Alterations in spinal cord injury-induced plasticity of spinal rhythm generating interneurons following treadmill training with epidural stimulation in mouse

Authors: D. GARCIA-RAMIREZ, N. HA, L. YAO, K. A. SCHMIDT, S. F. GISZTER, K. J. DOUGHERTY

D. Garcia-Ramirez PhD.
Dougherty Lab – DREXEL


Lab Abstract:
“Neuronal circuitry generating locomotion is located in the thoracolumbar spinal cord. Spinal rhythm generating interneurons (INs) convert descending inputs into rhythmic outputs. Rhythm generating INs are strongly influenced by afferent feedback and supraspinal control, including serotonergic modulation. Spinal cord injury (SCI) disrupts the descending control of spinal locomotor circuits but this circuitry is located below the level of most SCIs and is relatively intact; however, plasticity occurs. Current clinical therapies to recover motor control after SCI include treadmill training and epidural stimulation (ES), targeting the locomotor circuitry. However, the state of the spinal circuits targeted after SCI and rehabilitation is poorly understood. Rhythm generating INs should be a prime access point for these treatments. Previously we found that rhythm generating INs expressing the transcription factor Shox2 are modulated by serotonin (5-HT) in a dose-dependent manner, producing inhibitory actions at low concentrations and excitatory actions at high concentrations. Further, Shox2 INs received mainly polysynaptic afferent input mediated by both excitatory and inhibitory pathways. After SCI, 5-HT only increased the excitability of Shox2 INs, regardless of concentration, and Shox2 INs received only excitatory inputs from afferent pathways. The main objective of the present study was to identify how the combination of treadmill training and ES then modifies the SCI-induced plastic changes in afferent-evoked inputs to and 5-HT modulation of Shox2 INs. Complete thoracic spinal transections were performed on adult Shox2::Cre;Rosa26-lsl-tdTomato mice. ES wires were implanted at lumbar level L2 for ES during treadmill training (SCI+ES) for 5 weeks after SCI. Whole cell patch clamp recordings targeted Shox2 INs in lumbar spinal slices, with dorsal roots attached for afferent stimulation, from SCI and SCI+ES mice. After treadmill traning with ES, 5-HT hyperpolarized Shox2 INs and there was a return of afferent-evoked inhibitory inputs to Shox2 INs. This suggests that treadmill training with ES shifts the balance of excitatory/inhibitory afferent pathways to Shox2 INs and the serotonergic control of Shox2 INs back towards that observed in the uninjured state.”

*D. GARCIA-RAMIREZ1, N. HA1, L. YAO1, K. A. SCHMIDT2, S. F. GISZTER1, K. J. DOUGHERTY1;

1Neurobio. and Anat., Drexel Univ. Col. of Med., Philadelphia, PA; 2Biomed. Engineering, Sci. and Hlth. Systems, Drexel Univ., Philadelphia, PA. Alterations in spinal cord injury-induced plasticity of spinal rhythm generating interneurons following treadmill training with epidural stimulation in mouse. Program No. 065.13. 2018 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2018. Online.

Grant Support NIH R01 NS095366 and Wings for life

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