Abstract
The limited rewiring of the corticospinal tract (CST) only partially compensates the lost functions after stroke, brain trauma and spinal cord injury. Therefore it is important to develop new therapies to enhance the compensatory circuitry mediated by spared CST axons. Here by using a unilateral pyramidotomy model, we find that deletion of cortical suppressor of cytokine signaling 3 (SOCS3), a negative regulator of cytokine-activated pathway, promotes sprouting of uninjured CST axons to the denervated spinal cord. A likely trigger of such sprouting is ciliary neurotrophic factor (CNTF) expressed in local spinal neurons. Such sprouting can be further enhanced by deletion of phosphatase and tensin homolog (PTEN), a mechanistic target of rapamycin (mTOR) negative regulator, resulting in significant recovery of skilled locomotion. Ablation of the corticospinal neurons with sprouting axons abolishes the improved behavioural performance. Furthermore, by optogenetics-based specific CST stimulation, we show a direct limb motor control by sprouting CST axons, providing direct evidence for the reformation of a functional circuit.
Highlights
The limited rewiring of the corticospinal tract (CST) only partially compensates the lost functions after stroke, brain trauma and spinal cord injury
We asked whether suppressor of cytokine signaling 3 (SOCS3) deletion could affect the sprouting of CST axons after unilateral pyramidotomy (Fig. 1a)
To monitor collateral sprouting from uninjured CST axons, biotinylated dextran amines (BDAs) are injected into the intact side of sensorimotor cortex at indicated post-injury time points, and transverse sections from different levels of the spinal cord are analysed after an additional 2 weeks (Fig. 1a)
Summary
The limited rewiring of the corticospinal tract (CST) only partially compensates the lost functions after stroke, brain trauma and spinal cord injury. A number of studies have attempted to explore the underlying mechanisms and several manipulations have been developed to enhance such collateral sprouting[1,2,3,4,5,6,7,8,9,10,11,12] Both neutralizing extrinsic inhibitory activities and task-specific rehabilitation training are able to promote functional recovery by increasing axonal sprouting in different injury models[5,6,7,8,9,10]. By manipulating CNTF and other pathways, we achieved robust CST sprouting, forming new circuits almost as strong as intact ones and significant behavioural functional recovery By both optogenetic and behavioural approaches, we demonstrated that sprouting CST axons could relay the cortical signals to the spinal cord, controlling the limb movement
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