Acute and chronic changes in diaphragmatic activity and respiratory function following C3 spinal hemi-contusion in mice - 17/02/23

Cervical spinal cord injuries (cSCI) damage the bulbospinal respiratory pathways and the phrenic motoneurons they innervate, leading to respiratory impairments. We recently developed a mouse model of C3 hemi-contusion (C3-HC) to mimic human pathophysiology of cSCI. In the present study, we characterized the respiratory impacts of our C3-HC model at both acute (2 to 7 days – d2 – d7) and chronic stages (21 days – d21) post injury (P.I.).

In all, 27 male OF-1 mice were used in this study. Respiratory function was assessed using whole-body plethysmography at different time-points: before surgery, and at d2, d5, d7 and d21 P.I. or time-corresponding laminectomy. Moreover, electromyograms (EMG) of specific diaphragmatic areas (ventral, medial, and dorsal part of each hemi-diaphragm) were studied at d7 and d21 P.I. or laminectomy.

C3-HC led to an average 20% decrease in tidal volume (VT) at d2 P.I. compared to baseline, which did not recover spontaneously over time (d2, d5, d7 and d21 P.I. vs. Laminectomy, P<0.05). Breathing frequency (fB) increased at d5 P.I., allowing minute ventilation (VE) to be spontaneously restored at pre-surgery levels and did not change over time (d21: 271±44 vs. baseline: 191±25rpm, P<0.001, vs. laminectomy: 188±25rpm, P<0.01). EMG activity of the injured hemi-diaphragm was significantly reduced compared to the intact side in the medial and dorsal parts (63±37% and 51±31%, respectively, P<0.05), although it tended to increase in the ventral area (147±108%, P=0.09) at d7 P.I. At d21 after surgery, the reduction was still significant at the dorsal level for the C3-HC group compared to Laminectomy but not in the medial or ventral area.

Our results suggest that C3-HC has different impacts on the physiological responses of distinct diaphragm areas in mice, including non-resolving diaphragmatic alterations in the dorsal part until at least d21 P.I. Moreover, the increased in fB seems to be an adapting mechanism of VE recovery to counteract partial alteration in diaphragmatic activity. This model is relevant in the context of respiratory dysfunction following cSCI and will be useful to evaluate the benefits of novel treatments on respiratory pattern and diaphragmatic activity at both acute and chronic stages following cSCI.