Reorganization of Intact Descending Motor Circuits to Replace Lost Connections After Injury

Abstract

Neurons have a limited capacity to regenerate in the adult central nervous system (CNS). The inability of damaged axons to re-establish original circuits results in permanent functional impairment after spinal cord injury (SCI). Despite abortive regeneration of axotomized CNS neurons, limited spontaneous recovery of motor function emerges after partial SCI in humans and experimental rodent models of SCI. It is hypothesized that this spontaneous functional recovery is the result of the reorganization of descending motor pathways spared by the injury, suggesting that plasticity of intact circuits is a potent alternative conduit to enhance functional recovery after SCI. In support of this hypothesis, several studies have shown that after unilateral corticospinal tract (CST) lesion (unilateral pyramidotomy), the intact CST functionally sprouts into the denervated side of the spinal cord. Furthermore, pharmacologic and genetic methods that enhance the intrinsic growth capacity of adult neurons or block extracellular growth inhibitors are effective at significantly enhancing intact CST reorganization and recovery of motor function. Owing to its importance in controlling fine motor behavior in primates, the CST is the most widely studied descending motor pathway; however, additional studies in rodents have shown that plasticity within other spared descending motor pathways, including the rubrospinal tract, raphespinal tract, and reticulospinal tract, can also result in restoration of function after incomplete SCI. Identifying the molecular mechanisms that drive plasticity within intact circuits is crucial in developing novel, potent, and specific therapeutics to restore function after SCI. In this review we discuss the evidence supporting a focus on exploring the capacity of intact motor circuits to functionally repair the damaged CNS after SCI.Electronic supplementary materialThe online version of this article (doi:10.1007/s13311-016-0422-x) contains supplementary material, which is available to authorized users.

Plasticity in One Hemisphere, Control From Two: Adaptation in Descending Motor Pathways After Unilateral Corticospinal Injury in Neonatal Rats

“…The advantage of this model is that it specifically affects one tract in comparison to most other preclinical models of spinal injuries often affecting multiple tracts. Another advantage is the reproducibility of the CST lesion and its subsequent behavioral deficits (Lee and Lee, 2013 ; Kathe et al, 2014 ; Fink and Cafferty, 2016 ). Perhaps most importantly, pyramidotomy tests the limits of adaptation in the two circuits we studied by completely removing one half of the system and by preserving all of the motor cortex to red nucleus connections on the side of injury.…”

Closed-loop neuromodulation restores network connectivity and motor control after spinal cord injury

“…Plasticity in remaining networks could be harnessed to support recovery after SCI ( Fink and Cafferty, 2016 ; Manohar et al, 2017 ). Unilateral SCI resulted in extensive damage to gray matter, rubrospinal pathways, and propriospinal pathways in the right hemicord while largely sparing the right dorsal corticospinal tract (CST) ( Figure 2b and Figure 2—figure supplement 2 ).…”

Effects of a Contusive Spinal Cord Injury on Spinal Motor Neuron Activity and Conduction Time in Rats

“…An exemplar coronal histological section through the center of the injury is shown in Figure 4A. (Lemon, 2008;Fink and Cafferty, 2016). B) Representative image of spinal cord injury epicenter stained with cresyl violet 4 weeks after injury.…”