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The aim of the current study was to determine effects of mild traumatic brain injury (TBI), with or without blockade of purinergic ATP Y1 (P2Y1) receptors or store-operated calcium channels, on extracellular levels of ATP, glutamate, glucose and lactate. Concentrations of ATP, glutamate, glucose and lactate were measured in cerebral microdialysis samples obtained from the ipsilateral cortex and underlying hippocampus of rats with mild unilateral controlled cortical impact (CCI) or sham injury. Immediately after CCI, a large release of ATP was observed in the cortex (3.53-fold increase of pre-injury value) and hippocampus (2.97-fold increase of pre-injury value), with ATP returning to the baseline levels within 20 min post-injury and remaining stable for during the 3-h sampling period. In agreement with the results of previous studies, there was a significant increase in glutamate 20 min after CCI, which was concomitant with a decrease in extracellular glucose (20 min) and an increase in lactate (40-60 min) in both brain regions after CCI. Addition of a selective P2Y1 receptor blocker (MRS2179 ammonium salt hydrate) to the microdialysis perfusate significantly lowered pre-injury ATP and glutamate levels, and eliminated the post-CCI peaks. Addition of a blocker of store-operated calcium channels [2-aminoethoxy diphenylborinate (2-APB)] to the microdialysis perfusate significantly lowered pre-injury ATP in the hippocampus, and attenuated the post-CCI peak in both the cortex and hippocampus. 2-APB treatment significantly increased baseline glutamate levels, but the values post-injury did not differ from those in the sham group. Pre-injury glucose levels, but not lactate levels, were increased by MRS2179 and decreased by 2-APB. However, none of these treatments substantially altered the CCI-induced reduction in glucose and increase in lactate in the cortex. In conclusion, the results of the present study demonstrated that a short although extensive release of ATP immediately after experimental TBI can be significantly attenuated by blockade of P2Y1 receptors or store-operated calcium channels.

Experimental traumatic brain injury (TBI) is known to produce an acute increase in cerebral glucose utilization, followed rapidly by a generalized cerebral metabolic depression. The current studies determined effects of single or multiple treatments with sodium pyruvate (SP; 1000 mg/kg, i.p.) or ethyl pyruvate (EP; 40 mg/kg, i.p.) on cerebral glucose metabolism and neuronal injury in rats with unilateral controlled cortical impact (CCI) injury. In Experiment 1 a single treatment was given immediately after CCI. SP significantly improved glucose metabolism in 3 of 13 brain regions while EP improved metabolism in 7 regions compared to saline-treated controls at 24 h post-injury. Both SP and EP produced equivalent and significant reductions in dead/dying neurons in cortex and hippocampus at 24 h post-CCI. In Experiment 2 SP or EP were administered immediately (time 0) and at 1, 3 and 6 h post-CCI. Multiple SP treatments also significantly attenuated TBI-induced reductions in cerebral glucose metabolism (in 4 brain regions) 24 h post-CCI, as did multiple injections of EP (in 4 regions). The four pyruvate treatments produced significant neuroprotection in cortex and hippocampus 1 day after CCI, similar to that found with a single SP or EP treatment. Thus, early administration of pyruvate compounds enhanced cerebral glucose metabolism and neuronal survival, with 40 mg/kg of EP being as effective as 1000 mg/kg of SP, and multiple treatments within 6 h of injury did not improve upon outcomes seen following a single treatment.

Traumatic brain injury (TBI) results in well-known, significant alterations in structural and functional connectivity. Although this is especially likely to occur in areas of pathology, deficits in function to and from remotely connected brain areas, or diaschisis, also occur as a consequence to local deficits. As a result, consideration of the network wiring of the brain may be required to design the most efficacious rehabilitation therapy to target specific functional networks to improve outcome. In this work, we model remote connections after controlled cortical impact injury (CCI) in the rat through the effect of callosal deafferentation to the opposite, contralesional cortex. We show rescue of significantly reaching deficits in injury-affected forelimb function if temporary, neuromodulatory silencing of contralesional cortex function is conducted at 1 week post-injury using the γ-aminobutyric acid (GABA) agonist muscimol, compared with vehicle. This indicates that subacute, injury-induced remote circuit modifications are likely to prevent normal ipsilesional control over limb function. However, by conducting temporary contralesional cortex silencing in the same injured rats at 4 weeks post-injury, injury-affected limb function either remains unaffected and deficient or is worsened, indicating that circuit modifications are more permanently controlled or at least influenced by the contralesional cortex at extended post-injury times. We provide functional magnetic resonance imaging (MRI) evidence of the neuromodulatory effect of muscimol on forelimb-evoked function in the cortex. We discuss these findings in light of known changes in cortical connectivity and excitability that occur in this injury model, and postulate a mechanism to explain these findings.

Clinical studies have indicated an association between acute hyperglycemia and poor outcomes in patients with traumatic brain injury (TBI), although optimal blood glucose levels needed to maximize outcomes for these patients' remain under investigation. Previous results from experimental animal models suggest that post-TBI hyperglycemia may be harmful, neutral, or beneficial. The current studies determined the effects of single or multiple episodes of acute hyperglycemia on cerebral glucose metabolism and neuronal injury in a rodent model of unilateral controlled cortical impact (CCI) injury. In Experiment 1 , a single episode of hyperglycemia (50% glucose at 2 g/kg, i.p.) initiated immediately after CCI was found to significantly attenuate a TBI-induced depression of glucose metabolism in cerebral cortex (4 of 6 regions) and subcortical regions (2 of 7) as well as to significantly reduce the number of dead/dying neurons in cortex and hippocampus at 24 h post-CCI. Experiment 2 examined effects of more prolonged and intermittent hyperglycemia induced by glucose administrations (2 g/kg, i.p.) at 0, 1, 3 and 6 h post-CCI. The latter study also found significantly improved cerebral metabolism (in 3 of 6 cortical and 3 of 7 subcortical regions) and significant neuroprotection in cortex and hippocampus 1 day after CCI and glucose administration. These results indicate that acute episodes of post-TBI hyperglycemia can be beneficial and are consistent with other recent studies showing benefits of providing exogenous energy substrates during periods of increased cerebral metabolic demand.

We previously reported that traumatic brain injury (TBI) produced by moderate controlled cortical impact (CCI) attenuates the stress response of the hypothalamic-pituitary-adrenal (HPA) axis between 21 and 70 days postinjury and enhances the sensitivity of the stress response to glucocorticoid negative feedback. In the current study, we investigated two possible mechanisms for the CCI-induced attenuation of the HPA stress response-i.e, glucocorticoid receptor (GR) and GABA-mediated inhibition of the HPA axis, with the GR antagonist, mifepristone (RU486), or the GABA(A)-receptor antagonist, bicuculline. In addition, we examined the effect of moderate CCI on GR and inhibitory neurons histologically in subfields of the hippocampus, medial prefrontal cortex, and amygdala. We show that at 30-min after onset of restraint stress, GR as well as GABA antagonism with MIFE or BIC, respectively, reversed the attenuating effects of moderate CCI on the stress-induced HPA response. Our histological results demonstrate that moderate CCI led to a loss of glutamic acid decarboxylase 67 or parvalbumin-positive inhibitory neurons within regions of the hippocampus and amygdala but did not lead to significant increases in GR in these regions. These findings indicate that suppression of the stress-induced HPA response after moderate CCI is mediated by the inhibitory actions of both GR and GABA, with a corresponding loss of inhibitory neurons within brain regions with neural pathways affecting limbic stress-integrative pathways.

