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

Christopher N Hansen,Timothy D Faw,Susan White,James W Grau,D Michele Basso,John A Buford

doi:10.3389/fncir.2016.00011

Christopher N Hansen, Timothy D Faw + Show 4 more

Open Access

https://doi.org/10.3389/fncir.2016.00011

Copy DOI

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.

Highlights

Spinal cord injury (SCI) produces substantial loss of function that recovers over time (Basso et al, 1995; Curt et al, 1998; Kloos et al, 2005; Magnuson et al, 2005)
We found that interneurons known to critically regulate locomotor pattern generation develop a maladaptive, hyperexcitable phenotype in the absence of descending axonal communication during recovery
Long-term exposure to spared axons prevented a maladaptive phenotype while restoring segmental learning behavior

Summary

Introduction

Spinal cord injury (SCI) produces substantial loss of function that recovers over time (Basso et al, 1995; Curt et al, 1998; Kloos et al, 2005; Magnuson et al, 2005). There is typically loss of some, but not all, descending axons Sparing of these axons contributes to functional gains over time (Basso et al, 1996; Courtine et al, 2009). Intermediate interneurons are the postsynaptic site for descending motor systems typically spared after SCI (Erulkar et al, 1966; Scheibel and Scheibel, 1969; Nyberg-Hansen, 1968; Jankowska, 1992; MacLean et al, 1995; Basso et al, 2002) and modulate reflex and locomotor function (Tillakaratne et al, 2000). This article will systematically explore the impact of axonal sparing on downstream plasticity using a combination of behavioral and histological tools

Methods

Results

Conclusion