ABSTRACT:
Spinal cord injury (SCI) results in the devastating loss of motor, sensory, and autonomic function below the level
of the lesion. Importantly, most SCIs occur in the cervical and thoracic levels, leaving the locomotor circuits in
the lumbar segments, and sensory afferents below the injury, relatively intact. While these circuits may not be
directly affected by the injury, the loss of descending control can lead to changes in excitability, afferent sprouting,
and other compensatory changes. Regaining proper control of locomotor circuits after injury is crucial for
restoration of efficient locomotion, yet many of the specific circuit rearrangements induced by SCI remain
unknown. Inhibitory interneurons (INs) in the dorsal horn of the spinal cord finely tune incoming sensory afferent
input, and are a possible target for modulating afferent transmission to locomotor circuits after injury. Specifically,
INs regulating proprioceptive afferents are of great interest due to the importance of proprioception on locomotor
recovery after SCI. Locomotor circuits are comprised of spinal INs that control the pattern and rhythm of
locomotion, one population of which expresses the transcription factor Shox2. We have evidence that sensory
afferent pathways to Shox2 INs are a point of plasticity after SCI and treatment with epidural stimulation.
Specifically, the loss of the inhibitory sensory pathway to Shox2 INs after SCI suggests that inhibitory INs
interposed between sensory afferents and Shox2 INs are a potential novel target for improving locomotion after
SCI. Understanding the function of this population, and the mechanisms behind the plasticity of inhibitory sensory
pathways to locomotor circuits may then allow for proper modulation after injury to restore proper control of
locomotor circuits. The proposed experiments will test the overall hypothesis that medial laminae V/VI glycinergic
INs are required for skilled locomotion, and an SCI-induced disruption of proprioceptive afferent input to them is
responsible for the observed dysregulation of afferent pathways to Shox2 INs after SCI. Using a combination of
whole-cell patch clamp, pharmacology, and histology we will identify known deep dorsal inhibitory populations
that overlap with glycinergic INs interposed between sensory afferents and Shox2 INs. Then we will
chemogenetically silence this population of glycinergic INs during skilled locomotor tasks. Together, these
experiments will allow us to functionally identify medial lamina V/VI glycinergic INs. Next, we will use a
combinatorial approach to investigate the mechanism underlying the loss of inhibitory sensory afferent pathways
to Shox2 INs after SCI. Electrophysiology, neural tracing, and immunohistochemistry will be used to evaluate
the proprioceptive afferent input to medial laminae V/VI glycinergic INs and, Shox2 INs after SCI. The findings
from this proposal will provide insight into the role of a specific population of inhibitory INs, and the mechanistic
underpinnings of plasticity within inhibitory sensory pathways to locomotor circuits. This knowledge will be vital
to identify novel therapeutic targets, and guide strategies to restore locomotion after SCI.
