Sparing of Descending Axons Rescues Interneuron Plasticity in the Lumbar Cord to Allow Adaptive Learning After Thoracic Spinal Cord Injury

Abstract

This study evaluated the role of spared axons on structural and behavioral neuroplasticity in the lumbar enlargement after a thoracic spinal cord injury (SCI). Previous work has demonstrated that recovery in the presence of spared axons after an incomplete lesion increases behavioral output after a subsequent complete spinal cord transection (TX). This suggests that spared axons direct adaptive changes in below-level neuronal networks of the lumbar cord. In response to spared fibers, we postulate that lumbar neuron networks support behavioral gains by preventing aberrant plasticity. As such, the present study measured histological and functional changes in the isolated lumbar cord after complete TX or incomplete contusion (SCI). To measure functional plasticity in the lumbar cord, we used an established instrumental learning paradigm (ILP). In this paradigm, neural circuits within isolated lumbar segments demonstrate learning by an increase in flexion duration that reduces exposure to a noxious leg shock. We employed this model using a proof-of-principle design to evaluate the role of sparing on lumbar learning and plasticity early (7 days) or late (42 days) after midthoracic SCI in a rodent model. Early after SCI or TX at 7 days, spinal learning was unattainable regardless of whether the animal recovered with or without axonal substrate. Failed learning occurred alongside measures of cell soma atrophy and aberrant dendritic spine expression within interneuron populations responsible for sensorimotor integration and learning. Alternatively, exposure of the lumbar cord to a small amount of spared axons for 6 weeks produced near-normal learning late after SCI. This coincided with greater cell soma volume and fewer aberrant dendritic spines on interneurons. Thus, an opportunity to influence activity-based learning in locomotor networks depends on spared axons limiting maladaptive plasticity. Together, this work identifies a time dependent interaction between spared axonal systems and adaptive plasticity in locomotor networks and highlights a critical window for activity-based rehabilitation.

Consideration of Dose and Timing When Applying Interventions After Stroke and Spinal Cord Injury

“…Early after injury, interneuron atrophy and abnormal synpatic formations were evident, with greater abnormalities occurring as severity increased. 44 Electrophysiological testing of the ankle dorsIflexor reflex showed marked hyperexcitability regardless of severity of SCI. 44 The test for segmental learning required the rat to learn to hold the paw above a saline solution to avoid a small shock to the tibialis anterior (TA).…”

Lumbar Myeloid Cell Trafficking into Locomotor Networks after Thoracic Spinal Cord Injury

“…Spinal shock results from structural and biochemical indices of maladaptive neuroplasticity regulated by neuroinflammation. Findings of aberrant spine formations throughout dorsal, intermediate, and ventral neuron networks support this mechanism (Bandaru et al, 2015; Hains and Waxman, 2006; Hansen et al, 2016; Tan et al, 2008). We postulate that remote inflammatory signaling jeopardizes the homeostatic balance of excitatory and inhibitory synaptic contacts in locomotor networks after SCI.…”

“…Similarly, in our SCI model, we found that injury initiated the release of monocytes into circulation and that this was maintained through 7 dpi. Based on these findings, alongside work in our companion manuscript demonstrating segmental functional impairments in the lumbar cord (Hansen et al, 2016), we postulate that infiltrated macrophages around locomotor networks do not support adaptive function or repair. Instead, we suggest that lumbar macrophages take on a detrimental phenotype early after SCI that renders lumbar networks refractive to function and initiates an acute period of spinal shock.…”

“…Our work identifies a novel injury response caudal but not rostral to SCI that likely undermines recovery and further compounds the functional consequence of axon loss at the lesion epicenter. In a companion manuscript, we have further described segmental functional impairments of neural networks in the lumbar cord at 7d after a moderate/severe thoracic SCI (Hansen et al, 2016). Behaviorally, we found that lumbar segments were incapable of generating adaptive plasticity and learning.…”

What Is Being Trained? How Divergent Forms of Plasticity Compete To Shape Locomotor Recovery after Spinal Cord Injury

“…Despite many examples of successful neurorehabilitative efforts to reengage locomotor activity, evidence suggests that neurorehabilitation in current settings has limited effectiveness. 60 Maladaptive forms of plasticity such as hyper-reflexia/spasticity and chronic central pain can emerge spontaneously after SCI, [61][62][63][64] and once established, maladaptive spinal cord plasticity may undermine the effectiveness of common forms of adaptive rehabilitation including stand training and swimming therapy. 65,66 Accumulating evidence suggests that afferent input in the acute phase of injury can also contribute to maladaptive forms of plasticity, thus making attempts at later adaptive training more difficult.…”