Mechanisms and therapeutic potential of phrenic proprioceptors after spinal cord injury - PROJECT SUMMARY/ABSTRACT Breathing impairments are the primary cause of morbidity and mortality following cervical spinal cord injury (cSCI). Limited treatment options, beyond mechanical ventilation, are available to manage respiratory dysfunction. Electrical stimulation of the diaphragm (i.e., diaphragm pacing), is an emerging intervention used to manage breathing impairments in some individuals who fail to wean from the mechanical ventilator after cSCI. Clinical reports suggest that diaphragm pacing can promote ventilator weaning, but also shows promise in restoring independent breathing. Collectively, our preliminary data and literature reports have led to the fundamental hypothesis that diaphragm sensory neurons (i.e., phrenic afferents) are a novel therapeutic target to restore respiratory neural function and improve breathing following cSCI. Specifically, our preliminary data in anesthetized rats suggest that activation of phrenic proprioceptors induces a novel form of phrenic motor plasticity. Our data also show that daily diaphragm pacing in freely behaving rodents leads to a long-lasting increase in tidal volume after cSCI. Moreover, we show that activation of phrenic afferents is necessary for pacing-induced respiratory recovery. Finally, preliminary data demonstrate that phrenic afferent discharge is profoundly altered after cSCI and that diaphragm pacing restores discharge patterns necessary for the induction of plasticity. These results have led to the overarching hypothesis that phrenic proprioceptors induce mechanisms of spinal plasticity which promotes the recovery of breathing after cSCI. Aim 1 will test the hypothesis that phrenic proprioceptor activation induces a novel form of phrenic motor plasticity which is mechanically distinct from other forms of respiratory plasticity. This hypothesis will be tested using in vivo neurophysiology to enable studies examining spinal mechanisms of plasticity. Aim 2 will test the hypothesis that respiratory proprioceptors are necessary for diaphragm-pacing induced respiratory recovery. This hypothesis will be tested using a rodent model of daily, diaphragm pacing in freely behaving rodents and adeno-associated virus (AAV) mediated chemogenetic approaches to silence respiratory proprioceptors. Aim 3 will test the hypothesis that phrenic proprioceptor activity is altered following cSCI and diaphragm pacing promotes discharge in phase with breathing. This hypothesis will be tested using a neurophysiological approach to record phrenic afferent discharge and deliver diaphragm pacing. Our research will identify a novel target to improve breathing following cSCI and has the potential to lead to a paradigm shift in the management of breathing insufficiency after cSCI – a problem with limited treatment options and no cure.