Administration of sodium pyruvate (SP; 9.08μmol/kg, i.p.), ethyl pyruvate (EP; 0.34μmol/kg, i.p.) or glucose (GLC; 11.1μmol/kg, i.p.) to rats after unilateral controlled cortical impact (CCI) injury has been reported to reduce neuronal loss and improve cerebral metabolism. In the present study these doses of each fuel or 8% saline (SAL; 5.47 nmoles/kg) were administered immediately and at 1, 3, 6 and 23h post-CCI. At 24h all CCI groups and non-treated Sham injury controls were infused with [1,2 13C] glucose for 68min 13C nuclear magnetic resonance (NMR) spectra were obtained from cortex+hippocampus tissues from left (injured) and right (contralateral) hemispheres. All three fuels increased lactate labeling to a similar degree in the injured hemisphere. The amount of lactate labeled via the pentose phosphate and pyruvate recycling (PPP+PR) pathway increased in CCI-SAL and was not improved by SP, EP, and GLC treatments. Oxidative metabolism, as assessed by glutamate labeling, was reduced in CCI-SAL animals. The greatest improvement in oxidative metabolism was observed in animals treated with SP and fewer improvements after EP or GLC treatments. Compared to SAL, all three fuels restored glutamate and glutamine labeling via pyruvate carboxylase (PC), suggesting improved astrocyte metabolism following fuel treatment. Only SP treatments restored the amount of [4 13C] glutamate labeled by the PPP+PR pathway to sham levels. Milder injury effects in the contralateral hemisphere appear normalized by either SP or EP treatments, as increases in the total pool of 13C lactate and labeling of lactate in glycolysis, or decreases in the ratio of PC/PDH labeling of glutamine, were found only for CCI-SAL and CCI-GLC groups compared to Sham. The doses of SP, EP and GLC examined in this study all enhanced lactate labeling and restored astrocyte-specific PC activity but differentially affected neuronal metabolism after CCI injury. The restoration of astrocyte metabolism by all three fuel treatments may partially underlie their abilities to improve cerebral glucose utilization and to reduce neuronal loss following CCI injury.

The current dogma to explain the extent of injury related changes following rodent controlled cortical impact (CCI) injury is a focal injury with limited axonal pathology. However, there is in fact good, published histologic evidence to suggest that axonal injury is far more widespread in this model than generally thought. One possibility that might help to explain this is the often-used region-of-interest data analysis approach taken by experimental traumatic brain injury (TBI) diffusion tensor imaging (DTI) or histologic studies that might miss more widespread damage, when compared to the whole brain, statistically robust method of tract based analysis used more routinely in clinical research. To determine the extent of DTI changes in this model, we acquired in vivo DTI data before and at 1 and 4 weeks after CCI injury in 17 adult, male rats and analyzed parametric maps of fractional anisotropy (FA), axial, radial and mean diffusivity (AD, RD, MD), tensor mode (MO), and fiber tract density (FTD) using tract based spatial statistics. Contusion volume was used as a surrogate marker of injury severity and as a covariate for investigating severity dependence of the data. Mean fiber tract length was also computed from seeds in the cortical spinal tract regions. In parallel experiments (n=3–5/group) we investigated corpus callosum neurofilaments and demyelination using immunohistochemistry (IHC) at 3 days and 6 weeks, callosal tract patency using dual-label retrograde tract-tracing at 5 weeks, and the contribution of gliosis to DTI parameter maps using GFAP IHC at 4 weeks post-injury. The data show widespread ipsilateral regions of significantly reduced FA at 1 week post-injury, driven by temporally changing values of AD, RD and MD that persist to 4 weeks. Demyelination, retrograde label tract loss, and reductions in MO (tract degeneration) and FTD were shown to underpin these data. Significant FA increases occurred in subcortical and corticospinal tract regions that were spatially distinct from regions of FA decrease, grossly affected gliotic areas and from MO changes. However, there was good spatial correspondence between regions of increased FA and areas of increased FTD and mean fiber length. We discuss these widespread changes in DTI parameters in terms of axonal degeneration and potential reorganization, with reference to a resting state fMRI companion paper (Harris et al, 2016, Exp. Neurol.227:124–138) that demonstrated altered functional connectivity data acquired from the same rats used in this study.

Prior work indicates that cerebral glycolysis is impaired following traumatic brain injury (TBI) and that pyruvate treatment acutely after TBI can improve cerebral metabolism and is neuroprotective. Since extracellular levels of glucose decrease during periods of increased cognitive demand and exogenous glucose improves cognitive performance, we hypothesized that pyruvate treatment prior to testing could ameliorate cognitive deficits in rats with TBI. Based on pre-surgical spatial alternation performance in a 4-arm plus-maze, adult male rats were randomized to receive either sham injury or unilateral (left) cortical contusion injury (CCI). On days 4, 9 and 14 after surgery animals received an intraperitoneal injection of either vehicle (Sham-Veh, n = 6; CCI-Veh, n = 7) or 1000 mg/kg of sodium pyruvate (CCI-SP, n = 7). One hour after each injection rats were retested for spatial alternation performance. Animals in the CCI-SP group showed no significant working memory deficits in the spatial alternation task compared to Sham-Veh controls. The percent four/five alternation scores for CCI-Veh rats were significantly decreased from Sham-Veh scores on days 4 and 9 (p < 0.01) and from CCI-SP scores on days 4, 9 and 14 (p < 0.05). Measures of cortical contusion volume, regional cerebral metabolic rates of glucose and regional cytochrome oxidase activity at day 15 post-injury did not differ between CCI-SP and CCI-Veh groups. These results show that spatial alternation testing can reliably detect temporal deficits and recovery of working memory after TBI and that delayed pyruvate treatment can ameliorate TBI-induced cognitive impairments.

Sodium pyruvate (SP) treatment initiated within 5 min post-injury is neuroprotective in a rat model of unilateral cortical contusion injury (CCI). The current studies examined: (1) effects of delayed SP treatments (1000 mg/kg, i.p., at 1, 12 and 24 h), (2) effects of single (1 h) or multiple (1, 12 and 24 h) ethyl pyruvate treatments (EP; at 20 or 40 mg/kg, i.p.), and (3) mechanisms of action for pyruvate effects after CCI. In Experiment 1, both SP and EP treatment(s) significantly reduced the number of dead/dying cells in the ipsilateral hippocampus (dentate hilus+CA3c and/or CA3a-b regions) at 72 h post-CCI. Pyruvate treatment(s) attenuated CCI-induced reductions of cerebral cytochrome oxidase activity at 72 h, significantly improving activity in peri-contusional cortex after multiple SP or EP treatments. Optical density measures of ipsilateral CD11b immuno-staining were significantly increased 72 h post-CCI, but these measures of microglia activation were not different from sham injury values in SP and EP groups with three post-CCI treatments. In Experiment 2, three treatments (1, 12 and 24 h) of SP (1000 mg/kg) or EP (40 mg/kg) significantly improved recovery of beam-walking and neurological scores in the first three weeks after CCI, and EP treatments significantly improved spatial working memory one week post-CCI. Ipsilateral CA3b neuronal loss, but not cortical tissue loss, was significantly reduced one month post-CCI with pyruvate treatments begun 1 h post-CCI. Thus, delayed pyruvate treatments after CCI are neuroprotective and improve neurobehavioral recovery; these effects may be mediated by improved metabolism and reduced inflammation.

