Elsevier

Brain Research

Volume 1016, Issue 2, 6 August 2004, Pages 154-162
Brain Research

Research report
The upregulation of plasticity-related proteins following TBI is disrupted with acute voluntary exercise

https://doi.org/10.1016/j.brainres.2004.04.079Get rights and content

Abstract

Following traumatic brain injury (TBI), the brain undergoes a period of metabolic and neurochemical alterations that may compromise the reactivity of neuroplasticity-related molecular systems to physiological stimulation. In order to address the molecular mechanisms underlying plasticity following TBI and the effects of physical stimulation in the acute phase of TBI, levels of intracellular signaling molecules were assessed following voluntary exercise. Lateral fluid percussion injury (FPI) and sham-operated (Sham) rats were housed with or without access to a running wheel (RW) from postsurgery day 0 to 6. Parietal and occipital cortical tissues were analyzed for brain-derived neurotrophic factor (BDNF) using an enzyme-linked immunoabsorbant assay (ELISA). In addition, synapsin I, phospho-synapsin I, cyclic-AMP response-element-binding protein (CREB), phospho-CREB, calcium–calmodulin-dependent protein kinase II (CAMKII), mitogen-activated protein (MAP) kinase I and II (MAPKI and MAPKII), and protein kinase C (PKC) were analyzed by western blot. Results from this study indicated that FPI alone lead to significant increases in synapsin I, CAMKII, and phosphorylated (P) MAPKI (p44) and MAPKII (p42). Exercise in the sham operates led to significant cortical increases of CREB and synapsin I. However, in the FPI rats, the response to exercise was opposite to that seen in the shams in that exercise resulted in significant decreases of CREB, synapsin I, PKC, CAMKII, MAPKI, and MAPKII. Indeed, all the observed proteins in the acutely exercised FPI rats tended to be lower compared to the FPI sedentary (Sed) rats. These results indicate that intracellular signaling proteins are increased during the first week following FPI and that premature voluntary exercise may compromise plasticity.

Introduction

Several studies have reported that experience-dependent plasticity is related to activation of trophic factors. One that has received considerable attention is brain-derived neurotrophic factor (BDNF). In studies conducted by Gomez-Pinilla et al. [11], [12], [16], [26], animals exposed to voluntary exercise via a running wheel (RW) upregulated BDNF within both the dorsal hippocampus and cerebral cortex. Given the strong relationship between BDNF and neuroplasticity, we conducted several experiments to determine if voluntary exercise acutely following experimental traumatic brain injury (TBI) would improve outcome. To our surprise, not only did this type of physical therapy not result in improvement of cognitive functions in rats but it even worsened their outcome [16] This suggests that the injured brain may experience a period of time shortly after the insult during which activation may not be appropriate.

Voluntary exercise in normal uninjured rodents has been linked to neuronal protection [38], enhanced neurogenesis [40], and an increase in learning capabilities [10], [32], [40]. It is likely that all of these improvements are related to the subsequent increases in the expression of select neurotrophins such as brain-derived neurotrophic factor (BDNF) [11], [26], [27]. Recently, some of the pathways downstream to the action of BDNF have been identified. For example, BDNF-induced synaptic facilitation can result through activation of cyclic-AMP response-element-binding protein (CREB), mitogen-activated protein kinase (MAP-K), and synapsin I [25], [33]. BDNF leads to the activation of the MAP-K pathway through its signal transduction receptor, trkB. The MAP-K cascade leads to the phosphorylation of CREB [9] and synapsin I [13], [18], [20]. Synapsin I is a member of a family of terminal-specific phosphoproteins involved in synaptic vesicle (SV) clustering and release [14], [23], [24], [30]. In turn, the signal transcription factor, CREB, which is thought to play an important role in long-term plasticity and memory [1], [34], leads to the induction of its target genes, among them BDNF [8]. The phosphorylation of CREB is affected by several protein kinases, including protein kinase C (PKC), MAP-K, and calcium–calmodulin-dependent protein kinase II (CAMKII), among other kinases. CAMKII and PKC play key roles in neurotransmission, gene expression, and the regulation of glutamate receptors and calcium channels [4], [35], [36].

Given that acute exercise following TBI does not lead to an increase in BDNF and is associated with a cognitive impairment [16], we were interested in studying the intracellular signaling pathways underlying exercise-dependent plasticity following TBI.

Section snippets

Subjects

A total of 18 male Sprague–Dawley adult rats (250–300 g) were utilized in these experiments. Rats underwent lateral fluid percussion injury (FPI; n=10) or sham injury (n=8) and were housed with or without access to a running wheel from postinjury day 0 to 6. All animals were continually monitored and cared for by an IACUC-approved veterinary care staff upon arrival at UCLA. During the experiments, rats were single housed in opaque plastic bins (20×10×10 in.) which were lined with bedding

Results

Animals sustaining injury exhibited a period of unconsciousness ranging from 50 to 120 s (mean, 94 s; standard deviation, 34 s) and apnea time ranging from 5 to 30 s (mean, 17 s; standard deviation, 10). Two rats were dropped due to pronounced injury severity. All animals that survived displayed normal behavior after recovery from anesthesia. No significant differences were observed in beam walking ability following FPI compared to the preinjury baseline. The mean number (±S.E.M.) of nightly

Discussion

These results indicate that a mild FPI can lead to an increase in molecular markers of plasticity as measured at postinjury day 7. However, if injury is followed by acute voluntary exercise, these same molecular markers are now decreased. Indeed, these findings support current findings where early physiological stimulation although voluntary exercise reduces the capacity for plasticity in the injured brain [16].

Acknowledgements

Special thanks to Biesha Chang for her contribution in these studies. Supported by NS30308, NS27544, and NS38978.

References (41)

  • H. Katoh et al.

    The effect of Mk-801 on extracellular neuroactive amino acids in hippocampus after closed head injury followed by hypoxia in rats

    Brain Research

    (1997)
  • J.P. Kesslak et al.

    Spatial learning is delayed and brain-derived neurotrophic factor mRNA expression inhibited by administration of MK-801 in rats

    Neuroscience Letters

    (2003)
  • R.H. Melloni et al.

    Dynamics of synapsin I gene expression during the establishment and restoration of functional synapses in the hippocampus

    Neuroscience

    (1994)
  • S.A. Neeper et al.

    Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain

    Brain Research

    (1996)
  • J. Platenik et al.

    Molecular mechanisms associated with long-term consolidation of the NMDA signals [Review]

    Life Sciences

    (2000)
  • T. Samorajski et al.

    Effect of exercise on longevity, body weight, locomotor performance, and passive-avoidance memory of C57BL/6J mice

    Neurobiology of Aging

    (1985)
  • H. Shen et al.

    Physical activity elicits sustained activation of the cyclic AMP response element-binding protein and mitogen-activated protein kinase in the rat hippocampus

    Neuroscience

    (2001)
  • T.R. Soderling

    Modulation of glutamate receptors by calcium calmodulin-dependent protein kinase Ii

    Neurochemistry International

    (1996)
  • T.R. Soderling

    CaM-kinases: modulators of synaptic plasticity [Review]

    Current Opinion in Neurobiology

    (2000)
  • S. Vaynman et al.

    Interplay between brain-derived neurotrophic factor and signal transduction modulators in the regulation of the effects of exercise on synaptic-plasticity

    Neuroscience

    (2003)
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