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ABSTRACT: We have previously reported that experimental mild traumatic brain injury results in increased sensitivity to stressful events during the first post-injury weeks, as determined by analyzing the hypothalamic-pituitary-adrenal (HPA) axis regulation following restraint-induced stress. This is the same time period when rehabilitative exercise has proven to be ineffective after a mild fluid-percussion injury (FPI). Here we evaluated effects of stress on neuroplasticity. Adult male rats underwent either an FPI or sham injury. Additional rats were only exposed to anesthesia. Rats were exposed to 30 min of restraint stress, followed by tail vein blood collection at post-injury days (PID) 1, 7, and 14. The response to dexamethasone (DEX) was also evaluated. Hippocampal tissue was collected 120 min after stress onset. Brain-derived neurotrophic factor (BDNF) along with glucocorticoid (GR) and mineralocorticoid (MR) receptors was determined by Western blot analysis. Results indicated injury-dependent changes in glucocorticoid and mineralocorticoid receptors that were influenced by the presence of dexamethasone. Control and FPI rats responded differentially to DEX in that GR increases after receiving the lower dose of DEX were longer lasting in the FPI group. A suppression of MR was found at PID 1 in vehicle-treated FPI and Sham groups. Decreases in the precursor form of BDNF were observed in different FPI groups at PIDs 7 and 14. These findings suggest that the increased sensitivity to stressful events during the first post-injury weeks, after a mild FPI, has an impact on hippocampal neuroplasticity.
Neuroscience 03/2012; 210:393-402. · 3.38 Impact Factor
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ABSTRACT: The effects of a mild traumatic brain injury range from white matter disruption to affective disorders. We set out to determine the response to restraint-induced stress after a mild fluid-percussion injury (FPI), an experimental model for brain injury. Hypothalamic-pituitary-adrenal (HPA) axis regulation of corticosterone (CORT) and adrenocorticotropic hormone (ACTH) was determined during the first post-injury weeks, which corresponds to the same time period when rehabilitative exercise has been shown to be ineffective after a mild FPI. Adult male rats underwent either an FPI or sham injury. Additional rats were only exposed to anesthesia. HPA regulation was evaluated by measuring the effects of dexamethasone (DEX) treatment on CORT and ACTH. Tail vein blood was collected following 30-min restraint stress, at post-injury days (PID) 1, 7 and 14, prior to (0 min) and at 30, 60, 90 and 120 min after stress onset. Results from these studies indicate that the stress response was significantly more pronounced after FPI in that CORT and ACTH restraint-induced increases were more pronounced and longer lasting compared to controls. DEX suppression of CORT and ACTH was observed in all groups, suggesting that stress hyper-responsiveness after mild FPI is not attributable to reduced sensitivity of CORT feedback regulation. The increased sensitivity to stressful events in the first two post-injury weeks after a mild FPI may have a negative impact on early rehabilitative therapies.
Neuroscience 01/2011; 178:147-58. · 3.38 Impact Factor
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ABSTRACT: Prior work has shown that d-amphetamine (AMPH) treatment or voluntary exercise improves cognitive functions after traumatic brain injury (TBI). In addition, voluntary exercise increases levels of brain-derived neurotrophic factor (BDNF). The current study was conducted to determine how AMPH and exercise treatments, either alone or in combination, affect molecular events that may underlie recovery following controlled cortical impact (CCI) injury in rats. We also determined if these treatments reduced injury-induced oxidative stress. Following a CCI or sham injury, rats received AMPH (1 mg/kg/day) or saline treatment via an ALZET pump and were housed with or without access to a running wheel for 7 days. CCI rats ran significantly less than sham controls, but exercise level was not altered by drug treatment. On day 7 the hippocampus ipsilateral to injury was harvested and BDNF, synapsin I and phosphorylated (P) -synapsin I proteins were quantified. Exercise or AMPH alone significantly increased BDNF protein in sham and CCI rats, but this effect was lost with the combined treatment. In sham-injured rats synapsin I increased significantly after AMPH or exercise, but did not increase after combined treatment. Synapsin levels, including the P-synapsin/total synapsin ratio, were reduced from sham controls in the saline-treated CCI groups, with or without exercise. AMPH treatment significantly increased the P-synapsin/total synapsin ratio after CCI, an effect that was attenuated by combining AMPH with exercise. Exercise or AMPH treatment alone significantly decreased hippocampal carbonyl groups on oxidized proteins in the CCI rats, compared with saline-treated sedentary counterparts, but this reduction in a marker of oxidative stress was not found with the combination of exercise and AMPH treatment. These results indicate that, whereas exercise or AMPH treatment alone may induce plasticity and reduce oxidative stress after TBI, combining these treatments may cancel each other's therapeutic effects.