This study determined the effects of intraperitoneal sodium pyruvate (SP) treatment on the levels of circulating fuels and on cerebral microdialysis levels of glucose (MDglc), lactate (MDlac), and pyruvate (MDpyr), and the effects of SP treatment on neuropathology after left cortical contusion injury (CCI) in rats. SP injection (1000 mg/kg) 5 min after sham injury (Sham-SP) or CCI (CCI-SP) significantly increased arterial pyruvate (p

Having reported that traumatic brain injury (TBI), produced by moderate lateral controlled cortical impact (CCI), causes long-term dysregulation of the neuroendocrine stress response, the aim of this study was to assess short- and long-term effects of both moderate and mild CCI on stress-induced hypothalamic-pituitary-adrenal (HPA) function. TBI was induced to the left parietal cortex in adult male rats with a pneumatic piston, at two different impact velocities and compression depths to produce either a moderate or mild CCI. Controls underwent sham surgery without injury. Commencing at one week after recovery from surgery, rats were exposed to stressors: 30-min restraint (days 7, 34, and 70) or 15-min forced swim (days 21 and 54). Tail vein blood was analyzed for corticosterone (CORT) content by radioimmunoassay. On days 7 and 21, the stress-induced HPA responses were significantly attenuated by both mild and moderate CCI. Significant attenuation of the CORT response to stress persisted through day 70 after moderate CCI. In contrast, stress-induced CORT levels on days 34, 54, and 70 were significantly enhanced after mild CCI. Differential effects of injury severity were also observed on motor function in a forelimb test on post-injury day 12 and on cortical lesion volume and hippocampal cell loss at day 70, but not on working memory in a radial maze on day 15. The differing short- and long-term stress-induced HPA responses may be mediated by differential effects of moderate and mild CCI on the efficiency of glucocorticoid negative feedback or signaling among hypothalamic and extrahypothalamic components of the neuroendocrine stress-response system.

The impact of hyperglycemia after traumatic brain injury (TBI), and even the administration of glucose-containing solutions to head injured patients, remains controversial. In the current study adult male Sprague-Dawley rats were tested on behavioral tasks and then underwent surgery to induce sham injury or unilateral controlled cortical impact (CCI) injury followed by injections (i.p.) with either a 50% glucose solution (Glc; 2g/kg) or an equivalent volume of either 0.9% or 8% saline (Sal) at 0, 1, 3 and 6h post-injury. The type of saline treatment did not significantly affect any outcome measures, so these data were combined. Rats with CCI had significant deficits in beam-walking traversal time and rating scores (p's < 0.001 versus sham) that recovered over test sessions from 1 to 13 days post-injury (p's < 0.001), but these beam-walking deficits were not affected by Glc versus Sal treatments. Persistent post-CCI deficits in forelimb contraflexion scores and forelimb tactile placing ability were also not differentially affected by Glc or Sal treatments. However, deficits in latency to retract the right hind limb after limb extension were significantly attenuated in the CCI-Glc group (p < 0.05 versus CCI-Sal). Both CCI groups were significantly impaired in a plus maze test of spatial working memory on days 4, 9 and 14 post-surgery (p < 0.001 versus sham), and there was no effect of Glc versus Sal on this cognitive outcome measure. At 15 days post-surgery the loss of cortical tissue volume (p < 0.001 versus sham) was significantly less in the CCI-Glc group (30.0%; p < 0.05) compared to the CCI-Sal group (35.7%). Counts of surviving hippocampal hilar neurons revealed a significant (~40%) loss ipsilateral to CCI (p < 0.001 versus sham), but neuronal loss in the hippocampus was not different in the CCI-Sal and CCI-Glc groups. Taken together, these results indicate that an early elevation of blood glucose may improve some neurological outcomes and, importantly, the induction of hyperglycemia after isolated TBI did not adversely affect any sensorimotor, cognitive or histological outcomes.

The metabolic fate of [1,2 13C]-labeled glucose was determined in male control and unilateral controlled cortical impact (CCI) injured rats at 3.5 and 24 h after surgery. The concentration of 13C-labeled glucose, lactate, glutamate and glutamine were measured in the injured and contralateral cortex. CCI animals showed a 145% increase in 13C lactate in the injured cortex at 3.5 h, but not at 24 h after injury, indicating increased glycolysis in neurons and/or astrocytes ipsilateral to CCI. Total levels of 13C glutamate in cortical tissue extracts did not differ between groups. However, 13C glutamine increased by 40% in the left and 98% in the right cortex at 3.5 h after injury, most likely resulting from an increase in astrocytic metabolism of glutamate. Levels of 13C incorporation into the glutamine isotopomers had returned to control levels by 24 h after CCI. The singlet to doublet ratio of the lactate C3 resonances was calculated to estimate the flux of glucose through the pentose phosphate pathway (PPP). CCI resulted in bilateral increases (9-12%) in the oxidation of glucose via the PPP, with the largest increase occurring at 24 h. Since an increase in PPP activity is associated with NADPH generation, the data suggest that there was an increasing need for reducing equivalents after CCI. Furthermore, 13C was incorporated into glutamate and glutamine isotopomers associated with multiple turns of the tricarboxylic acid (TCA) cycle, indicating that oxidative phosphorylation of glucose was maintained in the injured cortex at 3.5 and 24 h after a moderate to severe CCI injury.

Microarray technology was employed to determine the differential pattern of gene expression within the hippocampus as a result of traumatic brain injury (TBI). The validity of the microarray data was confirmed using real-time RT-PCR. Following either moderate or severe lateral fluid percussion injury, rats were studied 0.5, 4, and 24 h after injury. In general, animals exhibited mRNA up or down regulation of approximately 10% of the genes studied. However, it was clear that the pattern of gene expression was influenced by both the severity of injury and the time after injury at which animals were studied. For example, genes encoding molecules for cellular signaling, synaptic plasticity, metabolism, ion channels and transporters were up regulated following severe injury, but down regulated following moderate injury. Furthermore, moderate injury was associated with an increasing number of responsive genes as a function of time post-injury. However, animals sustaining a severe level of injury exhibited decreasing number of responsive genes during the same post-injury period. The different patterns of gene expression between injury severity and across time after the insult suggests that the pathophysiological cascade induced by TBI is accompanied by a molecular response which, like the other aspects of the cellular response for survival, may indicate a "molecular window" that may offer an opportunity for therapeutic interventions involving gene therapy. Our results also suggest that fundamentally different pathophysiological processes or cascades may be induced by different severities of injury.

Object. Hyperbaric oxygenation (HBO) therapy has been shown to reduce mortality by 50% in a prospective randomized trial of severely brain injured patients conducted at the authors' institution. The purpose of the present study was to determine the effects of HBO on cerebral blood flow (CBF), cerebral metabolism, and intracranial pressure (ICP), and to determine the optimal HBO treatment paradigm. Methods. Oxygen (100% O2, 1.5 atm absolute) was delivered to 37 patients in a hyperbaric chamber for 60 minutes every 24 hours (maximum of seven treatments/patient). Cerebral blood flow, arteriovenous oxygen difference (AVDO2), cerebral metabolic rate of oxygen (CMRO2), ventricular cerebrospinal fluid (CSF) lactate, and ICP values were obtained 1 hour before and 1 hour and 6 hours after a session in an HBO chamber. Patients were assigned to one of three categories according to whether they had reduced, normal, or raised CBF before HBO. In patients in whom CBF levels were reduced before HBO sessions, both CBF and CMRO2 levels were raised 1 hour and 6 hours after HBO (p < 0.05). In patients in whom CBF levels were normal before HBO sessions, both CBF and CMRO2 levels were increased at 1 hour (p < 0.05), but were decreased by 6 hours after HBO. Cerebral blood flow was reduced 1 hour and 6 hours after HBO (p < 0.05), but CMRO2 was unchanged in patients who had exhibited a raised CBF before an HBO session. In all patients AVDO2 remained constant both before and after HBO. Levels of CSF lactate were consistently decreased 1 hour and 6 hours after HBO, regardless of the patient's CBF category before undergoing HBO (p < 0.05). Intracranial pressure values higher than 15 mm Hg before HBO were decreased 1 hour and 6 hours after HBO (p < 0.05). The effects of each HBO treatment did not last until the next session in the hyperbaric chamber. Conclusions. The increased CMRO2 and decreased CSF lactate levels after treatment indicate that HBO may improve aerobic metabolism in severely brain injured patients. This is the first study to demonstrate a prolonged effect of HBO treatment on CBF and cerebral metabolism. On the basis of their data the authors assert that shorter, more frequent exposure to HBO may optimize treatment.

