Combining task-based rehabilitative training with PTEN inhibition promotes axon regeneration and upper extremity skilled motor function recovery after cervical spinal cord injury in adult mice

Abstract

BACKGROUND\nConditional deletion of Pten in corticospinal neurons promotes axon sprouting and regeneration after spinal cord injury (SCI). However, regeneration studies targeted on PTEN inhibition seldom show motor function recovery. The promotion of functional recovery can be improved by rehabilitative training under a use-dependent plasticity mechanism.\n\n\nPURPOSE\nTo investigate the combined effects of PTEN inhibition and rehabilitative training on axon regeneration and subsequent motor functional improvement after cervical spinal cord injury.\n\n\nMETHODS\nLentiviral particles (Lenti-PTEN-RNAi or Lenti-Scrambled-EGFP) were injected into the right sensorimotor mouse cortex in four experimental groups (PTEN RNAi\u2009+\u2009Training, PTEN RNAi, Control\u2009+\u2009Training, Control). Two weeks after injection, all mouse groups received a left C5 crush injury. We performed task-based rehabilitative training for 4 weeks on the PTEN RNAi\u2009+\u2009Training and Control\u2009+\u2009Training groups. Biotinylated dextran amine (BDA) was used for anterograde tracing of the dorsal corticospinal tract (dCST). We analysed axonal regeneration through immunohistochemical methods. A battery of behavioral tests was employed to assess functional recovery at Day3 and every other week after injury.\n\n\nRESULTS\nCombining rehabilitative training with PTEN inhibition induced more axon regeneration and synapse reformation in the spinal cord caudal to the lesion site. Rostral to the lesion, the transected dCST axons sprouted into gray matter upon contact. Furthermore, forelimb function was found to be improved after combination therapy during behavioral testing.\n\n\nCONCLUSION\nCombining task-based rehabilitative training with PTEN inhibition further promotes axon regeneration, synaptic plasticity and reorganization of the neural network, with significant improvement in forelimb skilled motor function after cervical spinal cord injury. Our study provides new therapeutic insights for spinal cord injury management in the future.