A Latent Propriospinal Network Can Restore Diaphragm Function after High Cervical Spinal Cord Injury

Cregg, Jared M.; Chu, Kevin A.; Hager, Lydia E.; Maggard, Rachel S.J.; Stoltz, Daimen; Edmond, Michaela; Alilain, Warren J.; Philippidou, Polyxeni; Landmesser, Lynn T.; Silver, Jerry

doi:10.1016/j.celrep.2017.09.076

Cited by 40 publications

(43 citation statements)

References 49 publications

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“…respiration | breathing | oscillator | optogenetics M ammals constantly adapt their respiratory rate to meet both homeostatic and behavioral needs (1). Several distinct populations of hindbrain neurons modulate inspiratory frequency (2,3), which is ultimately controlled by the pre-Bötzinger complex (preBötC), a medullary nucleus required for generation of inspiratory bursts (4)(5)(6)(7)(8). The preBötC encompasses a heterogeneous population of neurons (9,10), of which a kernel of excitatory neurons gives rise to inspiratory bursts (11).…”

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confidence: 99%

Phasic inhibition as a mechanism for generation of rapid respiratory rhythms

Cregg

Chu

Dick

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Central neural networks operate continuously throughout life to control respiration, yet mechanisms regulating ventilatory frequency are poorly understood. Inspiration is generated by the pre-Bötzinger complex of the ventrolateral medulla, where it is thought that excitation increases inspiratory frequency and inhibition causes apnea. To test this model, we used an in vitro optogenetic approach to stimulate select populations of hindbrain neurons and characterize how they modulate frequency. Unexpectedly, we found that inhibition was required for increases in frequency caused by stimulation of Phox2b-lineage, putative CO-chemosensitive neurons. As a mechanistic explanation for inhibition-dependent increases in frequency, we found that phasic stimulation of inhibitory neurons can increase inspiratory frequency via postinhibitory rebound. We present evidence that Phox2b-mediated increases in frequency are caused by rebound excitation following an inhibitory synaptic volley relayed by expiration. Thus, although it is widely thought that inhibition between inspiration and expiration simply prevents activity in the antagonistic phase, we instead propose a model whereby inhibitory coupling via postinhibitory rebound excitation actually generates fast modes of inspiration.

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confidence: 99%

Phasic inhibition as a mechanism for generation of rapid respiratory rhythms

Cregg

Chu

Dick

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…However, there are also intersegmental interactions within the spinal cord that link the locomotor and respiratory circuits. For example, phrenic motor neurons can be driven by lumbar spinal circuits when local inhibition is blocked even following a C1 transection (Cregg et al, 2017). In addition, there is entrainment (a 1:1 coupling between successive periods) between locomotor and phrenic motor output in spinalized rabbits (Viala et al, 1987).…”

Section: Propriospinal Neurons Help Coordinate Ventilation and Motor mentioning

confidence: 99%

“…For example, blocking the effects of inhibitory interneurons using a GABA receptor antagonist can restore rhythmic bursting activity to a paralyzed hemidiaphragm below a C2 hemisection injury (Zimmer and Goshgarian, 2007). In addition, Cregg et al (2017) used an ex vivo neonatal spinal cord preparation to show that blocking inhibitory neurons could elicit phrenic motor neuron bursting even after complete C1 transection. Optogenetic stimulation of excitatory neurons could evoke phrenic bursts in their preparation, but only when inhibitory neurotransmission was blocked (Cregg et al, 2017).…”

Section: Propriospinal Neurons Modulate Respiratory Motor Output Follmentioning

confidence: 99%

“…In addition, Cregg et al (2017) used an ex vivo neonatal spinal cord preparation to show that blocking inhibitory neurons could elicit phrenic motor neuron bursting even after complete C1 transection. Optogenetic stimulation of excitatory neurons could evoke phrenic bursts in their preparation, but only when inhibitory neurotransmission was blocked (Cregg et al, 2017). Thus, phrenic motor neurons appear to be targets of excitatory pathways that are normally latent due to the activity of inhibitory neurons.…”

Section: Propriospinal Neurons Modulate Respiratory Motor Output Follmentioning

confidence: 99%

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Role of Propriospinal Neurons in Control of Respiratory Muscles and Recovery of Breathing Following Injury

Jensen

Alilain

Crone

2020

Front. Syst. Neurosci.

