Transformation of nonfunctional spinal circuits into functional states after the loss of brain input

• Published in: Nature neuroscience Vol. 12; no. 10; pp. 1333 - 1342
• Main Authors: Edgerton, V Reggie, Courtine, Grégoire, Gerasimenko, Yury, Roy, Roland R, Ichiyama, Ronaldo M, van den Brand, Rubia, Ao, Yan, Sofroniew, Michael V, Musienko, Pavel, Song, Bingbing, Lavrov, Igor, Yew, Aileen, Zhong, Hui
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2009; Nature Publishing Group
• Subjects: 8-Hydroxy-2-(di-n-propylamino)tetralin - therapeutic use; Analysis of Variance; Animal Genetics and Genomics; Animals; Behavioral Sciences; Biological Techniques; Biomechanical Phenomena - physiology; Biomedical and Life Sciences; Biomedicine; Brain - pathology; Disease Models, Animal; Electric Stimulation - methods; Electromyography - methods; Epidural; Female; Gait - drug effects; Gait - physiology; Hindlimb - physiopathology; Kinematics; Locomotion - drug effects; Locomotion - physiology; Motor Activity - drug effects; Motor Activity - physiology; Muscle, Skeletal - pathology; Muscle, Skeletal - physiopathology; Nerve Net - drug effects; Nerve Net - physiology; Neural circuitry; Neural Pathways - drug effects; Neural Pathways - physiopathology; Neural transmission; Neurobiology; Neuronal Plasticity - drug effects; Neuronal Plasticity - physiology; Neurosciences; Oncogene Proteins v-fos - metabolism; Paralysis; Physical Conditioning, Animal; Physiological aspects; Physiology; Principal Component Analysis; Quipazine - therapeutic use; Rats; Rats, Sprague-Dawley; Recovery of Function - drug effects; Recovery of Function - physiology; Reflex - physiology; Sensorimotor integration; Serotonin Receptor Agonists - therapeutic use; Spinal cord; Spinal cord injuries; Spinal Cord Injuries - pathology; Spinal Cord Injuries - physiopathology; Spinal Cord Injuries - therapy; Time Factors; United States; Los Angeles California; California; United States > US; Switzerland
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.2401

Spinal cord injury disrupts input from the brain to the spinal motor circuitry, but that circuitry and pattern generator circuits still exist below the lesion. A regime combining electrical and serotonergic agonist stimulation of the lesioned spinal cord with intensive treadmill training enabled rats to recover weight-bearing stepping that was very similar to normal walking. After complete spinal cord transections that removed all supraspinal inputs in adult rats, combinations of serotonergic agonists and epidural electrical stimulation were able to acutely transform spinal networks from nonfunctional to highly functional and adaptive states as early as 1 week after injury. Using kinematics, physiological and anatomical analyses, we found that these interventions could recruit specific populations of spinal circuits, refine their control via sensory input and functionally remodel these locomotor pathways when combined with training. The emergence of these new functional states enabled full weight-bearing treadmill locomotion in paralyzed rats that was almost indistinguishable from voluntary stepping. We propose that, in the absence of supraspinal input, spinal locomotion can emerge from a combination of central pattern-generating capability and the ability of these spinal circuits to use sensory afferent input to control stepping. These findings provide a strategy by which individuals with spinal cord injuries could regain substantial levels of motor control.