OBJECTIVE: Recent studies suggest that in some circumstances, alcohol intoxication at the time of severe head injury may be neuroprotective. The objective of this study was to determine the effect of acute and chronic alcohol ingestion on outcome in rodents sustaining multiple episodes of mild traumatic brain injury while intoxicated. METHOD: For two weeks before experimentation, adult male Sprague-Dawley rats received intoxicating levels of 95% ethanol (3 g/kg) or normal saline (NS) every other day by orogastric instillation. On the day of experimentation, the animals were randomized to receive alcohol or NS. Two hours later, the animals received either mild (1.2 +/- 0.4 ATA) fluid percussion injury (FPI) or no injury. The injured animals received a total of three episodes of FPI (once every four days). Mean reflex recovery time (RRT) was determined (seconds +/- SEM) immediately after each episode. Mean latency time (seconds +/- SEM) for Morris Water Maze (MWM) performance was assessed at post-trauma days 11-19. RESULTS: The chronic alcohol-exposed (CA) and the non-alcohol-exposed (NA) animals intoxicated when injured had prolonged escape, righting, and corneal RRTs after each FPI compared with the nonintoxicated injured animals and the non-injured shams. However, the CA animals had significantly shorter RRTs when compared with the NA rats. All the injured animals had MWM deficits on testing days 1-6 compared with the noninjured controls. On the last two MWM testing days, the injured NA animals had significantly better MWM performance than the injured CA rats. CONCLUSIONS: The injured intoxicated CA animals had a more rapid recovery of reflexes compared with the injured intoxicated NA animals. Despite initial MWM deficits, the injured NA rodents eventually began to learn the MWM. The injured CA rats never learned the maze. Under the conditions of this study, acute alcohol intoxication at the time of multiple episodes of minor head trauma did not provide neuroprotection for NA or CA rodents. Language: en

IL-8 involvement in neutrophil activation and chemotaxis may be important in inflammatory responses within the central nervous system, secondary to meningitis, encephalitis, and traumatic injury. The source of IL-8 within the brain during these inflammatory processes, however, is unknown. To explore the role of microglia in the production of IL-8, human fetal microglia, which are the resident macrophages of the brain, were treated with LPS and pro- and anti-inflammatory cytokines to determine their effects on IL-8 production. We found that IL-8 protein levels increased in response to LPS or IL-1β, or to TNF-α, which also corresponded to elevated IL-8 mRNA levels by RT-PCR. Pretreatment with IL-4, IL-10, or TGF-β1 potently inhibited the stimulatory effects of these proinflammatory agents. These findings indicate that human microglia synthesize IL-8 in response to proinflammatory stimuli, and that anti-inflammatory cytokines down-regulate the production of this chemokine. These results may have important therapeutic implications for certain central nervous system insults involving inflammation.

The present review highlights critical issues related to cerebral metabolism following traumatic brain injury (TBI) and the use of (13)C labeled substrates and nuclear magnetic resonance (NMR) spectroscopy to study these changes. First we address some pathophysiologic factors contributing to metabolic dysfunction following TBI. We then examine how (13)C NMR spectroscopy strategies have been used to investigate energy metabolism, neurotransmission, the intracellular redox state, and neuroglial compartmentation following injury. (13)C NMR spectroscopy studies of brain extracts from animal models of TBI have revealed enhanced glycolytic production of lactate, evidence of pentose phosphate pathway (PPP) activation, and alterations in neuronal and astrocyte oxidative metabolism that are dependent on injury severity. Differential incorporation of label into glutamate and glutamine from (13)C labeled glucose or acetate also suggest TBI-induced adaptations to the glutamate-glutamine cycle.

The beneficial effect of interventions with chondroitinase ABC enzyme to reduce axon growth-inhibitory chondroitin sulphate side chains after central nervous system injuries has been mainly attributed to enhanced axonal sprouting. After traumatic brain injury (TBI), it is unknown whether newly sprouting axons that occur as a result of interventional strategies are able to functionally contribute to existing circuitry, and it is uncertain whether maladaptive sprouting occurs to increase the well-known risk for seizure activity after TBI. Here, we show that after a controlled cortical impact injury in rats, chondroitinase infusion into injured cortex at 30 min and 3 days reduced c-Fos+ cell staining resulting from the injury alone at 1 week postinjury, indicating that at baseline, abnormal spontaneous activity is likely to be reduced, not increased, with this type of intervention. c-Fos+ cell staining elicited by neural activity from stimulation of the affected forelimb 1 week after injury was significantly enhanced by chondroitinase, indicating a widespread effect on cortical map plasticity. Underlying this map plasticity was a larger contribution of neuronal, rather than glial cells and an absence of c-Fos+ cells surrounded by perineuronal nets that were normally present in stimulated naïve rats. After injury, chondroitin sulfate proteoglycan digestion produced the expected increase in growth-associated protein 43–positive axons and perikarya, of which a significantly greater number were double labeled for c-Fos after intervention with chondroitinase, compared to vehicle. These data indicate that chondroitinase produces significant gains in cortical map plasticity after TBI, and that either axonal sprouting and/or changes in perineuronal nets may underlie this effect. Chondroitinase dampens, rather than increases nonspecific c-Fos activity after brain injury, and induction of axonal sprouting is not maladaptive because greater numbers are functionally active and provide a significant contribution to forelimb circuitry after brain injury.

OBJECTIVES. Injury is a major US public health problem, particularly in urban minority communities. This paper evaluates the impact of the Safe Block Project, a comprehensive injury prevention trial, on home hazards and injury prevention knowledge in a poor urban African-American community. METHODS. Nine census tracts in the community were allocated to either the intervention area or the control area. The intervention, carried out by trained community outreach workers, consisted of (1) home modification for simple prevention measures, (2) home inspection accompanied by information about home hazards, and (3) education about selected injury prevention practices. Approximately 12 months after the intervention, random samples of control and intervention homes were assessed for home hazards and injury prevention knowledge. RESULTS. A significantly larger proportion of intervention homes than control homes had functioning smoke detectors, syrup of ipecac, safely stored medications, and reduced electrical and tripping hazards. No consistent differences were observed between control and intervention homes on home hazards requiring major effort to correct. CONCLUSIONS. There was a distinct difference between control and intervention homes with respect to safety knowledge and home hazards requiring minimal to moderate effort to correct. The Safe Block Project could serve as a model for future urban injury prevention efforts.

