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

Abstract

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.Severe spinal cord injuries that remove all supraspinal input to lumbosacral spinal circuits lead to permanent paralysis of the legs in adult rodents 1-3 and humans. Nevertheless, networks of neurons in the lumbosacral spinal cord retain an intrinsic capability to oscillate and generate coordinated rhythmic motor outputs. Circuits underlying such rhythmic and oscillatory outputs are commonly referred to as central pattern generators (CPGs) and are found in all invertebrate and vertebrate animals 4,5 . Although the anatomical architecture of locomotor CPGs remains poorly understood, especially in mammals 5 , the functional phenomenon, central pattern generation, has been documented extensively. Indirect evidence suggests that CPGs are present in human spinal cord 6,7 . These observations offer the possibility of directly accessing and activating spinal cord CPGs to facilitate locomotor recovery after a severe spinal cord injury (SCI).Correspondence should be addressed to G.C. (gregoire.courtine@bli.uzh.ch). Note: Supplementary information is available on the Nature Neuroscience website.Author Contributions: G.C., Y.P.G., I.L., M.V.S. and V.R.E. designed the study. G.C., R.R.R., H.Z. and P.M. performed the surgeries. G.C., Y.P.G., R.v.d.B., P.M. and A.Y. carried out the experiments. G.C., A.Y., B.S., Y.A., R.I. and M.V.S. conducted the anatomical assessments. G.C. analyzed the data. G.C., R.R.R., M.V.S. and V.R.E. wrote the manuscript. G.C. supervised the study. 16,20,21 that lead to specific improvements of stepping patterns. These interventions, however, have shown limited potential for promoting weight-bearing capacities and there have been few attempts to correlate the specific functional states induced pharmacologically 9,10 , electrically [11][12][13]19,22 or by locomotor training 2,20 with distinct characteristics of stepping motor patterns. When studied in sufficient statistical detail, analyses of kinematics and...

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