Bilateral movement training promotes axonal remodeling of the corticospinal tract and recovery of motor function following traumatic brain injury in mice

Abstract

Traumatic brain injury (TBI) results in severe motor function impairment, and subsequent recovery is often incomplete. Rehabilitative training is considered to promote restoration of the injured neural network, thus facilitating functional recovery. However, no studies have assessed the effect of such trainings in the context of neural rewiring. Here, we investigated the effects of two types of rehabilitative training on corticospinal tract (CST) plasticity and motor recovery in mice. We injured the unilateral motor cortex with contusion, which induced hemiparesis on the contralesional side. After the injury, mice performed either a single pellet-reaching task (simple repetitive training) or a rotarod task (bilateral movement training). Multiple behavioral tests were then used to assess forelimb motor function recovery: staircase, ladder walk, capellini handling, single pellet, and rotarod tests. The TBI+rotarod group performed most forelimb motor tasks (staircase, ladder walk, and capellini handling tests) better than the TBI-only group did. In contrast, the TBI+reaching group did not perform better except in the single pellet test. After the injury, the contralateral CST, labeled by biotinylated dextran amine, formed sprouting fibers into the denervated side of the cervical spinal cord. The number of these fibers was significantly higher in the TBI+rotarod group, whereas it did not increase in the TBI+reaching group. These results indicate that bilateral movement training effectively promotes axonal rewiring and motor function recovery, whereas the effect of simple repetitive training is limited.

Increased Network Excitability Due to Altered Synaptic Inputs to Neocortical Layer V Intact and Axotomized Pyramidal Neurons after Mild Traumatic Brain Injury

“…5), suggesting that the increased mEPSC frequency is due instead to increased afferents onto these intact pyramidal neurons. Axonal sprouting has previously been observed in response to TBI 30,35,36 and axotomy. 37-40 It is unclear why a delay to sprouting onto these cells occurs.…”

Rehabilitative skilled forelimb training enhances axonal remodeling in the corticospinal pathway but not the brainstem-spinal pathways after photothrombotic stroke in the primary motor cortex

“…Vicariation, or substitution of lost function by the residual network, would dominate in patients with more severe damage [ 24 ], suggesting a greater restorative effect of neural network remodeling in more severely affected individuals. Interestingly, general functional improvement was induced by skilled forelimb reach training only when training enhanced axonal remodeling in the corticospinal tract from the contralesional hemisphere; Starkey et al [ 21 ] reported enhanced axonal remodeling but we [ 15 ] and Nakagawa et al [ 22 ] did not observe a significant effect in the corticospinal tract from the contralesional hemisphere. Therefore, the extent of the brain area in which training induces axonal plasticity may be a deciding factor in the translatability of rehabilitation-induced functional recovery.…”

“…The translatability of the functional recovery induced by the skilled forelimb task differs between experiment settings. For example, Starkey et al reported that skilled forelimb reach training (50 successful attempts, 5 days per week for 6 weeks) after unilateral pyramidotomy led to an improved success rate in the horizontal ladder walk and the staircase task [ 21 ], while Nakagawa et al reported that skilled forelimb reach training (60 attempts, 6 days per week for 4 weeks) after traumatic brain injury improved the success rate only in the skilled forelimb reaching test but not in the staircase test, ladder walk test, or Capellini handling test [ 22 ]. These differences may be a result of the intensity of the training or the severity and type of injury.…”

Effect of Inhibition of DNA Methylation Combined with Task-Specific Training on Chronic Stroke Recovery

“…Axonal remodeling is accepted as one of the components of TST-induced functional recovery and has been detected in parts of the CST [ 7 ]. Several studies of the beneficial effect of TST on functional recovery after injury have reported that rehabilitative training induces the growth of saved CST axons and the projection of new axons into the damaged spinal cord, subsequently contributing to motor recovery [ 8 , 29 , 38 , 39 ]. Our previous research demonstrated that early TST after stroke enhanced the contralesional plasticity of the CSTs in motor cortical and sensorimotor cortical lesions at the acute stage after stroke [ 5 ].…”