Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Jefferson College of Life Sciences, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Department of Neuroscience, Jefferson Weinberg Amyotrophic Lateral Sclerosis (ALS) Center, Sidney Kimmel Medical College, Jefferson College of Life Sciences, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
FASEB J. 2019 Dec;33(12):13775-13793. doi: 10.1096/fj.201901730R. Epub 2019 Oct 2.
More than half of spinal cord injury (SCI) cases occur in the cervical region, leading to respiratory dysfunction due to damaged neural circuitry that controls critically important muscles such as the diaphragm. The C3-C5 spinal cord is the location of phrenic motor neurons (PhMNs) that are responsible for diaphragm activation; PhMNs receive bulbospinal excitatory drive predominately from supraspinal neurons of the rostral ventral respiratory group (rVRG). Cervical SCI results in rVRG axon damage, PhMN denervation, and consequent partial-to-complete paralysis of hemidiaphragm. In a rat model of C2 hemisection SCI, we expressed the axon guidance molecule, brain-derived neurotrophic factor (BDNF), selectively at the location of PhMNs (ipsilateral to lesion) to promote directed growth of rVRG axons toward PhMN targets by performing intraspinal injections of adeno-associated virus serotype 2 (AAV2)-BDNF vector. AAV2-BDNF promoted significant functional diaphragm recovery, as assessed by electromyography. Within the PhMN pool ipsilateral to injury, AAV2-BDNF robustly increased sprouting of both spared contralateral-originating rVRG axons and serotonergic fibers. Furthermore, AAV2-BDNF significantly increased numbers of putative monosynaptic connections between PhMNs and these sprouting rVRG and serotonergic axons. These findings show that targeting circuit plasticity mechanisms involving the enhancement of synaptic inputs from spared axon populations is a powerful strategy for restoring respiratory function post-SCI.-Charsar, B. A., Brinton, M. A., Locke, K., Chen, A. Y., Ghosh, B., Urban, M. W., Komaravolu, S., Krishnamurthy, K., Smit, R., Pasinelli, P., Wright, M. C., Smith, G. M., Lepore, A. C. AAV2-BDNF promotes respiratory axon plasticity and recovery of diaphragm function following spinal cord injury.
超过一半的脊髓损伤 (SCI) 病例发生在颈椎区域，由于控制膈肌等重要肌肉的神经回路受损，导致呼吸功能障碍。C3-C5 脊髓是膈神经运动神经元 (PhMNs) 的位置，负责膈肌的激活；PhMNs 主要从呼吸中枢的延髓腹侧呼吸组 (rVRG) 的上位神经元接收球脊兴奋性驱动。颈椎 SCI 导致 rVRG 轴突损伤、PhMN 去神经支配以及随之而来的半膈肌部分至完全瘫痪。在 C2 半切 SCI 的大鼠模型中，我们选择性地在 PhMN 位置（损伤侧对侧）表达轴突导向分子脑源性神经营养因子 (BDNF)，通过向脊髓内注射腺相关病毒血清型 2 (AAV2)-BDNF 载体，促进 rVRG 轴突向 PhMN 靶标定向生长。AAV2-BDNF 通过肌电图评估显著促进膈神经功能恢复。在损伤对侧的 PhMN 池中，AAV2-BDNF 强烈促进了保留的对侧起源的 rVRG 轴突和 5-羟色胺能纤维的发芽。此外，AAV2-BDNF 显著增加了 PhMN 与这些发芽的 rVRG 和 5-羟色胺能轴突之间假定的单突触连接的数量。这些发现表明，靶向涉及增强来自保留轴突群体的突触输入的电路可塑性机制是恢复 SCI 后呼吸功能的有力策略。-Charsar, B. A., Brinton, M. A., Locke, K., Chen, A. Y., Ghosh, B., Urban, M. W., Komaravolu, S., Krishnamurthy, K., Smit, R., Pasinelli, P., Wright, M. C., Smith, G. M., Lepore, A. C. AAV2-BDNF 促进呼吸轴突可塑性和脊髓损伤后膈神经功能恢复。
