Reticulospinal and corticospinal axon regeneration after complete spinal cord injury

Abstract

Neuroprosthetic rehabilitation demonstrated that significant functional benefit could be achieved with lumbosacral neuromodulation in both human and animal models of spinal cord injury. It promoted the recovery of voluntary leg movements through the reorganization of residual reticulospinal and propriospinal projections pathways. However, in case of complete spinal cord injuries (SCI), which isolate the circuits under the lesion from any supraspinal control, the outcome of neuroprosthetic rehabilitation is still not sufficient. Indeed, it will require the restoration of robust regrowth and sprouting of several types of axons across the injury. Axons fail to regrow across spinal lesions because of different inhibitory mechanisms. It has been demonstrated that this spontaneous axon regeneration failure can be reversed by i) stimulating the neuronal intrinsic growth capacity using viral technology, ii) remodeling the lesion core with growth factors, in order to create a more permissive environment, and iii) guiding axons with chemo-attractive molecules across and beyond the SCI site. It was thus demonstrated that propriospinal axons are able to regrow and build a robust descending bridge across complete SCIs when the needed facilitators are provided. However, this robust propriospinal bridging failed to promote functional recovery by itself. It might be explained by an insufficient descending motor control partly supported by other systems such as the reticulospinal tract (RtST) and the corticospinal tract (CST). Therefore we wanted to study the regenerative potential of the RtST and CST pathways. The RtST arises from the brainstem and reaches for the spinal cord acting as relay for descending motor cortical commands. The CST is the main descending motor cortical command arising from the primary motor cortex. In the present study, we applied the same strategy to enhance sprouting and regrowth of reticulospinal and corticospinal neurons across anatomically complete SCI. We first activated the neuronal intrinsic growth capacity of both tracts using viral technology. The lesion environment was then remodeled with growth factors, delivered using a biocompatible hydrogel. Finally, we established chemical axon guidance using chemoattractant molecules. These interventions were delivered with a spatiotemporal profile corresponding to the axon growth sequence during development. We did not obtain any CST regeneration, due to the severe crush injury model inducing extensive CST axons degeneration probably caused by ischemic phenomenon. Regarding the RtST, we obtained significant reticulospinal regeneration into the lesion core with some fibers growing across the lesion reaching the healthy caudal tissue. This regeneration remained limited though as compared with the propriospinal results indicating the importance of identifying complementary strategies to increase the density of the regenerated tract and to attract the axons in the healthy tissue below the SCI. Our ultimate goal is to restore anatomical communications across complete SCI and promote their functional integration using neuroprosthetic rehabilitation program