Plasticity for recovery after partial spinal cord injury – Hierarchical organization

Highlights

• Studies on the partial spinal cord injury model in macaque monkeys are reviewed.

• During the recovery, drastic reorganization of the neural circuits occurs.

• It depends on the times after the lesion.

• It occurs not only in the spinal cord, but also in motor cortex, and further beyond.

Abstract

To cure the impaired physiological functions after the spinal cord injury, not only development of molecular therapies for axonal regeneration, but also that of therapeutic strategies to induce appropriate rewiring of neural circuits should be necessary. For this purpose, understanding the plastic changes in the central nervous system during spontaneous recovery following the injury would be helpful. In this article, a series of studies conducted in the authors’ laboratory on the reorganization of neural networks in the partial spinal cord injury model using macaque monkeys are reviewed. In this model, after selective lesion of the lateral corticospinal tract at the fifth cervical segment, dexterous digit movements are once impaired, but recover through rehabilitative training in a few weeks to a few months. During the recovery, synaptic transmission and organization of the neural circuits exhibit drastic changes depending on the time after the injury, not only in the spinal cord, but also in hierarchically higher order structures such as motor-related cortical areas and even in limbic structures. It is suggested that on top of the molecular therapies, neurorehabilitative and neuromodulatory therapies targeting such higher order structures should be helpful in inducing appropriate rewiring of the neural circuits.

Introduction

Over the last several decades, a great deal of effort has been devoted to the researches to cure the spinal cord injury (SCI), such as stem cell graft and drug administration, in human patients and animal models. These researches were initially focused on stimulating axonal regeneration, in which providing the tissue with a growth-stimulatory environment was expected to enable the severed axons to regenerate across the injury and re-connect with their target neurons (David and Aguayo, 1981). This line of studies was further facilitated by finding of myelin-derived inhibitors of axonal growth and trials to neutralize such inhibitory myelin proteins (Caroni and Schwab, 1988, Schnell and Schwab, 1990, Akbik et al., 2012). Moreover, understanding the reactive changes that occur after injury and impede the recovery processes, such as inflammation, glial scar formation, cavitation and demyelination, led to development of therapeutic approaches to target these processes (Bunge et al., 1993, Fitch et al., 1999, Schwab and Bartholdi, 1996). In these studies, significant axonal regeneration has been shown, but the extent was relatively modest. On the other hand, a recent study by Mark Tsuzynski and colleagues showed remarkable extension of axons and synapse formation from the human neuronal stem cells grafted into the site of complete thoracic spinal cord injury in rats, in which a variety of treatments, such as fixing the implanted cells in the tissue with fibrin, administration of the cocktail of immune-depressant drugs and more than 20 agents to facilitate the axonal growth were combined (Lu et al., 2012). For further facilitation of functional recovery, now importance of induction of appropriate plasticity and removal of mal-plasticity of the surviving neurons or grafted cells, by combination with neurorehabilitative or neuromodulatory therapies is becoming more and more seriously recognized (Brown and Weaver, 2011, García-Alías and Fawcett, 2011).

Previous studies investigating the effects of stem cell graft or drug administration on the functional recovery were mainly performed in rodent models of the spinal cord injury. In many of them, apparent recovery of locomotor functions could be observed (e.g. in BBB score), and the effectiveness of the treatment was claimed. However, the justification of such paradigm has been challenged, because the recovery of locomotor functions on the flat floor does not always indicate the recovery of descending tract across the injury level; the spinal cord by itself can generate highly coordinated locomotor behavior without the descending input from the brain (Courtine et al., 2009). This is because apparent locomotor ability could be explained by up-regulation of the central pattern generator circuits intrinsic to the lumbar spinal cord (Graham-Brown, 1911, Grillner and Zangger, 1984, Barbeau and Rossignol, 1987, De Leon et al., 1998). Thus, to demonstrate the regeneration of the injured spinal cord, researchers are now required to show that the voluntary control has been recovered, and that the descending tract, either from the cerebral cortex or brainstem, was surely re-connected to the neurons caudal to the lesion either directly or indirectly via the intercalated neurons, anatomically and electrophysiologically (van den Brand et al., 2012).

To demonstrate the voluntary control, movement repertories which require more volitional control, such as forelimb reach and grasp movements, or ladder walk with varying step intervals or bipedal locomotion (over the obstacle) should be tested.

Collectively, for further development of the treatment against the spinal cord injury, understanding the recovery process at the systems level is necessary (Baker, 2011). In this review article, we will introduce our studies during the last decade on the reorganization of large-scaled neuronal network which occurs during functional recovery after the partial cervical spinal cord injury in the non-human primate model. It will be shown that remarkable reorganization occurs not only at the spinal cord level (Sasaki et al., 2004, Nishimura et al., 2009), but also in higher hierarchical levels in the central nervous system (Nishimura et al., 2007a, Nishimura et al., 2007b, Nishimura et al., 2011, Nishimura and Isa, 2012).