ABSTRACT Epidural stimulation (ES) has shown great promise for the restoration of motor functioning after SCI both clinically and in animal models. Despite its success in activating silenced circuits below the level of the injury allowing for movement of paralyzed limbs, the mechanisms contributing to its long-term effects are unknown. Central pattern generators (CPG) in the lumbar spinal cord control both the rhythm and pattern of locomotion. CPGs are below the level of most injuries, and, therefore, relatively intact and accessible by ES. Recent efforts in our lab to determine the mechanisms by which ES exerts its beneficial effects at the level of the spinal locomotor circuit have revealed alterations in sensory pathways to the locomotor CPG following SCI which are either prevented or reversed by ES at intensities that are subthreshold for motor activation (sub-motor-threshold ES) while the mouse is on a treadmill. In a complete transection SCI model, these circuit alterations are evident despite the apparent lack of locomotor-related hindlimb activity on the treadmill. Our current proposal will directly test whether sub-motor-threshold ES alone is sufficient to induce beneficial plasticity and/or prevent maladaptive plasticity at the level of spinal locomotor circuits in mice. In humans, ES alone does not support walking without extensive concomitant rehabilitative training since the afferent activation by ES occludes the normal proprioceptive sensory signal. Additionally, although there may be a post-injury critical window for maximum plasticity, extensive activity-based rehabilitation is often not possible at these early time points. If the circuit plasticity observed with ES occurs in the absence of motor training, this will suggest sub-motor-threshold ES as a method that could be used for bedridden patients as a bridge for future rehabilitation. For the second aim of the proposal, we will determine the neural substrates of the alterations in spinal sensory pathways to locomotor circuits that are evident after SCI and after ES. We will focus on CPG neurons and inhibitory neurons interposed between CPG neurons and primary afferents. Together, we propose to reveal whether sub-motor-threshold ES is a potential strategy to alter spinal circuits prior to the time when activity-based therapies are feasible. If this is the case, it will suggest a treatment strategy that can be used either in place of or as a bridge until active rehabilitation is possible. Further, we propose to identify a key population of neurons involved in this plasticity, thereby suggesting a specific target of future cell-specific therapeutics.

NARRATIVE Epidural stimulation (ES) has shown great promise for the restoration of motor functioning after SCI both clinically and in animal models but detailed mechanistic actions are currently unknown. This proposal will reveal whether sub-motor-threshold ES has the potential to alter spinal locomotor circuits relatively early post- injury, serving as a potential bridge until active rehabilitation is feasible. Further, mechanistic insights will provide specific targets for future cell-specific therapeutics related to recovery of locomotor function after SCI.