Search bioRxiv⌕ Search

bioRxiv · 10.1101/2021.09.21.457706

Laryngeal and swallow dysregulation following acute cervical spinal cord injury

Abstract

Proper function of the larynx is vital to airway protection, including swallow. While the swallow reflex is controlled by the brainstem, patients with cervical spinal cord injuries (cSCI) are likely at increased risk of disordered swallow (dysphagia) and pneumonia, and the underlying mechanisms are unknown. We aimed to determine if acute spinal cord injury would disrupt swallow function in animal models. We hypothesized that 1) loss of descending efferent information to the diaphragm would affect swallow and breathing differently, and that 2) loss of ascending spinal afferent information would alter central swallow regulation to change motor drive to the upper airway. We recorded amplitudes of laryngeal and inspiratory muscle electromyograms (EMGs), submental and pharyngeal muscle EMGs, and cardiorespiratory measures in freely breathing pentobarbital-anesthetized cats and rats. First, we assessed the effect of a lateral hemisection at the second cervical level (C2) in cats during breathing. Posterior cricoarytenoid (laryngeal abductor) EMG activity during inspiration increased nearly two-fold, indicating that inspiratory laryngeal drive increased following cSCI. Ipsilateral to the injury, the crural diaphragm EMG was significantly reduced during breathing (62 {+/-} 25 percent change post-injury), but no animal had a complete termination of all activity; 75% of animals had an increase in contralateral diaphragm recruitment after cSCI, but this did not reach significance. Next, we assessed the effect of C2 lateral hemisection in cats during swallow. The thyroarytenoid (laryngeal adductor) and thyropharyngeus (pharyngeal constrictor) both increased EMG activity during swallow, indicating increased upper airway drive during swallow following cSCI. There was no change in the number of swallows stimulated per trial. We also found that diaphragm activity during swallow (schluckatmung) was bilaterally suppressed after lateral C2 hemisection, which was unexpected because this injury did not suppress contralateral diaphragm activity during breathing. Swallow-breathing coordination was also affected by cSCI, with more post-injury swallows occurring during early expiration. Finally, because we wanted to determine if the chest wall is a major source of feedback for laryngeal regulation, we performed T1 total transections in rats. As in the cat C2 lateral hemisection, a similar increase in inspiratory laryngeal activity (posterior cricoarytenoid) was the first feature noted after rat T1 complete spinal cord transection. In contrast to the cat C2 lateral hemisection, diaphragmatic respiratory drive increased after T1 transection in every rat (215 {+/-} 63 percent change), and this effect was significant. Overall, we found that spinal cord injury alters laryngeal drive during swallow and breathing, and alters swallow-related diaphragm activity. Our results show behavior-specific effects, suggesting that swallow may be more affected than breathing is by cSCI, and emphasizing the need for additional studies on laryngeal function during breathing and swallow after spinal cord injury.

Source connections

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Pitts, T., Iceman, K. E., Huff, A., Musselwhite, M. N., Frazure, M. L., Young, K. C., Greene, C. L., Howland, D. R.. 2021-09-24. Laryngeal and swallow dysregulation following acute cervical spinal cord injury. https://doi.org/10.1101/2021.09.21.457706

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

Epidermal Langerhans Cells Act as Neuroimmune Regulators of Pain and Itch

Neuroimmune interactions in the skin coordinate immune defense and somatosensory perception, yet how immune cells shape sensory signaling remains poorly defined. Here, we show that Langerhans cells (LCs), epidermal antigen-presenting cells, function as local immune-derived amplifiers of cutaneous sensory signaling. Anatomical and transcriptomic analyses reveal preferential LC association with non-peptidergic sensory neurons. LC activation increases neuronal and behavioral responses to thermal, mechanical, and pruritic stimuli without directly exciting sensory neurons, whereas LC inhibition or ablation selectively reduces pruritogen-evoked itch. We identified semaphorin 7A as a candidate LC-expressed mediator. Semaphorin 7A sensitized cultured sensory neurons to chloroquine and histamine, and neutralizing semaphorin 7A abolished the increase in chloroquine-evoked scratching produced by LC activation. Its receptor PlexinC1 was expressed by most MrgprA3 pruriceptors and blocking PlexinC1 reduced semaphorin 7A-evoked neuronal responses. Together, these findings identify epidermal LCs as local immune-derived amplifiers that regulate the responsiveness of cutaneous sensory circuits and identify semaphorin 7A as a mediator of LC-induced itch potentiation.

neuroscience↗

Feasible closed-loop stimulation for neural latent dynamics control

Modern neuroscience benefits from powerful computational and experimental methods for studying neural populations, including latent dynamics models that predict behavior with few dimensions. But despite their explanatory utility, latent factors are seldom targeted explicitly with experimental perturbations, leaving causal relationships to behavior and inferred dynamical landscapes untested. A promising solution is closed-loop, multi-channel optogenetic control, which, when paired with model predictions, could steer neural trajectories in real time--a feat impossible for traditional, hand-designed stimulation. However, because closed-loop latent control has not been demonstrated in vivo, the hardware and software requirements remain unclear--particularly the necessary stimulation dimensionality and how limited resources such as implant volume and bandwidth should be allocated between stimulation and recording capabilities. Preliminary experiments would thus help guide ongoing technological development. As large-scale exploration of these design spaces in vivo is prohibitively expensive, we conducted a high-throughput simulation survey using biophysically grounded spiking neural networks. We found that low-dimensional actuation is sufficient: in the reference configuration, ~20% of the stimulation channels achieved ~85% of peak control performance, far fewer than the number of neurons. Furthermore, allocating channels roughly equally between stimulation and recording optimized behavioral control, whereas pairing many electrodes with a single light source--the prevailing practice in experimental labs--performed poorly. Even without heavily optimizing modeling or control, we obtained >60% tracking error reduction and >90% evoked behavior accuracy on average for optimal channel counts. These results held across extensive parameter variations, suggesting that closed-loop latent control is feasible with accessible channel counts and establishing design principles for future tool development and in vivo experiments.

neuroscience↗

Identification of Kinome Biomarkers and Therapeutic Rescue in cGMP-Linked Retinal Degeneration

Inherited retinal degenerations, such as Retinitis Pigmentosa (RP) and Leber's congenital amaurosis (LCA), are major causes of progressive and irreversible vision loss. The large number of genes associated with these disorders makes their clinical and molecular characterization difficult, while systemic biomarkers for disease progression or treatment response remain limited. These challenges were addressed by targeting cGMP-associated mechanisms shared by RP and LCA and integrating systemic biomarker profiling with retinal outcomes. Kinase activity analysis (kinome analysis) in peripheral blood mononuclear cells distinguished healthy and diseased states and captured therapy-associated signatures in rd10 mice treated with LP-CN03, a liposomal formulation of the cGMP analog CN03. This first systemic analysis in a therapeutically responsive animal model highlights kinome analysis as a potential translational readout. Given shared cGMP signaling in RP and AIPL1-associated LCA, LP-CN03's therapeutic potential was further evaluated in a new CRISPR-Cas9-generated Aipl1-/- mouse model. Treatment with LP-CN03 preserved retinal structure and function, as shown by electroretinography, longitudinal optical coherence tomography, fundus imaging, optomotor testing, and photoreceptor-specific gene expression. Together, these findings provide independent in vivo evidence for the neuroprotective effect of LP-CN03 in both cGMP-related RP and LCA, also highlighting the translational value of kinome profiling.

neuroscience↗