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Respiratory motor failure is the leading cause of death in spinal cord injury (SCI). Cervical injuries disrupt connections between brainstem neurons that are the primary source of excitatory drive to respiratory motor neurons in the spinal cord and their targets. In addition to direct connections from bulbospinal neurons, respiratory motor neurons also receive excitatory and inhibitory inputs from propriospinal neurons, yet their role in the control of breathing is often overlooked. In this review, we will present evidence that propriospinal neurons play important roles in patterning muscle activity for breathing. These roles likely include shaping the pattern of respiratory motor output, processing and transmitting sensory afferent information, coordinating ventilation with motor activity, and regulating accessory and respiratory muscle activity. In addition, we discuss recent studies that have highlighted the importance of propriospinal neurons for recovery of respiratory muscle function following SCI. We propose that molecular genetic approaches to target specific developmental neuron classes in the spinal cord would help investigators resolve the many roles of propriospinal neurons in the control of breathing. A better understanding of how spinal circuits pattern breathing could lead to new treatments to improve breathing following injury or disease.

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“…Contrary to this, the respiratory motor system is capable of plastic alteration and reorganisation following trauma. 34,35 Indeed, it has been previously demonstrated modest functional restoration of respiratory function following ChABC application after acute C2 hemisection injury. 36 The application of a plasticity inducing enzyme has never been used to treat respiratory motor dysfunction following the more clinically relevant severe mid-cervical contusion injury.…”

Section: Introductionmentioning

confidence: 99%

Plasticity Induced Recovery of Breathing Occurs at Chronic Stages after Cervical Contusion

Warren

Alilain

2019

Journal of Neurotrauma

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Severe mid-cervical contusion injury causes profound deficits throughout the respiratory motor system which last from acute to chronic time points post injury. Here we use chondroitinase ABC (ChABC) to digest chondroitin sulphate proteoglycans (CSPGs) within the extracellular matrix (ECM) surrounding the respiratory system at both acute and chronic time points post injury to explore whether augmentation of plasticity can recover normal motor function. We demonstrate that, regardless of time post injury or treatment application, the lesion cavity remains consistent showing little regeneration or neuroprotection within our model. However, through electromyography (EMG) recordings of multiple inspiratory muscles, we show that application of the enzyme at chronic time points post injury initiates the recovery of normal breathing in previously paralysed respiratory muscles. This reduced the need for compensatory activity throughout the motor system. Application of ChABC at acute time points recovered only modest amounts of respiratory function. To further understand this effect, we assessed the anatomical mechanism of this recovery. Increased EMG activity in previously paralyzed muscles was brought about by activation of spared bulbospinal pathways through the site of injury and/or sprouting of spared serotonergic fibres from the contralateral side of the cord. Accordingly, we demonstrate that alterations to the ECM and augmentation of plasticity at chronic time points post cervical contusion can cause functional recovery the respiratory motor system and reveal mechanistic evidence of the pathways which govern this effect.

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A Latent Propriospinal Network Can Restore Diaphragm Function after High Cervical Spinal Cord Injury

Cited by 40 publications

References 49 publications

Phasic inhibition as a mechanism for generation of rapid respiratory rhythms

Phasic inhibition as a mechanism for generation of rapid respiratory rhythms

Role of Propriospinal Neurons in Control of Respiratory Muscles and Recovery of Breathing Following Injury

Plasticity Induced Recovery of Breathing Occurs at Chronic Stages after Cervical Contusion

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