Despite various lines of evidence pointing to the compartmentation of metabolism within the brain, few studies have reported the effect of a traumatic brain injury (TBI) on neuronal and astrocyte compartments and/or metabolic trafficking between these cells. In this study we used ex vivo 13C NMR spectroscopy following an infusion of [1-13C] glucose and [1,2-13C2] acetate to study oxidative metabolism in neurons and astrocytes of sham-operated and fluid percussion brain injured (FPI) rats at 1, 5, and 14 days post-surgery. FPI resulted in a decrease in the 13C glucose enrichment of glutamate in neurons in the injured hemisphere at day 1. In contrast, enrichment of glutamine in astrocytes from acetate was not significantly decreased at day 1. At day 5 the 13C enrichment of glutamate and glutamine from glucose in the injured hemisphere of FPI rats did not differ from sham levels, but glutamine derived from acetate metabolism in astrocytes was significantly increased. The 13C glucose enrichment of the C3 position of glutamate (C3) in neurons was significantly decreased ipsilateral to FPI at day 14, whereas the enrichment of glutamine in astrocytes had returned to sham levels at this time point. These findings indicate that the oxidative metabolism of glucose is reduced to a greater extent in neurons compared to astrocytes following a FPI. The increased utilization of acetate to synthesize glutamine, and the acetate enrichment of glutamate via the glutamate-glutamine cycle, suggests an integral protective role for astrocytes in maintaining metabolic function following TBI-induced impairments in glucose metabolism.

Traumatic brain injury (TBI) results in enduring functional deficits. Strategies aimed at promoting plasticity within the injured brain may aid in enhancing functional outcome. We have previously shown that spontaneous pericontusional axon sprouting occurs within 7–14 days after controlled cortical impact injury in the adult rat, but ultimately fails due to an increasingly growth-inhibitory environment. We therefore sought to determine whether acute infusion of chondroitinase ABC into the site of the cortical contusion, to further reduce pericontusional growth-inhibitory chondroitin sulfate proteoglycans (CSPGs), would enhance and prolong the sprouting response. We also wanted to determine if chondroitinase-enhanced sprouting would ameliorate the behavioral deficits in forelimb function that occur in this model. Acute chondroitinase infusion decreased intact CSPGs and significantly increased pericontusional cortical grey and white matter growth-associated protein 43 (GAP43)-positive axon sprouting at 7 days post-injury. A return of intact CSPGs at later time points likely contributed to the absence of persistently increased levels of axon sprouting by 14–21 days post-injury. There was no overall benefit on forelimb function during the time of maximal sprouting or at any subsequent times in three of four behavioral outcome measures. However, there was a chondroitinase-induced improvement in recovery from unskilled limb use deficits on the staircase forelimb reaching test toward sham-injured values at 28 days, which was not achieved by the vehicle-treated rats, indicating that there is some minor functional benefit of the increased sprouting induced by chondroitinase treatment. The current results, together with data from spinal cord injury models after chondroitinase intervention, suggest that a combinatorial approach with the addition of neurotrophins and rehabilitation would result in more robust axon sprouting and consequently improve behavioral outcome.

We have reported differential short- and long-term dysregulation of the neuroendocrine stress response after traumatic brain injury (TBI) produced by controlled cortical impact (CCI). We have now investigated three possible mechanisms for this TBI-induced dysregulation: (1) effects on the sensitivity of negative-feedback systems to glucocorticoids; (2) effects on the sensitivity of pituitary corticotrophs to corticotropin-releasing hormone (CRH); and (3) effects on neuronal loss in the hilar region of the dentate gyrus and in the CA3b layer of the dorsal hippocampus. TBI was induced to the left parietal cortex in adult male rats with a pneumatic piston, at two different impact velocities and compression depths, to produce either moderate or mild CCI. At 7 and 35 days after surgery, the rats were injected SC with the synthetic glucocorticoid analog dexamethasone (DEX; 0.01, 0.10, or 1.00 mg/kg) or saline, and 2 h later were subjected to 30 min of restraint stress and tail vein blood collection. Whereas all doses of DEX suppressed corticosterone (CORT) and adrenocorticotropic hormone (ACTH) responses to stress on both days, CORT and ACTH were significantly more suppressed after 0.01 mg/kg DEX in the moderate TBI group than in the mild TBI or sham groups. At both 7 and 35 days post-TBI, CRH (1.0 and 10.0 microg/kg IP) stimulated CORT and ACTH in all rats, regardless of injury condition. Hippocampal cell loss was greatest at 48 days after moderate TBI. Enhanced sensitivity to glucocorticoid negative feedback and greater hippocampal cell loss, but not altered pituitary responses to CRH, contribute to the short- and long-term attenuation of the neuroendocrine stress response following moderate TBI. The role of TBI-induced alterations in glucocorticoid receptors in limbic system sites in enhanced glucocorticoid feedback sensitivity requires further investigation.

We previously reported that pericontusional extracellular chondroitin sulfate proteoglycans (CSPGs) are profoundly reduced for 3 weeks after experimental traumatic brain injury, indicating a potential growth-permissive window for plasticity. Here, we investigate the extracellular environment of sprouting neurons after controlled cortical impact injury in adult rats to determine the spatial and temporal arrangement of inhibitory and growth-promoting molecules in relation to growth-associated protein 43-positive (GAP43+) neurons. Spontaneous cortical sprouting was maximal in pericontused regions at 7 and 14 days after injury but absent by 28 days. Perineuronal nets containing CSPGs were reduced at 7 days after injury in the pericontused region (p0.05), which was commensurate with a reduction in extracellular CSPGs. Sprouting was restricted to the perineuronal nets and CSPG-deficient regions at 7 days, indicating that the pericontused region is temporarily and spatially permissive to new growth. At this time point,GAP43+ neurons were associated with brain regions containing cells positive for polysialic acid neural cell adhesion molecule but not with fibronectin-positive cells. Brain-derived neurotrophic factor was reduced in the immediate pericontused region at 7 days. Along with prior Western blot evidence, these data suggest that a lowered intrinsic growth stimulus, together with a later return of growth-inhibitory CSPGs, may contribute to the ultimate disappearance of sprouting neurons after traumatic brain injury.

The maturation of brain oxidative capacity was studied in kittens, using cytochrome oxidase histochemistry, at different ages throughout development. Optical densitometry values of reacted tissue were obtained for 50 different structures of the brain. In general, most structures reached adult levels of oxidative capacity by 30 days of age with some motor areas (e.g., cerebellum, red nucleus) exhibiting adult values as early as 7 days of age. Thereafter, some structures (e.g., basal ganglia, thalamus) exhibited levels of cytochrome oxidase activity that exceeded adult values for varying periods of time. These findings indicate regional heterogeneity in the maturation of cerebral oxidative capacity. Furthermore, these maturational patterns appear to correlate well with previous observations from anatomical, physiological and neuro-behavioral studies.

Rats trained to traverse a narrow elevated beam were given a single intraperitoneal injection of either D-amphetamine, clonidine, L-phenylephrine, prazosin, yohimbine, or saline 24 h after ablation of the right sensorimotor cortex and tested for recovery of beam-walking (BW) ability to day 16 postsurgery. Clonidine, prazosin and L-phenylephrine did not significantly affect BW recovery. A 10 mg/kg dose of yohimbine significantly accelerated BW recovery, as did D-amphetamine (2 mg/kg). Since D-amphetamine and yohimbine both increase norepinephrine (NE) release and prior research has implicated NE but not dopamine in BW recovery, these data support the hypothesis that increased NE release benefits functional recovery in this model of cortical injury. However, a possible role of dopaminergic or serotonergic influences of D-amphetamine or yohimbine treatment cannot be ruled out. To investigate the role of the NE system in maintenance of recovery, animals recovered from BW deficits 18 days after injury were administered clonidine, prazosin, or yohimbine and retested on the BW task. Both the α1-NE antagonist prazosin (2 or 4 mg/kg) and the α2-NE agonist clonidine (0.1 or 0.4 mg/kg) produced a dose-dependent, transient worsening of BW performance. This reinstatement of deficits in recovered rats suggests that integrity of the α-NE system is necessary for maintaining functional recovery.

