Recovery after spinal cord injury (SCI) depends on plasticity of the nervous system, both spontaneous and induced by task-specific training. Traditional activity-based paradigms produce modest functional gains. However, pronounced deficits in eccentric motor control persist, making independent ambulation impossible for most individuals with SCI. Eccentric-focused downhill treadmill training is a novel, challenging intervention designed to promote greater skill learning of locomotion. Interestingly, MRI studies in healthy rodents and humans show that motor skill learning is accompanied by white matter plasticity along tracts activated by the training paradigm. Further, animal studies show that differentiation of oligodendrocyte progenitors, known as NG2 cells, and subsequent new myelin formation are required for learning of a motor skill. This proposal will employ a novel experimental design that uses similar outcome measures (MRI, 3D Kinematics) to examine white matter plasticity and motor learning in humans alongside mechanistic animal experiments following an equivalent downhill training paradigm. Because white matter plasticity and motor learning are understudied in both rodent and human SCI, the proposal aims to determine the role of newly formed myelin in recovery and motor learning after SCI in rodents (Aim 1) as well as the extent of myelin plasticity induced by motor learning in animals and humans with SCI (Aim 2).
In Aim 1, we will use transgenic reporter mice that allow fate mapping of NG2 cells along with novel multicomponent T2 relaxation imaging (MCRI) to identify myelin formed in response to eccentric-focused downhill training. Additionally, we will use a strong proof-of- principle design in which we will examine training-induced motor learning after SCI in the absence of new myelin.
Aim 2 will leverage an ongoing clinical trial examining downhill treadmill training after SCI in humans along with MCRI obtained from animals in Aim 1 to determine the extent of myelin plasticity induced by motor learning across species. Preliminary data in rodents show that downhill training mitigates the persistent eccentric motor control deficits after SCI and improves overground locomotion. Thus, eccentric-focused training may indeed be novel and challenging enough to drive white matter plasticity and motor learning. Therefore, we hypothesize that task-specific interventions that are novel and challenging, in this case downhill treadmill exercise, improve locomotor recovery across species via active myelination of spared CNS axons remote from the SCI.

Public Health Relevance

White matter plasticity has recently been implicated in motor learning and may play a significant role in functional recovery after spinal cord injury (SCI). This project will identify the relationship between new myelin and motor learning in rodents and humans following a novel eccentric-focused training intervention. We will identify whether this training promote adaptive myelination across species as well as the mechanisms underlying this response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31NS096921-01A1
Application #
9192667
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Jakeman, Lyn B
Project Start
2016-08-08
Project End
2017-08-07
Budget Start
2016-08-08
Budget End
2017-08-07
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Ohio State University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210