Descending motor circuitry required for NT-3 mediated locomotor recovery after spinal cord injury in mice

Qi Han,Nai-Kui Liu,George M Smith,Josue D Ordaz,Wenrui Qu,Wei Wu,Christopher B Shields,Heqiao Dai,Xiao-Ming Xu,Zoe Richardson,Yongzhi Xia,Yi Ping Zhang,Ying Wang

doi:10.1038/s41467-019-13854-3

Abstract

Locomotor function, mediated by lumbar neural circuitry, is modulated by descending spinal pathways. Spinal cord injury (SCI) interrupts descending projections and denervates lumbar motor neurons (MNs). We previously reported that retrogradely transported neurotrophin-3 (NT-3) to lumbar MNs attenuated SCI-induced lumbar MN dendritic atrophy and enabled functional recovery after a rostral thoracic contusion. Here we functionally dissected the role of descending neural pathways in response to NT-3-mediated recovery after a T9 contusive SCI in mice. We find that residual projections to lumbar MNs are required to produce leg movements after SCI. Next, we show that the spared descending propriospinal pathway, rather than other pathways (including the corticospinal, rubrospinal, serotonergic, and dopaminergic pathways), accounts for NT-3-enhanced recovery. Lastly, we show that NT-3 induced propriospino-MN circuit reorganization after the T9 contusion via promotion of dendritic regrowth rather than prevention of dendritic atrophy.

Highlights

Locomotor function, mediated by lumbar neural circuitry, is modulated by descending spinal pathways
We show that a moderate thoracic contusion at T9 abolishes the corticospinal tract (CST) and rubrospinal tract (RST) projections down to the spinal cord, but retains partial neural transmissions downstream, which can be reinforced by the NT-3 therapy through residual descending propriospinal neurons and their tract
Our previous results demonstrated that retrograde transport of adeno-associated virus-NT-3 (AAV-NT-3) to lumbar motor neurons (MNs) partially restored lumbar motor circuitry, including both lumbar MNs and surrounding residual descending fibers, leading to enhanced locomotor recovery after T9 contusion[7]

Summary

Introduction

Locomotor function, mediated by lumbar neural circuitry, is modulated by descending spinal pathways. We previously reported that retrogradely transported neurotrophin-3 (NT-3) to lumbar MNs attenuated SCI-induced lumbar MN dendritic atrophy and enabled functional recovery after a rostral thoracic contusion. Imaging[10], electrophysiological[11], and anatomical evaluations[12,13] reveal that SCIs, even in the most severe cases, usually spare some region of the spinal cord These spared neural tissues contain residual fibers from mixed supraspinal and propriospinal pathways that maintain a physical connection with the lumbar motor circuits which coordinate locomotion[14,15]. If residual projections are involved, which descending pathways survive a contusion injury, respond to NT-3 treatment, and contribute to the reorganization of the lumbar neural circuit and to the recovery of locomotor function? Is the extent of NT-3induced recovery related to the preservation of lumbar MN dendrites or the degree of spared and/or sprouted descending pathways, or both? if residual projections are involved, which descending pathways survive a contusion injury, respond to NT-3 treatment, and contribute to the reorganization of the lumbar neural circuit and to the recovery of locomotor function? Addressing these questions has considerable therapeutic implications for developing care and treatment of SCI

Methods

Results

Conclusion