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: 6.03). 07/2007; 55(9):966-75. DOI: 10.1002/glia.20521
Source: PubMed


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.

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Available from: Cristina A Ghiani,
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    • "The up-regulation of plasticity-inhibiting PNN is surprising considering that locomotor exercise training enhances synaptic plasticity after a spinal cord injury (Ichiyama et al., 2011), suggesting that increased PNN expression in combined injured and trained animals may be due the injury rather than the exercise training. On the other hand, it has also been shown that other inhibitory factors, such as myelinassociated glycoprotein (MAG) is reduced in response to exercise training; however, this is believed to be related to increased BDNF levels (Ghiani et al., 2007). Given our results, it seems these two inhibitory factors are differentially regulated by exercise training in the spinal cord. "
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    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 · 2.72 Impact Factor
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    • "It is also feasibly that the injured neurons and their projections from the peri-injury region may reduce supply of BDNF. In addition, production of BDNF may be affected by the release of growth inhibitors molecules such as myelin-associated glycoproteins [21] after the injury, which are known to exert inhibitory effects on BDNF levels and function [22]. Thus, it is possible that a combination of factors may play a role in the injury-related reduction in SC BDNF plasticity. "
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    ABSTRACT: We have investigated the effects of a spinal cord injury on the brain and spinal cord, and whether exercise provided before the injury could organize a protective reaction across the neuroaxis. Animals were exposed to 21 days of voluntary exercise, followed by a full spinal transection (T7-T9) and sacrificed two days later. Here we show that the effects of spinal cord injury go beyond the spinal cord itself and influence the molecular substrates of synaptic plasticity and learning in the brain. The injury reduced BDNF levels in the hippocampus in conjunction with the activated forms of p-synapsin I, p-CREB and p-CaMK II, while exercise prior to injury prevented these reductions. Similar effects of the injury were observed in the lumbar enlargement region of the spinal cord, where exercise prevented the reductions in BDNF, and p-CREB. Furthermore, the response of the hippocampus to the spinal lesion appeared to be coordinated to that of the spinal cord, as evidenced by corresponding injury-related changes in BDNF levels in the brain and spinal cord. These results provide an indication for the increased vulnerability of brain centers after spinal cord injury. These findings also imply that the level of chronic activity prior to a spinal cord injury could determine the level of sensory-motor and cognitive recovery following the injury. In particular, exercise prior to the injury onset appears to foster protective mechanisms in the brain and spinal cord.
    PLoS ONE 02/2012; 7(2):e32298. DOI:10.1371/journal.pone.0032298 · 3.23 Impact Factor
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    • "Recently, it has become clear that specific physiological stimuli can also impact the expression of growth-inhibitors of the extracellular milieu (Rossi et al., 2007), such as CNS myelin molecules (Nogo-A, MAG, and OMgp, see for review Xie and Zheng, 2008) and extracellular matrix components (e.g., CSPGs, tenascin-R, see for review Kwok et al., 2008). Voluntary running leads to decreased expression of myelin components both in the intact spinal cord (Ghiani et al., 2007), and in the injured cortex (Chytrova et al., 2008), and all these effects depend on BDNF activity (Ghiani et al., 2007; Chytrova et al., 2008). Experience-dependent changes of extracellular matrix components have been investigated in the hypothalamo-neurohypophysial system, where magnocellular neurons of the hypothalamic supraoptic nucleus undergo dramatic structural plasticity and synaptogenesis in response to chronic salt overload. "
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    ABSTRACT: Information processing, memory formation, or functional recovery after nervous system damage depend on the ability of neurons to modify their functional properties or their connections. At the cellular/molecular level, structural modifications of neural circuits are finely regulated by intrinsic neuronal properties and growth-regulatory cues in the extracellular milieu. Recently, it has become clear that stimuli coming from the external world, which comprise sensory inflow, motor activity, cognitive elaboration, or social interaction, not only provide the involved neurons with instructive information needed to shape connection patterns to sustain adaptive function, but also exert a powerful influence on intrinsic and extrinsic growth-related mechanisms, so to create permissive conditions for neuritic remodeling. Here, we present an overview of recent findings concerning the effects of experience on molecular mechanisms underlying CNS structural plasticity, both in physiological conditions and after damage, with particular focus on activity-dependent modulation of growth-regulatory genes and epigenetic modifications.
    Frontiers in Molecular Neuroscience 11/2011; 4:50. DOI:10.3389/fnmol.2011.00050 · 4.08 Impact Factor
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