Restoration of skilled locomotion by sprouting corticospinal axons induced by co-deletion of PTEN and SOCS3

作者：Duo Jin, Yuanyuan Liu, Fang Sun, Xuhua Wang, Xuefeng Liu, Zhigang He · 发表于：Nature Communications · 年份：2015 · DOI：10.1038/ncomms9074 · 被引用次数：189 · 研究领域：Neurogenesis and neuroplasticity mechanisms、Nerve injury and regeneration、Transcranial Magnetic Stimulation Studies

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.