Neuroscience 07/2008; 154(2):530-40. · 3.38 Impact Factor
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ABSTRACT: Voluntary exercise leads to an upregulation of brain-derived neurotrophic factor (BDNF) and associated proteins involved in synaptic function. Activity-induced enhancement of neuroplasticity may be considered for the treatment of traumatic brain injury (TBI). Given that during the first postinjury week the brain is undergoing dynamic restorative processes and energetic changes that may influence the outcome of exercise, we evaluated the effects of acute and delayed exercise following experimental TBI. Male Sprague-Dawley rats underwent either sham or lateral fluid-percussion injury (FPI) and were housed with or without access to a running wheel (RW) from postinjury days 0-6 (acute) or 14-20 (delayed). FPI alone resulted in significantly elevated levels of hippocampal phosphorylated synapsin I and phosphorylated cyclic AMP response element-binding-protein (CREB) at postinjury day 7, of which phosphorylated CREB remained elevated at postinjury day 21. Sham and delayed FPI-RW rats showed increased levels of BDNF, following exercise. Exercise also increased phosphorylated synapsin I and CREB in sham rats. In contrast to shams, the acutely exercised FPI rats failed to show activity-dependent BDNF upregulation and had significant decreases of phosphorylated synapsin I and total CREB. Additional rats were cognitively assessed (learning acquisition and memory) by utilizing the Morris water maze after acute or delayed RW exposure. Shams and delayed FPI-RW animals benefited from exercise, as indicated by a significant decrease in the number of trials to criterion (ability to locate the platform in 7 s or less for four consecutive trials), compared with the delayed FPI-sedentary rats. In contrast, cognitive performance in the acute FPI-RW rats was significantly impaired compared with all the other groups. These results suggest that voluntary exercise can endogenously upregulate BDNF and enhance recovery when it is delayed after TBI. However, when exercise is administered to soon after TBI, the molecular response to exercise is disrupted and recovery may be delayed.
Neuroscience 02/2004; 125(1):129-39. · 3.38 Impact Factor
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ABSTRACT: The effects of dizocilpine maleate (MK-801) on vicarious trial-and-error (VTE), and on simultaneous olfactory discrimination learning and its reversal, were observed in weanling rats. The term VTE was used by Tolman (The determiners of behavior at a choice point. Psychol. Rev. 1938;46:318-336), who described it as conflict-like behavior at a choice-point in simultaneous discrimination learning. It takes the form of head movements from one stimulus to the other, and has recently been proposed by Amsel (Hippocampal function in the rat: cognitive mapping or vicarious trial-and-error? Hippocampus, 1993;3:251-256) as related to hippocampal, nonspatial function during this learning. Weanling male rats received systemic MK-801 either 30 min before the onset of olfactory discrimination training and its reversal, or only before its reversal. The MK-801-treated animals needed significantly more sessions to acquire the discrimination and showed significantly fewer VTEs in the acquisition phase of learning. Impaired reversal learning was shown only when MK-801 was administered during the reversal-learning phase, itself, and not when it was administered throughout both phases.
Behavioural Brain Research 01/1999; 97(1-2):29-38. · 3.42 Impact Factor
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ABSTRACT: These experiments observed the immediate and long-term effects of neonatal treatment with MK-801 on patterned single alternation (PSA), a form of nonspatial, memory-based learning. Rat pups were injected daily on postnatal days (PND) 7-19, with MK-801 (MK+) or the less active isomer of MK-801 (MK-) (0.25 mg/kg), and trained at either PND 22 or 60. Rats treated with MK+ or MK- and trained on PND 22 were significantly impaired in PSA when compared with the saline control. Beyond the learning impairment, MK+ rats showed an overall decreased running speed during training. They also presented an array of abnormal behaviors and significant weight loss. These nonassociative variables were determined for several doses (0.025, 0. 05, 0.1, 0.15, and 0.20 mg/kg) through PND days 22-25. Rats that received the threshold dose for secondary effects (0.025 mg/kg) also showed an overall decrease in running speed, but failed to show a significant nonspatial learning impairment on PSA. The PSA learning impairment was found to be not long lasting; rats trained at PND 60, after neonatally receiving the original high dose of MK-801, did not differ from controls.
Proceedings of the National Academy of Sciences 10/1998; 95(19):11435-9. · 9.68 Impact Factor
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ABSTRACT: Prior work has shown that d-amphetamine (AMPH) treatment or voluntary exercise improves cognitive functions after traumatic brain injury (TBI). In addition, voluntary exercise increases levels of brain-derived neurotrophic factor (BDNF). The current study was conducted to determine how AMPH and exercise treatments, either alone or in combination, affect molecular events that may underlie recovery following controlled cortical impact (CCI) injury in rats. We also determined if these treatments reduced injury-induced oxidative stress. Following a CCI or sham injury, rats received AMPH (1 mg/kg/day) or saline treatment via an ALZET® pump and were housed with or without access to a running wheel for 7 days. CCI rats ran significantly less than sham controls, but exercise level was not altered by drug treatment. On day 7 the hippocampus ipsilateral to injury was harvested and BDNF, synapsin I and phosphorylated (P) -synapsin I proteins were quantified. Exercise or AMPH alone significantly increased BDNF protein in sham and CCI rats, but this effect was lost with the combined treatment. In sham-injured rats synapsin I increased significantly after AMPH or exercise, but did not increase after combined treatment. Synapsin levels, including the P-synapsin/total synapsin ratio, were reduced from sham controls in the saline-treated CCI groups, with or without exercise. AMPH treatment significantly increased the P-synapsin/total synapsin ratio after CCI, an effect that was attenuated by combining AMPH with exercise. Exercise or AMPH treatment alone significantly decreased hippocampal carbonyl groups on oxidized proteins in the CCI rats, compared with saline-treated sedentary counterparts, but this reduction in a marker of oxidative stress was not found with the combination of exercise and AMPH treatment. These results indicate that, whereas exercise or AMPH treatment alone may induce plasticity and reduce oxidative stress after TBI, combining these treatments may cancel each other's therapeutic effects.
Neuroscience.
