Lesion and activity dependent corticospinal tract plasticity

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Corticospinal tract (CST) injury deprives spinal circuits of movement control signals. This leads to loss of function—muscle weakness and paralysis—and gain of dysfunction—including hyperreflexia and spasticity. To repair the CST after injury and restore motor control, it is necessary to abrogate the impairments due to both the loss of function and gain of dysfunction following injury. Our research during the prior funding period shows that activity-dependent processes underlie both the loss of function and gain of dysfunction after CST injury. This finding provides the foundation for developing new therapeutic neuromodulatory approaches to target activity dependence using motor cortex (MCX) stimulation and transspinal direct current stimulation (tsDCS). MCX stimulation after injury is effective in CST repair and motor recovery. In Aim 1 we will determine the most effective MCX neuromodulation treatment to produce persistent structural and functional plasticity of the corticospinal system. Using different stimulation patterns, we will ask if efficacy depends on recruiting CST axon growth-promoting signaling. Using optogenetics to identify activated CST axons, we will test how stimulation patterns determine anatomical and physiological outcomes. Knowing that recovery is more than CST sprouting, we will ask if efficacy depends on producing long-term physiological changes in spinal circuits. We recently showed that selective CST injury or MCX inactivation produces trans-neuronal loss of spinal cholinergic interneurons and that this loss can be rescued by spinal activation. In Aim 2 we will determine how MCX neuromodulation regulates transneuronal segmental circuit remodeling after injury to promote spinal circuit repair. We will ask how CST injury impacts the major class of excitatory premotor interneurons of the CST. We will test if MCX stimulation ameliorates trans-neuronal circuit changes and then examine the interplay of repair strategies differentially targeting microglial-based spinal circuit remodeling and CST sprouting In Aim 3 we will harness the differential actions of tsDCS on spinal circuits to enhance repair and rehabilitation efficacy after cervical SCI. Spinal circuits integrate motor control signals with afferent information. After SCI, with the loss of motor pathways, spared afferent feedback dominates segmental circuit function. We recently showed that afferent competition diminishes CST connection strength, to reinforce afferent over integrated control. We will use the differential actions of tsDCS to promote spared CST function and weaken potentially “runaway” afferent input, to rebalance segmental control. We will develop a novel strategy that combines neuromodulation-based repair with neuromodulation-assisted rehabilitation to promote recovery. Successful completion of our studies will advance our understanding of the mechanisms of impairment and the mechanisms underlying novel neuromodulatory repair strategies after SCI. Results will inform how best to integrate motor behavioral rehabilitation and activity-based interventions to provide potentially clinically relevant approaches to improve motor control in humans after cervical SCI.