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

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.

SUBMITTER: Han Q

PROVIDER: S-EPMC6925225 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Han Qi Q Ordaz Josue D JD Liu Nai-Kui NK Richardson Zoe Z Wu Wei W Xia Yongzhi Y Qu Wenrui W Wang Ying Y Dai Heqiao H Zhang Yi Ping YP Shields Christopher B CB Smith George M GM Xu Xiao-Ming XM

Nature communications 20191220 1

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 ...[more]

PMID: 31862889

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Project description:Microtubule stabilization through epothilones is a promising preclinical therapy for functional recovery following spinal cord injury that stimulates axon regeneration, reduces growth-inhibitory molecule deposition and promotes functional improvements. Rehabilitation therapy is the only clinically validated approach to promote functional improvements following spinal cord injury. However, whether microtubule stabilization can augment the beneficial effects of rehabilitation therapy or act in concert with it to further promote repair remains unknown. Here, we investigated the pharmacokinetic, histological and functional efficacies of epothilone D, epothilone B and ixabepilone alone or in combination with rehabilitation following a moderate contusive spinal cord injury. Pharmacokinetic analysis revealed that ixabepilone only weakly crossed the blood-brain barrier and was subsequently excluded from further investigations. In contrast, epothilones B and D rapidly distributed to CNS compartments displaying similar profiles after either subcutaneous or intraperitoneal injections. Following injury and subcutaneous administration of epothilone B or D, rats were subjected to 7 weeks of sequential bipedal and quadrupedal training. For all outcome measures, epothilone B was efficacious compared with epothilone D. Specifically, epothilone B decreased fibrotic scaring which was associated with a retention of fibronectin localized to perivascular cells in sections distal to the lesion. This corresponded to a decreased number of cells present within the intralesional space, resulting in less axons within the lesion. Instead, epothilone B increased serotonergic fibre regeneration and vesicular glutamate transporter 1 expression caudal to the lesion, which was not affected by rehabilitation. Multiparametric behavioural analyses consisting of open-field locomotor scoring, horizontal ladder, catwalk gait analysis and hindlimb kinematics revealed that rehabilitation and epothilone B both improved several aspects of locomotion. Specifically, rehabilitation improved open-field locomotor and ladder scores, as well as improving the gait parameters of limb coupling, limb support, stride length and limb speed; epothilone B improved these same gait parameters but also hindlimb kinematic profiles. Functional improvements by epothilone B and rehabilitation acted complementarily on gait parameters leading to an enhanced recovery in the combination group. As a result, principal component analysis of gait showed the greatest improvement in the epothilone B plus rehabilitation group. Thus, these results support the combination of epothilone B with rehabilitation in a clinical setting.

Dataset Information

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

Publications

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

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