Exercise decreases myelin-associated glycoprotein expression in the spinal cord and positively modulates neuronal growth

Jane and Terry Semel Institute for Neuroscience and Human Behavior, Department of Neurobiology and Psychiatry, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
Glia (Impact Factor: 5.47). 07/2007; 55(9):966-75. DOI: 10.1002/glia.20521
Source: PubMed

ABSTRACT To successfully grow, neurons need to overcome the effects of hostile environments, such as the inhibitory action of myelin. We have evaluated the potential of exercise to overcome the intrinsic limitation of the central nervous system for axonal growth. In line with the demonstrated ability of exercise to increase the regenerative potential of neurons, here we show that exercise reduces the inhibitory capacity of myelin. Cortical neurons grown on myelin from exercised rats showed a more pronounced neurite extension compared with neurons grown on poly-D-lysine, or on myelin extracted from sedentary animals. The activity of cyclin-dependent kinase 5, a kinase involved in neurite outgrowth, was found to be increased in cortical neurons grown on exercise-myelin and in the lumbar spinal cord enlargement of exercised animals. Exercise significantly decreased the levels of myelin-associated glycoprotein (MAG), a potent axonal growth inhibitor, suggesting that downregulation of MAG is part of the mechanism through which exercise reduces growth inhibition. It is known that exercise elevates brain-derived neurotrophic factor (BDNF) spinal cord levels and that BDNF acts to overcome the inhibitory effects of myelin. Accordingly, we blocked the action of BDNF during exercise, which suppressed the exercise-related MAG decrease. Protein kinase A (PKA) has been related to the ability of BDNF to overcome growth inhibition; in agreement, we found that exercise increased PKA levels and this effect was reverted by blocking BDNF. Overall, these results show that exercise promotes a permissive cellular environment for axonal growth in the adult spinal cord requiring BDNF action.


Available from: Cristina A Ghiani, Jun 03, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Perineuronal nets (PNNs) are lattice like structures which encapsulate the cell body and proximal dendrites of many neurons and are thought to be involved in regulating synaptic plasticity. It is believed that exercise can enhance the plasticity of the Central Nervous System (CNS) in healthy and dysfunctional states by shifting the balance between plasticity promoting and plasticity inhibiting factors in favor of the former. Recent work has focused on exercise effects on trophic factors but its effect on other plasticity regulators is poorly understood. In the present study we investigated how exercise regulates PNN expression in the lumbar spinal cord and areas of the brain associated with motor control and learning and memory. Adult, female Sprague-Dawley rats with free access to a running wheel for 6 weeks had significantly increased PNN expression in the spinal cord compared to sedentary rats (PNN thickness around motoneurons, exercise=15.75μm±0.63, sedentary=7.98μm±1.29, p<0.01). Conversely, in areas of the brain associated with learning and memory there was a significant reduction in perineuronal net expression (number of neurons with PNN in hippocampus CA1- exercise 21±0.56 and sedentary 24±0.34, p<0.01, thickness- exercised=2.37μm±0.13, sedentary=4.27μm±0.21; p<0.01).Our results suggest that in response to exercise, PNNs are differentially regulated in select regions of the CNS, with a general decreased expression in the brain and increased expression in the lumbar spinal cord. This differential expression may indicate different regulatory mechanisms associated with plasticity in the brain compared to the spinal cord. Copyright © 2014. Published by Elsevier Inc.
    Brain Research Bulletin 12/2014; 111. DOI:10.1016/j.brainresbull.2014.12.005 · 2.97 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Sacrocaudal motoneuron gene expression is altered following a spinal transection. Of interest here is the regulation of serotonin (5-HT) receptors, mGluR1 and KCC2 which mediate motoneuron excitability, locomotor recovery and spasticity post-transection. The examination of these genes in lumbar motoneurons post-transection has not been studied, which is necessary for developing potential pharmacological interventions aimed at restoring locomotion and or reducing spasticity. Also, if activity is to be used to promote recovery or reduce spasticity post-injury, a further examination of neuromuscular activity on gene expression post-transection is warranted. The purpose of this study was to examine motoneuronal gene expression of 5-HT receptors, KCC2 and mGluR1 at three months following a complete thoracic spinal cord transection, with and without the inclusion of daily passive cycling. Physiological hindlimb extensor and flexor motoneurons were differentially identified with two retrograde fluorescent tracers, allowing for the identification and separate harvesting of extensor and flexor motoneurons with laser capture microdissection, and the subsequent examination of mRNA content using qRT-PCR analysis. We demonstrate that post-transection, 5-HT1AR, 5-HT2CR, and mGluR1 expression was down-regulated, whereas the 5-HT2AR was up-regulated. These alterations in gene expression were observed in both flexor and extensor motoneurons, whereas passive cycling influenced gene expression in extensor but not flexor motoneurons. Passive cycling in extensor motoneurons further enhanced 5-HT2AR expression and increased 5-HT7R and KCC2 expression. Our results demonstrate that passive cycling influences serotonin receptor and KCC2 gene expression and that extensor motoneurons compared to flexor motoneurons may be more plastic to activity based interventions post-transection. Copyright © 2014, Journal of Neurophysiology.
    Journal of Neurophysiology 12/2014; DOI:10.1152/jn.00550.2014 · 3.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Injury of a peripheral nerve not only leads to target denervation, but also induces massive stripping of spinal synapses on axotomized motoneurons, with disruption of spinal circuits. Even when regeneration is successful, unspecific reinnervation and the limited reconnection of the spinal circuits impair functional recovery. The aim of this study was to describe the changes that axotomized motoneurons suffer after peripheral nerve injury and how activity-dependent therapies and neurotrophic factors can modulate these events. We observed a marked decrease in glutamatergic synapses, with a maximum peak at two weeks post-axotomy, which was only partially reversed with time. This decrease was accompanied by an increase in gephyrin immunoreactivity and a disintegration of perineuronal nets (PNNs) surrounding the motoneurons. Direct application of neurotrophins at the proximal stump was not able to reverse these effects. In contrast, activity-dependent treatment, in the form of treadmill running, reduced the observed destructuring of perineuronal nets and the loss of glutamatergic synapses two weeks after injury. These changes were proportional to the intensity of the exercise protocol. Blockade of sensory inputs from the homolateral hindlimb also reduced PNN immunoreactivity around intact motoneurons, and in that case treadmill running did not reverse that loss, suggesting that the effects of exercise on motoneuron PNN depend on increased sensory activity. Preservation of motoneuron PNN and reduction of synaptic stripping by exercise could facilitate the maintenance of the spinal circuitry and benefit functional recovery after peripheral nerve injury.
    Experimental Neurology 01/2015; 263. DOI:10.1016/j.expneurol.2014.10.009 · 4.62 Impact Factor