Time window for voluntary exercise-induced increases in hippocampal neuroplasticity molecules after traumatic brain injury is severity dependent.
ABSTRACT We recently found that an exercise-induced increase in hippocampal brain-derived neurotrophic factor (BDNF) is dependent when exercise is initiated after traumatic brain injury (TBI). When voluntary exercise was delayed by 2 weeks after a mild fluid-percussion injury (FPI) in rats, an increase in BDNF and an improvement in behavioral outcome were observed. This suggests that following FPI there is a therapeutic window for the implementation of voluntary exercise. To determine if more severely injured animals require more time after TBI before voluntary exercise can increase neuroplasticity, adult male rats with a moderate lateral FPI or sham injury were housed with or without access to a running wheel from post-injury-day (PID) 0-6, 14-20 or 30-36. Rats with a mild injury only had access to the running wheel from PID 0-6 or 14-20. Rats were sacrificed at PID 7, 21, or 37. BDNF, synapsin I, and cyclic AMP response element binding protein (CREB) were analyzed within the ipsilateral hippocampus. Whereas BDNF levels significantly increased with exercise in the mild FPI rats that were exercised from PID 14 to 20, the moderate FPI rats only showed significant increases in BDNF when exercised from PID 30 to 36. In addition, moderate FPI rats that were allowed to exercise from PID 30 to 36 also exhibited significant increases in synapsin I and CREB. These results indicate that the time window for exercise-induced increases in BDNF, synapsin I, and CREB is dependent on injury severity.
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ABSTRACT: Exercise has been reported to attenuate rewarding symptoms related to addictive drugs mainly by affecting the brain neuroplasticity and neurotransmission. In this study, we investigated the influence of physical exercise on the behavioral and enzymatic status related to drug relapse in rats. Animals were primarily treated with amphetamine (AMPH; 4.0mg/kg, i.p.) or vehicle (C; NaCl 0.9% solution) in the conditioned place preference (CPP) paradigm for 14 days. Half of each experimental group was then submitted to swimming sessions (60min/day, 5 days/week) for 5 weeks. Animals were re-exposed to AMPH- or vehicle-CPP paradigm for another 3 days, in order to observe drug relapse and anxiety-like symptoms, which were observed 24h after AMPH reconditioning in CPP and elevated plus maze (EPM), respectively, and brain biochemical evaluations were carried out subsequently. While AMPH was related to place preference and anxiety, indicating drug addiction and abstinence symptoms, respectively, physical activity was able to prevent relapse symptoms after AMPH reconditioning, as observed through consecutive decreased CPP and anxiety-like symptoms. In addition, AMPH exposure increased reactive species (RS) generation and protein carbonyl (PC) levels together with decreased activity of catalase- and Na(+)K(+)-ATPase in hippocampus. On the other hand, while all AMPH-induced effects were prevented by physical activity, there was a negative correlation between PC levels (r=0.65; p<0.003) and CAT activity, and a positive correlation between RS generation and PC levels (r=0.54; r=0.52, p<0.05) with AMPH-CPP after exercise. These results indicate that exercise has a clear beneficial influence on the prevention of psychostimulant drug relapse.Behavioural brain research 01/2014; · 3.22 Impact Factor
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ABSTRACT: Background: Moderate-severe traumatic brain injury (TBI) is increasingly being understood as a progressive disorder, with growing evidence of reduced brain volume and white matter (WM) integrity as well as lesion expansion in the chronic phases of injury. The scale of these losses has yet to be investigated, and pattern of change across structures has received limited attention. Objectives: (1) To measure the percentage of patients in our TBI sample showing atrophy from 5 to 20 months post-injury in the whole brain and in structures with known vulnerability to acute TBI, and (2) To examine relative vulnerability and patterns of volume loss across structures. Methods: Fifty-six TBI patients [complicated mild to severe, with mean Glasgow Coma Scale (GCS) in severe range] underwent MRI at, on average, 5 and 20 months post-injury; 12 healthy controls underwent MRI twice, with a mean gap between scans of 25.4 months. Mean monthly percent volume change was computed for whole brain (ventricle-to-brain ratio; VBR), corpus callosum (CC), and right and left hippocampi (HPC). Results: (1) Using a threshold of 2 z-scores below controls, 96% of patients showed atrophy across time points in at least one region; 75% showed atrophy in at least 3 of the 4 regions measured. (2) There were no significant differences in the proportion of patients who showed atrophy across structures. For those showing decline in VBR, there was a significant association with both the CC and the right HPC (P < 0.05 for both comparisons). There were also significant associations between those showing decline in (i) right and left HPC (P < 0.05); (ii) all combinations of genu, body and splenium of the CC (P < 0.05), and (iii) head and tail of the right HPC (P < 0.05 all sub-structure comparisons). Conclusions: Atrophy in chronic TBI is robust, and the CC, right HPC and left HPC appear equally vulnerable. Significant associations between the right and left HPC, and within substructures of the CC and right HPC, raise the possibility of common mechanisms for these regions, including transneuronal degeneration. Given the 96% incidence rate of atrophy, a genetic explanation is unlikely to explain all findings. Multiple and possibly synergistic mechanisms may explain findings. Atrophy has been associated with poorer functional outcomes, but recent findings suggest there is potential to offset this. A better, understanding of the underlying mechanisms could permit targeted therapy enabling better long-term outcomes.Frontiers in Human Neuroscience 01/2014; 8:67. · 2.91 Impact Factor
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ABSTRACT: Traumatic brain injury (TBI) induces secondary biochemical changes that contribute to delayed neuroinflammation, neuronal cell death, and neurological dysfunction. Attenuating such secondary injury has provided the conceptual basis for neuroprotective treatments. Despite strong experimental data, more than 30 clinical trials of neuroprotection in TBI patients have failed. In part, these failures likely reflect methodological differences between the clinical and animal studies, as well as inadequate pre-clinical evaluation and/or trial design problems. However, recent changes in experimental approach and advances in clinical trial methodology have raised the potential for successful clinical translation. Here we critically analyze the current limitations and translational opportunities for developing successful neuroprotective therapies for TBI.International Journal of Molecular Sciences 01/2014; 15(1):1216-1236. · 2.46 Impact Factor