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.

Keywords: Axon; Neuron; Plasticity; Regeneration; Repair; Spinal cord injury.

Fig. 1

Schematic organization of descending motor tracts. (A) Bilateral location of corticospinal motor neurons (CSMNs) in layer V of sensorimotor cortex, the somata of which give rise to the corticospinal (CST) and corticofugal projections. Green CSMNs are highlighted to represent the descending fasciculated spinal course (C) and termination pattern of one side of the CST projection. (B) Location of motor center brainstem nuclei including the red nucleus (RN; red), medullary reticular nuclei (RtN; blue), vestibular nuclei (VtN; orange), tectospinal nuclei (TcN; purple), and the nucleus raphe magnus (NRM; cyan). These nuclei give rise to (C) the rubrospinal tract (RST; red), the reticulospinal tract (RtST; blue), the vestibulospinal tract (VtST; orange), tectospinal tract (TcST; purple) and the raphespinal tract (RpST; cyan). One side of the fasciculated projections of these pathways are schematized in (C) and their terminals within spinal gray matter in (D). Note extensive overlap of motor terminal distribution in the spinal ventral horn. Lesion models to study regeneration and sprouting of lesioned axons are schematized in (Ei–iii). The transection model completely interrupts all descending projections [hatched lines in (i)], the dorsal hemisection (DhX) model lesions the dorsal half of the spinal cord (ii) interrupting the CST and RST, leaving the VtST, TcST, and RtST intact. (iii) Moderate thoracic contusion destroys the central core of the spinal cord at the lesion epicenter, thus ablating spinal gray matter entirely and sparing a limited amount of all circumferential descending motor pathways. (Eiv–vi) Lesion models to study plasticity of intact motor pathways. (iv) The unilateral pyramidotomy (uPyX) model lesions 1 side of the CST in the brainstem, thereby sparing the contralateral CST and all other descending motor pathways. (v) Bilateral pyramidotomy (bPyX) lesions both sides of the CST, sparing all other descending motor tracts. (vi) RN lesion specifically ablates the RST, sparing all other descending motor pathways

Fig. 2

Schematic summary of anatomical plasticity of intact descending motor pathways after partial spinal cord injury. (A) The normal termination pattern of intact corticofugal circuitry (green lines) and lesion-induced de novo circuits (green stippled lines) after unilateral pyramidotomy (PyX; black cross). Corticofugal connections with the red nucleus (RN) and the basilar pontine nuclei (BPN) are unilateral in the intact adult; however, intact corticofugal neurons make bilateral connections after unilateral PyX. (B) After decussating in the caudal medulla, the majority of the corticospinal tract (CST) projects down the spinal cord in the ventral dorsal columns and terminates unilaterally within spinal gray matter (green lines). However, after unilateral PyX intact CST neurons sprout axons across the midline into denervated spinal territory (green stippled lines). (C) Normal path of the rubrospinal tract (RST) through the brainstem and de novo termination pattern or rubral circuitry (red stippled lines) after bilateral PyX (black crosses). In the intact adult, the RST does not make significant contact with the BPN or the nucleus raphe magnus (NRM); however, after complete bilateral destruction of CST, de novo rubral connections between the RN and the BPN and RN and NRM emerge. (D) After decussating in the tegmentum, the RST projects down the spinal cord in the lateral columns and terminates unilaterally within intermediate spinal lamina ( red lines). However, after bilateral PyX intact RST neurons sprout into more dorsal and ventral regions of the spinal cord (red stippled lines)