Traumatic brain injury (TBI) is associated with significant neurological deficits that in most cases do not completely resolve with time. Because axonal injury produced by shearing impact forces is a major hallmark of TBI (Adams et al., 1989), it seems likely that therapies directed toward enhancing axon repair and connectivity have the potential to improve functional outcomes after TBI. However, there is a large amount of literature that describes a significant axon growth inhibitory environment after central nervous system (CNS) lesions (Asher et al., 2000, 2002; Levine et al., 2001; Chen et al., 2003; Dobbertin et al., 2003; Sandvig et al., 2004; Silver and Miller, 2004; Dubreuil et al., 2006; Marklund et al., 2006; Thompson et al., 2006). This environment consists of increases in axon growth inhibitory extracellular matrix and myelin-associated molecules (growth-IMs) as well as increases in reactive astrocytes, microglia, and oligodendrocytes, all of which are associated with glial scar formation and can contribute to prevention of axon plasticity or synapse formation (Fawcett and Asher, 1999). Unfortunately, there has been little research to determine how the brain responds to TBI in terms of the glial scar and the local brain environment for growth inhibition. By addressing this gap in our knowledge, it should be possible to determine whether axon sprouting could underlie some spontaneous recovery of function after CNS injury, as some studies suggest (Castro-Alamancos and Borrell, 1995; Christman et al., 1997; Hulsebosch et al., 1998; Emery et al., 2000), and then proceed to determine whether this might be enhanced through therapeutic measures. The major growth-IMs so far identified consist of myelin-associated glycoprotein, oligodendrocyte myelin glycoprotein, chondroitin sulfate proteoglycans (CSPGs), and NOGO, and these growth-IMs are generally, but not always, up-regulated after CNS injury (Fawcett and Asher, 1999; Sandvig et al., 2004; Silver and Miller, 2004). The CSPGs are extracellular molecules composed of secreted and transmembrane forms. They have a central protein core attached to glycosaminoglycan side chains containing repeating dissacharide units. The members of the CSPG family, versican, neurocan, phosphacan, brevican, neurocan, and NG2, differ in the protein core and the number and length of sulfation of the side chains (Morgenstern et al., 2002), which confers binding properties and hence function (Properzi et al., 2003). CSPGs undergo proteolytic cleavage to create additional forms (Morgenstern et al., 2002), and most are normally expressed by astrocytes, although there is now good evidence that immature oligodendrocytes either produce and/or associate with neurocan, versican, and NG2 (Ong and Levine, 1999; Asher et al., 2000, 2002) and that neurons produce at least some species of aggrecan, brevican, and neurocan (Oohira et al., 1994; Lander et al., 1998; Seidenbecher et al., 2002). The CSPGs are present in normal brain, either within the extracellular space or aggregated as perineuronal nets that encase or surround neurons (Lander et al., 1998). They have been shown to be up-regulated after spinal cord injury (Lemons et al., 1999; Jones et al., 2003; Tang et al., 2003), stroke (Carmichael et al., 2005), hypoxic-ischemic injury (Aya-ay et al., 2005), or nigrostriatal lesion (Moon et al., 2002), and they are major inhibitory components of the resulting glial scar (Fawcett and Asher, 1999). A CSPG receptor site has not been identified, but Rho GTPase, which is increased after TBI (Dubreuil et al., 2006), appears to play a role (Jain et al., 2004) as does the epidermal growth factor receptor (Koprivica et al., 2005). The idea that all CSPGs are largely up-regulated after CNS injury and that they are all inhibitory to axon outgrowth is an oversimplification. Individual CSPGs have differential and even opposing effects on outgrowth, depending on the specific neuronal population and the developmental state of the neuron (Maeda and Noda, 1996). Previous reports suggest that the CSPG response to injury is quite heterogenous and may vary as a function of injury model or clinical disease state, temporal factors, or the specific species of growth-IMs (Levine, 1994; Jaworski et al., 1999; Asher et al., 2000, 2002; Lemons et al., 2001; Garwood et al., 2003; Dobbertin et al., 2003; Okamoto et al., 2003; Miyata et al., 2004). Although on the face of it one might anticipate similar pathophysiology after TBI and other CNS injuries such as stroke, the initial insult very clearly differs between these two injuries, especially with regard to the mechanism of primary axonal damage (Bramlett and Dietrich, 2004). Differences might therefore be expected in the temporal and/or spatial expression of molecules that affect axonal repair as a function of injury model. We reasoned that a study designed to investigate CSPGs associated with the glial scar after TBI would be an important first step for future efforts to design therapies that might enhance axon repair and functional outcome following TBI. The current study was designed to determine temporal changes in mRNA and protein expression levels of the CSPGs aggrecan, phosphacan, versican, and neurocan and to determine their regional localization and cellular association by using immunohistochemistry, in a controlled cortical impact (CCI) model of mild-to-moderate TBI.

We investigated whether a learning impairment after a controlled cortical impact (CCI) injury was associated with alterations in molecules involved in synaptic plasticity and learning and memory. Adult male rats with moderate CCI to the left parietal cortex, tested in a Morris water maze (MWM) beginning at postinjury day 10, showed impaired cognitive performance compared with sham-treated rats. Tissue was extracted for mRNA analysis on postinjury day 21. The expression of brain-derived neurotrophic factor (BDNF), synapsin I, cyclic-AMP response element binding protein (CREB), and calcium-calmodulin-dependent protein kinase II (alpha-CAMKII) were all significantly decreased compared with sham injury levels within the ipsilateral hippocampus after CCI. No significant molecular level changes were found in the contralateral hippocampus. Decreased expression of BDNF and synapsin I was also found within the ipsilateral parietal cortex of CCI-injured rats compared with shams. However, BDNF and synapsin I expressions were significantly increased in the contralateral parietal cortex of the CCI rats. CREB expression was significantly decreased within the contralateral cortex of the CCI group. These findings show enduring reductions in the expression of BDNF, synapsin I, CREB, and alpha-CAMKII ipsilateral to a CCI injury, which seem associated with the spatial learning deficits observed in this injury model. In addition, the delayed increase in the expression of BDNF and synapsin I within the cortex contralateral to CCI may reflect restorative processes in areas homotypical to the injury.

Although tremendous effort and finances were spent in developing small animal PET scanners, this technology remains under utilized as a research tool to study disease states. To advance this goal, we previously developed a microfluidic blood sampling device to overcome the problem of blood sampling and fluid volume loss when performing quantitative PET studies. The device was previously shown to be reliable for deriving input function without changing the physiological stability of a mouse. In this study, we improved methodologies and optimized the animal surgical preparation necessary for prolonging the patency of chronic indwelling catheters. We have also added several features to improve functionality and ease of use for a new prototype of a microfluidic blood sampler and tested this device for accuracy in determining FDG blood curves in rats with a chronic indwelling catheter. We modified the hardware and software of the previous blood sampling device to reduce the cost and provide a more user-friendly interface. We successfully prepared the animal for deriving input functions for multiple microPET studies. Our results suggest that longitudinal microPET imaging in the same animal is possible. These new developments should increase the use of PET imaging in drug development and translational research using small animals.

