Several interventions exploiting chemical and electrical neuromodulation therapies have been designed to engage spinal sensorimotor circuits in order to facilitate the recovery of standing and walking after spinal cord injury. However, the mechanisms through which electrical and chemical stimulation modulate spinal circuits remain poorly understood. To study these mechanisms, we investigated the circuit-level interactions between noradrenergic receptor modulation and epidural electrical stimulation during standing and walking after a complete spinal cord injury. Previous work suggested that epidural electrical stimulation facilitates motor control through the modulation of proprioceptive feedback circuits. Using genetic deletion experiments and calcium imaging, we confirmed that epidural electrical stimulation promotes locomotion through the activation of proprioceptive feedback circuits. Anatomical experiments in genetically modified mice revealed that noradrenergic receptors are prominently expressed on these circuits. In turn, pharmacological testing in rats and genetic deletion in mice showed that the manipulation of noradrenergic pathways strongly modulated the gain in proprioceptive feedback circuits, which abolished or augmented the effects of epidural electrical stimulation. This electrochemical stimulation strategy restored robust locomotion in paralyzed animals. Our findings provide new insights into the mechanisms through which electrochemical neuromodulation therapies facilitate motor control after injury, and provide a framework to refine these interventions for clinical applications.
*K. BARTHOLDI1, Q. BARRAUD1, E. FORMENTO1, A. ROWALD1, P. MUSIENKO2, M. CAPOGROSSO1, G. COURTINE1;
1EPFL, Lausanne, Switzerland; 2Pavlov Inst. of Physiol., Saint Petersburg, Russian Federation
K. Bartholdi: None. Q. Barraud: None. E. Formento: None. A. Rowald: None. P. Musienko: None. M. Capogrosso: None. G. Courtine: None.