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

Abstract

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.

Disproportionate loss of excitatory inputs to smaller phrenic motor neurons following cervical spinal hemisection

“…In addition to excitatory inputs from the rVRG, a complex network of interneurons throughout the spinal cord send excitatory inputs to PhMNs and can modulate DIAm activity (see reviews (Jensen et al . 2019; Sunshine et al . 2020)).…”

“…Following spinal cord injury, an increase in the excitatory input from these spinal interneurons may be important in recovery (Jensen et al . 2019). However, size‐dependent differences in the excitatory input of spinal interneurons to PhMNs has not been examined.…”

“…In addition to excitatory inputs from the rVRG, a complex network of interneurons throughout the spinal cord send excitatory inputs to PhMNs and can modulate DIAm activity (see reviews (Jensen et al 2019;Sunshine et al 2020)). There exist anatomical projections from interneurons in upper cervical segments to PhMNs (Dobbins & Feldman, 1994;Lane et al 2008a,b), constituting a premotor interneuron population that does not mediate inspiratory drive but may affect PhMN excitability (Lu et al 2004;Gonzalez-Rothi et al 2017;Streeter et al 2017).…”

“…There exist anatomical projections from interneurons in upper cervical segments to PhMNs (Dobbins & Feldman, 1994;Lane et al 2008a,b), constituting a premotor interneuron population that does not mediate inspiratory drive but may affect PhMN excitability (Lu et al 2004;Gonzalez-Rothi et al 2017;Streeter et al 2017). Following spinal cord injury, an increase in the excitatory input from these spinal interneurons may be important in recovery (Jensen et al 2019). However, size-dependent differences in the excitatory input of spinal interneurons to PhMNs has not been examined.…”

Restoration of breathing after opioid overdose and spinal cord injury using temporal interference stimulation

“…Inspiratory-related depolarization of phrenic motor neurons arises primarily from excitatory bulbospinal pathways in the ventrolateral white matter of the mid-cervical spinal cord 23 . There also exists a complex propriospinal network that can excite or inhibit phrenic motor neurons 24 (Fig. 5a ).…”