The corticospinal tract (CST) is key to skilled motor control. During development, CST damage can have more complex effects than similar damage in maturity because of robust activity-dependent competition between developing CST axons for establishing connections with spinal motor circuits. More active CST neurons are more competitive than less active CST neurons in establishing spinal connections. Loss of CST connections with spinal motor circuit's leads to impaired or loss of movement. Competitive gain of new CST connections by reactive axon sprouting in the spinal cord leads to new, potentially maladaptive, functions. In humans, CST injury during development can produce cerebral palsy, a common and devastating developmental motor disorder. Spasticity, limb incoordination, stereotypic motor synergies, and mirror movements in cerebral palsy are thought to be produced by new maladaptive CST connections. The overall hypothesis to be tested is that unilateral CST injury during development leaves spared contralateral CST axons vulnerable to further loss. Spared CST axons are less competitive in establishing their contralateral connections because they are less effective than normal in activating spinal motor circuits. We propose that this competitive disadvantage worsens as the intact CST from the noninvolved hemisphere develops robust ipsilateral spinal connections that strengthen and out compete the damaged CST. We further propose that competitive pressure is also exerted by the intact brain stem pathways.
We aim to repair damaged CST connections and restore motor function by making spared CST axons more competitive in establishing spinal connections through direct activation or by making the undamaged systems less competitive by deactivation and disuse.
Aim 1 directly tests the hypothesis that imbalance in activity-dependent competition between the developing CSTs from each hemisphere creates a vicious circle: the CST injured early in development progressively loses its capacity to drive contralateral spinal motor circuits, as the undamaged CST develops new bilateral connections and bilateral motor control functions.
We aim to interrupt the circle to restore contralateral connections and function of the impaired side by redirecting activity-dependent competition. We will assay changes in connectivity and function in awake behaving cats using chronic electrophysiological recording techniques we have developed. This new approach will allow real-time assessment of developmental plasticity and enable testing hypotheses not possible in staged, acute experiments.
Aim 2 tests the hypothesis using a new mouse model with bilateral CSTs and mirror movements, as in cerebral palsy. Bilateral CSTs and aberrant control are expressed, not by reaction to injury or inactivity as in other models, but by a CST axon guidance defect produced by conditional excision of the gene for EphA4 receptor. Reactive models are clinically relevant but cannot distinguish if the ipsilateral CST is maladaptive because of aberrant connections or, because it outcompetes the contralateral CST, so that its connections and functions are lost. Using this new model, we uncouple these alternatives and harness activity-dependent competition to promote greater contralateral CST function.
Aim 3 tests a novel activity-dependent competition between the developing corticospinal and brain stem systems. We will test the hypothesis that the developing CST, rubrospinal tract (RST) and reticulospinal tracts (ReST) compete for access to spinal motor circuits. Restricting corticospinal system activity, which leads to aberrant CST spinal connections and motor impairment, will enable the RST/ReST to outcompete the CST for spinal connections. Whereas this could help restore function, since the RST and ReST functions are limited compared with the CST, motor skills remain impaired. Stronger brain stem systems, we propose, means a weakened CST. !

Public Health Relevance

Our experiments probe the mechanisms of movement impairment and paralysis after damage to the developing corticospinal tract. We will test novel hypotheses to explain the loss of function after injury and gain of maladaptive functions brought about by the highly plastic immature motor systems. We aim to establish novel therapeutic strategies in animal models that will inform treatment decisions in cerebral palsy, a common and devastating developmental disorder. !

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (ZRG1)
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Chen, Daofen
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City College of New York
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New York
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Williams, Preston T J A; Jiang, Yu-Qiu; Martin, John H (2017) Motor system plasticity after unilateral injury in the developing brain. Dev Med Child Neurol 59:1224-1229
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