. Nakazono ◽  
M. Aoki
Keyword(s):  
Phrenic Nerve ◽  
Respiratory Neurons ◽  
Transmission Delays ◽  
Phrenic Motoneurons ◽  
Inspiratory Neurons ◽  
Upper Cervical ◽  
Cervical Segment ◽  
Focal Cooling ◽  
Descending Influences ◽  
Phrenic Motoneuron

This study aimed to determine whether upper cervical inspiratory neurons (UCINs), which are localized in the intermediolateral part of the gray matter of the upper cervical segments, have propriospinal connections to phrenic motoneurons of the ipsilateral lower cervical segment in anesthetized cats. Unit action potentials of UCINs were extracellularly recorded simultaneously with ipsilateral phrenic nerve activity. To eliminate the descending influences from medullary respiratory neurons to phrenic motoneurons, bulbospinal conduction paths were temporarily blocked by focal cooling applied to the ventral caudal medulla at the pyramidal decussation level by means of a cooling thermode (1 mm tip diam). By using a spike-triggered method, during cooling phrenic nerve activities were evoked by UCIN spikes that were elicited by microinjection of L-glutamate for 20 of the 55 (36%) UCIN units examined. The onset latencies of these phrenic motoneuron responses ranged from 1.5 to 7.1 ms (mean 3.6 ms), depending on synaptic transmission delays. These results clearly demonstrate that UCINs have, at least in part, excitatory mono- and paucisynaptic connections with ipsilateral phrenic motoneurons.

scholarly journals Breathing: Motor Control of Diaphragm Muscle

Physiology ◽  
2018 ◽  
Vol 33 (2) ◽  
pp. 113-126 ◽  
Author(s):  
Matthew J. Fogarty ◽  
Carlos B. Mantilla ◽  
Gary C. Sieck
Keyword(s):  
Neural Network ◽  
Motor Control ◽  
Motor Unit ◽  
Motor Neurons ◽  
Muscle Fibers ◽  
Motor Units ◽  
Diaphragm Muscle ◽  
Final Output ◽  
Unit Organization

Breathing occurs without thought but is controlled by a complex neural network with a final output of phrenic motor neurons activating diaphragm muscle fibers (i.e., motor units). This review considers diaphragm motor unit organization and how they are controlled during breathing as well as during expulsive behaviors.

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