Peripheral Trafficking in Locomotor Networks After Thoracic SCI

Ohio State University, Columbus OH

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Abstract

DESCRIPTION (provided by applicant): Spinal cord injury (SCI) initiates rapid inflammatory signaling at least 10 segments caudal to the lesion in the lumbar enlargement. As a result of remote neuroinflammation, sensory and motor systems display permanent deficits. The mechanisms that initiate these remote effects are largely speculative. This proposal examines a novel source of toxic inflammation around locomotor networks in the lumbar cord that impedes activity-based exercise interventions. We will use a GFP+ bone marrow (BM) chimera model to differentiate between resident and peripheral immune responses after SCI (Aim 1). Immune cells with be isolated and characterized using NanoString gene arrays. Additionally, we will describe endothelial stability by administering vascular tracers and examining remote lumbar anatomy using immunohistochemistry. To examine the cellular and molecular interaction between lumbar-focused exercise interventions and remote neuroinflammation, we will deliver training interventions early (2-7d) after SCI. Proof of principle designs will be used to examine the influence of neuroinflammation derived from peripheral immune cells on activity-based recovery by depleting peripheral monocyte populations (Aim 2). Throughout the proposal, we will apply a novel mouse model in GFP+ BM-chimeric mice that express YFP on neurons under control of the Thy-1 promoter to examine the relationship between regional inflammation and neuroplasticity via dendritic spine composition. The proposal is supported by strong preliminary evidence that myeloid trafficking and vascular breakdown occurs at least 13 segments below the lesion throughout the lumbar and sacral cord after midthoracic SCI. Therefore, we hypothesize that thoracic SCI results in peripheral myeloid trafficking remote to the lesion that jeopardizes function and plasticity of locomotor networks.