Modest spontaneous recovery of ventilation following chronic high cervical hemisection in rats

Abstract

Following C2 spinal hemisection (C2HS) in adult rats, ipsilateral phrenic motoneuron (PhMN) recovery occurs through a time-dependent activation of latent, crossed-spinal collaterals (i.e., spontaneous crossed phrenic phenomenon; sCPP) from contralateral bulbospinal axons. Ventilation is maintained during quiet breathing after C2HS, but the ability to increase ventilation during a respiratory stimulation (e.g. hypercapnia) is impaired. We hypothesized that long-term expression of the sCPP would correspond to a progressive normalization in ventilatory patterns during respiratory challenge. Breathing was assessed via plethsymography in unanesthetized animals and phrenic motor output was measured in urethane-anesthetized, paralyzed and vagotomized rats. At 2-week post-C2HS, minute ventilation (VE) was maintained during baseline (room air) conditions as expected but was substantially blunted during hypercapnic challenge (68±3% of VE in uninjured, weight-matched rats). However, by 12 weeks the spinal-lesioned rats achieved a hypercapnic VE response that was 85±7% of control (p = 0.017 vs. 2 wks). These rats also exhibited augmented breaths (AB's) or "sighs" more frequently (p<0.05) than controls; however, total AB volume was significantly less than control at 2-and 12-week post-injury (69±4% and 80±5%, p<0.05, respectively). We also noted that phrenic neurograms demonstrated a consistent delay in onset of the ipsilateral vs. contralateral inspiratory phrenic burst at 2-12-week post-injury. Finally, the ipsilateral phrenic response to respiratory challenge (hypoxia) was greater, though not normalized, at 4-12-vs. 2-week post-injury. We conclude that recovery of ventilation deficits occurs over 2-12-week post-C2HS; however, intrinsic neuroplasticity remains insufficient to concurrently restore a normal level of ipsilateral phrenic output.

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

“…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. 3,7,24 In the present study, respiratory frequency was not significantly increased. This is most likely due to the effect of the anesthetic and the fact that we did not maintain blood gases constant.…”

“…In studies of anesthetized rats, frequency is not always significantly elevated after SCI. 6,7,14,24 Activity in the paralyzed hemidiaphragm can be partially restored due to the activation of crossed phrenic pathways that have been localized in the spinal cord contralateral and below the site of SCI. These crossed phrenic pathways consist of latent bulbospinal pathways that cross below the site of SCI, 4 and possibly inputs from propriospinal interneurons located within the cervical spinal cord.…”

“…8,23 Multiple methods to restore function to the previously paralyzed hemidiaphragm have been examined in both males and females and, so far to date, enhancement of respiratory drive or synaptic input to phrenic motoneurons, or a decrease in inhibition, results in some restoration of phrenic activity below the site of SCI. 6,[25][26][27][28][29] Functionally, the activation of the crossed phrenic pathways appears to make a meaningful contribution to ventilation in anesthetized rats after SCI, 7,24,30 which may contribute even more during augmented breaths or sighs. 6 Spontaneous activation of the crossed phrenic pathway also occurs over time.…”

“…More recent studies have showed that the spontaneous activation of the crossed phrenic phenomenon is also present in young male rats as early as 2-4 weeks after SCI. [5][6][7][8]10,24,25,27 It is unknown whether this is due to age, sex, or individual rat strains. The diaphragm is not the only respiratory muscle that is affected by upper SCI.…”

Systemic Administration of Rolipram Increases Medullary and Spinal cAMP and Activates a Latent Respiratory Motor Pathway After High Cervical Spinal Cord Injury

“…Although the preparation may not reflect normal physiologic conditions, the results obtained with this approach have provided valuable information regarding respiratory mechanisms and the effect of various drugs on respiratory neural output. It is also well established that crossed phrenic activity detected in the phrenic nerve translates into both diaphragmatic and actual breathing function (30,33,34). In a previous study, we showed that chronic administration of rolipram for 3 days leads to long-lasting restoration of phrenic nerve motor function after high cervical spinal cord hemisection.…”