Weight-Bearing Locomotion in the Developing Opossum, Monodelphis domestica following Spinal Transection: Remodeling of Neuronal Circuits Caudal to Lesion

Abstract

Complete spinal transection in the mature nervous system is typically followed by minimal axonal repair, extensive motor paralysis and loss of sensory functions caudal to the injury. In contrast, the immature nervous system has greater capacity for repair, a phenomenon sometimes called the infant lesion effect. This study investigates spinal injuries early in development using the marsupial opossum Monodelphis domestica whose young are born very immature, allowing access to developmental stages only accessible in utero in eutherian mammals. Spinal cords of Monodelphis pups were completely transected in the lower thoracic region, T10, on postnatal-day (P)7 or P28 and the animals grew to adulthood. In P7-injured animals regrown supraspinal and propriospinal axons through the injury site were demonstrated using retrograde axonal labelling. These animals recovered near-normal coordinated overground locomotion, but with altered gait characteristics including foot placement phase lags. In P28-injured animals no axonal regrowth through the injury site could be demonstrated yet they were able to perform weight-supporting hindlimb stepping overground and on the treadmill. When placed in an environment of reduced sensory feedback (swimming) P7-injured animals swam using their hindlimbs, suggesting that the axons that grew across the lesion made functional connections; P28-injured animals swam using their forelimbs only, suggesting that their overground hindlimb movements were reflex-dependent and thus likely to be generated locally in the lumbar spinal cord. Modifications to propriospinal circuitry in P7- and P28-injured opossums were demonstrated by changes in the number of fluorescently labelled neurons detected in the lumbar cord following tracer studies and changes in the balance of excitatory, inhibitory and neuromodulatory neurotransmitter receptors’ gene expression shown by qRT-PCR. These results are discussed in the context of studies indicating that although following injury the isolated segment of the spinal cord retains some capability of rhythmic movement the mechanisms involved in weight-bearing locomotion are distinct.

Cellular reactions and compensatory tissue re‐organization during spontaneous recovery after spinal cord injury in neonatal mice

“…The behavioral recovery seen in our initial study using this model was reminiscent of that seen in similar neonatal mammalian models (Saunders et al, ; Wang et al, : Wheaton et al, ), and we showed additionally a parallel neurophysiological recovery involving the re‐establishment and reorganization of synaptic connections (Boulland et al, ). The relevant permissive cellular mechanisms operating in this and other neonatal spinal cord injury models have not been well characterized, however, in contrast to the relatively extensive literature on this point in the adult spinal cord.…”

“…Hence, recovery from damage to the spinal cord is likely to be greater in neonatal and young postnatal animals and humans than in adults. Evidence for this in mammals comes from a limited number of studies (Saunders et al, 1995(Saunders et al, , 1998Wang et al, 1998;Wheaton et al, 2011Wheaton et al, , 2013Boulland et al, 2013), including observations in humans (Hadley et al, 1988;Birney and Hanley, 1989;Hamilton and Myles, 1992;Wang et al, 2004). To better understand the difference in pathophysiology and recovery between the injured immature and adult spinal cord, we recently developed a standardized neonatal mouse spinal cord compression injury model (Boulland et al, 2013;Z€ uchner et al, 2016).…”

Treadmill exercise with bone marrow stromal cells transplantation facilitates neuroprotective effect through BDNF-ERK1/2 pathway in spinal cord injury rats

“…Physical activities, such as voluntary wheel running, swimming, weight bearing, and treadmill exercise improve activity of neuronal and non-neuronal cell and axonal regrowth after peripheral and central nerve injury ( Cotman et al, 2007 ; Liao et al, 2017 ; Wheaton et al, 2013 ). Previous studies reported that exercise might be a critical mediator to improve functional recovery and pain-related cellular reactions with the cell survival and differentiation in the injured area ( Fouad et al, 2000 ; Sumizono et al, 2018 ).…”

A bipedal mammalian model for spinal cord injury research: The tammar wallaby

“…This makes the swim test a good test to detect the effects of locomotion in the absence of this reflex input, and a good measure of supraspinal control ( Saunders et al , 1998; Smith et al , 2006; Magnuson et al , 2009; Wheaton et al , 2011; Wheaton et al , 2013). …”