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.
The project will examine the interaction between activity-based exercise and remote neuroinflammation after spinal cord injury. We will examine the influence of a novel source of inflammatory signaling in the lumbar cord and its effect on neural function by characterizing structural plasticity. We will differentiate central and peripheral inflammatory responses and identify novel therapeutic options to promote recovery of locomotion.