The crossed phrenic phenomenon and recovery of function following spinal cord injury

Abstract

This review will focus on neural plasticity and recovery of respiratory function after spinal cord injury and feature the "crossed phrenic phenomenon" (CPP) as a model for demonstrating such plasticity and recovery. A very brief summary of the earlier literature on the CPP will be followed by a more detailed review of the more recent studies. Two aspects of plasticity associated with the CPP that have been introduced in the literature recently have been spontaneous recovery of ipsilateral hemidiaphragmatic function following chronic spinal cord injury and drug-induced persistent recovery of the ipsilateral hemidiaphragm lasting long after animals have been weaned from drug treatment. The underlying mechanisms for this plasticity and resultant recovery will be discussed in this review. Moreover, two new models involving the CPP have been introduced: a mouse model which now provides for an opportunity to study CPP plasticity at a molecular level using a genetic approach and light-stimulated induction of the CPP accomplished by transfecting mammalian cells with channelrhodopsin. Both models provide an opportunity to sort out the intracellular signaling cascades that may be involved in motor recovery in the respiratory system after spinal cord injury. Finally, the review will examine developmental plasticity of the CPP and discuss how the expression of the CPP changes in neonatal rats as they mature to adults. Understanding the underlying mechanisms behind the spontaneous expression of the crossed phrenic pathway either in the developing animal or after chronic spinal cord injury in the adult animal may provide clues to initiating respiratory recovery sooner to alleviate human suffering and eventually eliminate the leading cause of death in human cases of spinal cord injury.

A Murine Model of Cervical Spinal Cord Injury to Study Post-lesional Respiratory Neuroplasticity

“…), and minimizes animal subject distress; 7) unlike the locomotor function, the respiratory function does not require animal motivation and is easily quantifiable (diaphragm EMG, phrenic nerve ENG, tidal volume and frequency); 8) one key aspect is the "crossed phrenic phenomenon" (CPP). This particular topic has an extensive published literature using rats as a model (see Goshgarian et al 5,16 for reviews); 9) Rats and humans share many common features in their respiratory control system, which make the rat a good preclinical model to study respiratory insufficiency following cervical SCI12. Moreover, one laboratory has started to successfully develop a C2 hemisection on a mouse model 25 .…”

“…This model is currently used by several laboratories around the world (for reviews: [4][5][6][7][8][9][10][11][12][13] ). However, slight differences in the surgical procedure can be observed among the different investigators to generate this particular cervical injury murine model.…”

Ipsilateral inspiratory intercostal muscle activity after C2 spinal cord hemisection in rats

“…[18][19][20] C2 hemisection results in complete paralysis of the ipsilateral hemidiaphragm due to the interruption of signals that arise primarily from descending monosynaptic, bulbospinal premotor neurons. 4,[21][22][23] This results in a decreased tidal volume and a compensatory increase in respiratory frequency which is observed consistently in unanesthetized rats.…”

Contribution of the spontaneous crossed-phrenic phenomenon to inspiratory tidal volume in spontaneously breathing rats

“…We conclude that by 2 wk post-C2HS the sCPP makes a meaningful contribution to VT that is similar across different levels of respiratory drive. plasticity; hemisection; phrenicotomy; cervix SEVERING IPSILATERAL BULBOSPINAL inputs to phrenic motoneurons via lateral hemisection of the C2 spinal cord (C2HS) transiently paralyzes the hemidiaphragm (22,23,27,48). However, a partial return of ipsilateral phrenic motoneuron inspiratory bursting occurs over a period of weeks to months following C2HS (14,15,20,37).…”

“…22,28,40). The sCPP provides an important experimental model of neuroplasticity and associated functional recovery (i.e., phrenic bursting) after spinal cord injury (22,28,40). However, the functional contribution of the sCPP to ventilation (V E) has not been definitively established.…”