Axotomized Corticospinal Neurons Increase Supra-Lesional Innervation and Remain Crucial for Skilled Reaching after Bilateral Pyramidotomy

Abstract

Skilled upper limb function heavily depends on the corticospinal tract. After bilateral lesions to this tract, motor control is disrupted but can be partially substituted by other motor systems to allow functional recovery. However, the remaining roles of motor cortex and especially of axotomized corticospinal neurons (CSNs) are not well understood. Using the single pellet retrieval task in adult rats, we induced significant recovery of skilled reaching after bilateral pyramidotomy by rehabilitative reaching training, and show that reach-related motor cortex activity, recorded in layer V, topographically reappeared shortly after axotomy. Using a chemogenetic neuronal silencing technique, we found that axotomized CSNs retained a crucial role for the recovered pellet retrieval success. The axotomized CSNs sprouted extensively in the red nucleus supplying new innervation to its magnocellular and parvocellular parts. Specific silencing of the rubrospinal tract (RST) also strongly abolished the recovered pellet retrieval success, suggesting a role of this cervically projecting nucleus in relaying cortical motor control. In summary, our results show that after bilateral corticospinal axotomy, motor cortex still actively engages in forelimb motor control and axotomized CSNs are crucially involved in the recovered reaching movement, potentially by relaying motor control via the RST.

Changes of motor corticobulbar projections following different lesion types affecting the central nervous system in adult macaque monkeys

“…There is still incomplete understanding of the precise role played by brainstem-descending pathways in motor recovery from lesion, as well as by corticobulbar pathways. Although previous reports speculated that corticobulbar projections may play an important role in motor recovery after lesion of the CNS (Beaud et al, 2008;Hoogewoud et al, 2013;Mosberger et al, 2017;Wyss et al, 2013;Zörner & Schwab, 2010), this descending tract still remains mysterious for the most part, possibly due in part to its location and the difficult access to the corresponding target nuclei in the brainstem. The present study is original as it represents a unique study in nonhuman primates quantitatively investigating the rearrangement of the corticobulbar projections onto the PMRF following different pathologies affecting the CNS, such as motor cortex lesion, PD or SCI.…”

Synergistic Effects of Enriched Environment and Task-Specific Reach Training on Poststroke Recovery of Motor Function

“…Preclinical studies have demonstrated significant functional recovery based on neuroplastic changes within both perilesional 5,14 and contralesional cortex, 16 spinal cord, 17,18 and rubrospinal tracts. 19,20 This has led to the view that by utilizing task-specificity principles and focusing treatment on surviving networks and their connections, it will be possible to tailor rehabilitative strategies to maximize poststroke recovery. [21][22][23] Previous investigations have demonstrated the efficacy of combining of environmental enrichment and task-specific reach training to promote poststroke recovery.…”

Cortical Reorganization of Sensorimotor Systems and the Role of Intracortical Circuits After Spinal Cord Injury

“…Studies have largely attributed cortical reorganization in rodents to remodeling of the corticospinal tract or other descending tracts [64,[89][90][91][92][93]. This is due, in part, to the observation that injured, and intact, axons departing the cerebral cortex (corticofugal axons) have been found to elicit new growth coincident with the changes in cortical motor maps.…”

“…Alternative pathways for cortical input to the spinal cord exist and even arise as collateral projections from corticospinal neurons. After bilateral transection at the level of the medullary pyramids (pyramidotomy), injured corticospinal axons sprout into the red nucleus, supporting recovery of skilled forelimb function [91]. Chemogenetic silencing of the injured corticospinal neurons, or forelimb motor cortex stroke, disrupts this behavioral recovery [91].…”

“…After bilateral transection at the level of the medullary pyramids (pyramidotomy), injured corticospinal axons sprout into the red nucleus, supporting recovery of skilled forelimb function [91]. Chemogenetic silencing of the injured corticospinal neurons, or forelimb motor cortex stroke, disrupts this behavioral recovery [91]. Additional corticofugal pathways likely contribute to the recovery of skilled function.…”