Secondary ischemia (SI) following traumatic brain injury (TBI) increases damage to the brain in both animals and humans. The current study determined if SI after TBI alters the extent or duration of reduced energy production within the first 24 h post-injury and hippocampal cell loss at one week post-injury. Adult male rats were subjected to sham injury, lateral (LFPI) or central fluid percussion injury (CFPI) only, or to combined LFPI or CFPI with SI. The SI was 8 min of bilateral forebrain ischemia combined with hemorrhagic hypotension, applied at 1 h following FPI. After LFPI alone adenosine triphosphate (ATP) levels within the ipsilateral CA1 were reduced at 2 h (p

Traumatic brain injury (TBI) continues to be one of the leading causes of mortality and morbidity, with approximately 5.3 million Americans suffering from enduring disabilities resulting from TBI (Binder et al., 2005). Despite many experimental and clinical efforts using numerous therapeutic approaches, there are currently no proven treatments to alleviate the sequelae of TBI or to enhance recovery of function. Our laboratories have been investigating treatment strategies that may facilitate endogenous repair mechanisms and enhance functional recovery after experimental TBI in the rat. One approach has been to use spontaneous or voluntary exercise, obtained via running wheel (RW) exposure. Exercise is known to increase key molecules involved in neuroplasticity, such as brain-derived neurotrophic factor (BDNF) and synapsin I (Neeper et al., 1995; van Praag et al., 1999; Cotman and Berchtold, 2002), as well as reduce markers of oxidative stress (Navarro et al., 2004; Wu et al., 2004; Pan et al., 2007). While experimental TBI can acutely decrease expression of BDNF mRNA within the hippocampus (Hellmich et al., 2005), most studies have reported hippocampal increases in BDNF mRNA within the first 24 h following TBI (Oyesiku et al., 1999; Truettner et al., 1999; Morrison et al., 2000). At later post-injury times, neither hippocampal BDNF mRNA (Hicks et al., 2002) nor BDNF protein differs from that of controls (Griesbach et al., 2004b, 2007; Chen et al., 2005). However, spontaneous exercise in rats with TBI can increase the expression and/or levels of BDNF and synapsin I within the hippocampus (Hicks et al., 1998; Griesbach et al., 2004b, 2007), and this effect is associated with an improvement in cognitive performance (Griesbach et al., 2004b). The timing of this post-injury exercise has been shown to play an important role after experimental fluid percussion injury (FPI) to the brain. We previously reported that voluntary exercise during the first week after sham injury increased hippocampal BDNF and synapsin I protein, but exercise did not increase these molecules after a FPI (Griesbach et al., 2004a, 2007). The mechanisms underlying the inability of acute exercise to up-regulate BDNF after TBI are not known, but may be related to alterations in neurotransmitter systems during this acute period following injury. Transmitter depletion studies have shown that norepinephrine (NE) is necessary for voluntary wheel-running to up-regulate BDNF mRNA in the hippocampus (Garcia et al., 2003). Anti-depressant drugs, which increase synaptic levels of NE and 5-HT, have been reported to increase levels of hippocampal BDNF mRNA (Nibuya et al., 1995) and protein (Peng et al., 2008; Kozisek et al., 2008). In addition, anti-depressant drugs strengthen BDNF mRNA up-regulation when given in combination with exercise (Russo-Neustadt et al., 1999, 2000). Repeated treatments with d-amphetamine (AMPH) have also been reported to increase BDNF levels in multiple brain regions (Meredith et al., 2002). Brain injury induced by experimental stroke or cortical ablation reduces brain levels and/or turnover rates of NE, dopamine (DA) and/or 5-HT for days or weeks after injury (Feeney and Sutton, 1987). Experimental TBI in the rat produces early and widespread reductions in brain NE levels and turnover (Dunn-Meynell et al., 1994; Krobert et al., 1994; Levin et al., 1995). Hence, although exercise in non-injured rats is known to increase NE release (Dunn et al., 1996; Dishman et al., 2000; Garcia et al., 2003), a TBI-induced reduction of NE could conceivably prevent exercise-dependent increases in NE and BDNF during the acute period after injury. Another approach for the treatment of TBI has been to administer treatments that increase central levels of monoamines. Single or multiple treatments with AMPH have been frequently reported to accelerate functional recovery in various brain injury models (Feeney and Sutton, 1988; Sutton and Feeney, 1994), including cortical contusion (Sutton et al., 1987) or FPI (Prasad et al., 1994; Hovda, 1996). While AMPH increases levels of all the mono-amines (Fleckenstein et al., 2007), the beneficial effects of post-injury AMPH treatment appear to be mediated by NE release since intraventricular NE, but not DA (Boyeson and Feeney, 1990) or 5-HT (Boyeson et al., 1994), mimics the AMPH induced recovery of function in ablation models. In addition, drugs causing central NE release induce recovery similar to AMPH (Sutton and Feeney, 1992; Goldstein, 1993), and drugs that interfere with NE release or synaptic transmission can retard recovery or reinstate deficits in recovered animals (Feeney and Westerberg, 1990; Goldstein and Davis, 1990; Dunn-Meynell et al., 1997). In addition to AMPH, multiple treatments with methylphenidate (Kline et al., 2000), a D2 receptor agonist (Kline et al., 2002) or a 5- HT(1A) receptor agonist (Kline et al., 2004) are reported to improve outcome after experimental TBI. More recently, chronic intermittent vagus nerve stimulation, which increases NE release (Roosevelt et al., 2006) and BDNF mRNA levels (Follesa et al., 2007) in cortex and hippocampus, has been shown to improve outcome after experimental TBI (Smith et al., 2005, 2006; Clough et al., 2007). Given these preceding reports on the effects of TBI and the apparent links between AMPH, NE, exercise and BDNF, the current study was designed to determine if AMPH administration during the acute period after TBI would enable or facilitate spontaneous exercise-induced increases of hippocampal BDNF and synapsin I. Because oxidative stress plays an important role in neuronal injury after TBI (Shohami et al., 1997; Sullivan et al., 1998; Hall et al., 2004), we also determined if these treatments would alter oxidative stress after TBI. We employed the controlled cortical impact (CCI) model of TBI for this study, as this injury model is known to produce molecular changes and cellular damage in the hippocampus (Dash et al., 1995; Colicos et al., 1996; Oyesiku et al., 1999; McCullers et al., 2002; Saatman et al., 2006), induce hippocampal-dependent learning deficits (Hamm et al., 1992; Lindner et al., 1998; Dixon et al., 1999), and to reduce brain NE levels and turnover (Dunn-Meynell et al., 1994; Levin et al., 1995). While increased expression or production of hippocampal BDNF and synapsin I has been reported to occur after exercise in both intact rats and in rats with FPI (Timmusk et al., 1993; Neeper et al., 1996; Molteni et al., 2002; Griesbach et al., 2004b, 2007), exercise-induced effects of these markers of plasticity have not yet been evaluated in the CCI model. Based on prior studies we hypothesized that: 1) acute exercise after CCI would have detrimental or neutral effects on outcome measures, 2) low-dose AMPH treatment would improve these outcome measures, and 3) AMPH treatment combined with RW exposure would enable acute exercise to up-regulate BDNF and synapsin I and reduce oxidative stress.

The present study determined the metabolic fate of [1, 2 13C2] glucose in male control rats and in rats with moderate lateral fluid percussion injured (FPI) at 3.5 h and 24 h post-surgery. After a 3-h infusion, the amount of 13C-labeled glucose increased bilaterally (26% in left/injured cerebral cortex and 45% in right cerebral cortex) at 3.5 h after FPI and in injured cortex (45%) at 24 h after injury, indicating an accumulation of unmetabolised glucose not seen in controls. No evidence of an increase in anaerobic glycolysis above control levels was found after FPI, as 13C-labeled lactate tended to decrease at both time points and was significantly reduced (33%) in the injured cortex at 24 h post-FPI. A bilateral decrease in the 13C-labeling of both glutamate and glutamine was observed in the FPI rats at 3.5 h and the glutamine pool remained significantly decreased in the injured cortex at 24 h, suggesting reduced oxidative metabolism in both neuronal and astrocyte compartments after injury. The percentage of glucose metabolism through the pentose phosphate pathway (PPP) increased in the injured (13%) and contralateral (11%) cortex at 3.5 h post-FPI and in the injured cortex (9%) at 24 h post-injury. Based upon the changes in metabolite pools, our results show an injury-induced decrease in glucose utilization and oxidation within the first 24 h after FPI. Increased metabolism through the PPP would result in increased NADPH synthesis, suggesting a need for reducing equivalents after FPI to help restore the intracellular redox state and/or in response to free radical stress.

FDG-PET imaging was performed in rats using a small animal PET scanner. The purpose was to improve the accuracy and precision of quantitative rat brain PET imaging and make longitudinal studies feasible. We evaluated bed position(s), scan time, movement correction, image reconstruction algorithms, input function (IF) derivation and methods for quantification of cerebral metabolic rate of glucose (CMRG, mumol/min/100g). The optimum protocol includes: (1) acquisition of PET data in two-bed positions: 0-45 minutes centered at the heart for determination of IF and 45-65 minutes centered at the brain; (2) minimization of head movements with a restraining device; (3) a single tail vein blood sample to increase accuracy of the image-derived IF; (4) application of FBP reconstruction to the heart data and both FBP and MAP reconstructions to the brain data and (5) application of a CT-based attenuation correction. We generated CMRG parametric images by applying the Sokoloff's operational equation to the FBP brain images. The IF required by the operational equation was derived from the FBP heart images using a modified factor analysis program. Regions of brain were drawn on the MAP-reconstructed 'anatomical images' and superimposed on the parametric images to yield mean CMRG values. CMRG values were comparable to those from a FDG 3-compartmental model fit to the time activity curves of the brain regions.

The spectrum of pathobiological events occurring with traumatic brain injury (TBI) can be extremely diverse and heterogeneous in nature, reflecting not only the mechanism(s), location, and severity of the initial or primary damage but also the progression of reactive events that contribute to delayed, or secondary damage. Over the last five decades a variety of rodent models of TBI have been developed in attempts to mimic the clinical features of closed head injury. Given the diverse causes and biomechanical forces that contribute to the heterogeneity of human TBI, it is not realistic to expect that any single rodent model can fully replicate the spectrum of pathobiological events that contribute to morbidity and mortality in humans. This chapter reviews some of the objectives, applications, experimental findings, and limitations of some rat models of TBI currently in use. In this overview the models discussed include those that are generally categorized as rigid indentation or direct brain deformation (i.e., a percussion concussion injury induced after a craniectomy), most of which have been developed within the past decade. For overviews of TBI model developments in numerous animal species, including fluid percussion and impact acceleration (closed head injury) models of TBI in rodents, the readers are referred to previous reviews (1–8). Readers interested in penetrating or missile injury models of brain injury are referred to a recent review by Torbati (9).

Cognitive deficits are the most enduring and disabling sequelae of human traumatic brain injury (TBI), but quantifying the magnitude, duration, and pattern of cognitive deficits produced by different types of TBI has received little emphasis in preclinical animal models. The objective of the present study was to use a battery of behavioral tests to determine if different impact sites produce different patterns of behavioral deficits and to determine how long behavioral deficits can be detected after TBI. Prior to surgery, rats were trained to criteria on delayed nonmatching to position, radial arm maze, and rotarod tasks. Rats received sham surgery (controls), midline frontal contusions (frontal TBI, 2.25 m/sec impact), or unilateral sensorimotor cortex contusions (lateral TBI, 3.22 m/sec impact) at 12 months of age and were tested throughout the next 12 months. Cognitive deficits were more robust and more enduring than sensorimotor deficits for both lateral TBI and frontal TBI groups. Lateral TBI rats exhibited transient deficits in the forelimb placing and in the rotarod test of motor/ambulatory function, but cognitive deficits were apparent throughout the 12-month postsurgery period on tests of spatial learning and memory including: (1)reacquisition of a working memory version of the radial arm maze 6-7 months post-TBI, (2) performance in water maze probe trials 8 months post-TBI, and (3) repeated acquisition of the Morris water maze 8 and 11 months post-TBI. Frontal TBI rats exhibited a different pattern of deficits, with the most robust deficits in tests of attention/orientation such as: (1) the delayed nonmatching to position task (even with no delays) 1-11 weeks post-TBI, (2) the repeated acquisition version of the water maze--especially on the first "information" trial 8 months post-TBI, (3) a test of sensorimotor neglect or inattention 8.5 months post-TBI, and (4) a DRL20 test of timing and/or sustained attention 11 months after surgery. These results suggest that long-term behavioral deficits can be detected in rodent models of TBI, that cognitive deficits seem to be more robust than sensorimotor deficits, and that different TBI impact sites produce dissociable patterns of cognitive deficits in rats.

Rats with contusion injury to the right cortex exhibited significant formation of edema 6 and 24 hours after injury which resolved by 8 days and was replaced by cavitation necrosis. The contusions produced hyperglycolysis and ischemia in the impacted cortical tissue and underlying hippocampus immediately through 30 minutes post-injury. Glucose utilization was depressed throughout the contused cortex and in ipsilateral subcortical regions, as was blood flow, at chronic (1 and 10 days) periods after injury.

Violence has been recognized as a significant health problem. This study describes fatal and nonfatal interpersonal violence-related injury events over 1 year in an indigent African-American community in Philadelphia. Information on injuries was collected from emergency rooms, the Office of the Medical Examiner, and death certificate files. For persons aged 15 through 49 years, violence-related injury rates surpassed any other injury type. The overall violence-related injury rate was 28.7 per thousand population. Interpersonal violence-related injuries were important for the 0- to 4-year age group (9.19 injuries per 1000 population), and continued as a major cause of morbidity through age 59 (12.08 injuries per 1000 population). For more than half of the events, information from the emergency room chart was sufficient only to categorize the incident as a "fight" or that it was intentional; no further classification was possible.

After thermal cauterization of the area postrema in rats the absence of conditioned taste aversion to sucrose paired with lithium chloride (0.15 M, 3.3 ml/kg) was used as a pharmacologic/behavioral index of area postrema damage. In a subsequent experiment the effects of area postrema lesions on three measures proposed as species-relevant measures of motion sickness were studied, using off-vertical rotation at 150 degrees/s for either 30 or 90 min. Lesions of area postrema did not alter postrotational suppression of drinking or amount of defecation during motion. The initial acquisition of conditioned taste aversion to a novel cider vinegar solution paired with motion was not affected by lesioning of the area postrema, but these taste aversions extinguished more slowly in lesioned rats than in sham-operates or intact controls. Results are discussed in terms of proposed humoral factors which may induce motion sickness and in light of recent data on the role of the area postrema in similar measures in species possessing the complete emetic reflex.

The effect of seizures on recovery of motor function was studied in rats following unilateral contusion of the sensorimotor cortex. Animals receiving two electroconvulsive seizures (ECSs) within the first 24 hours postcontusion showed accelerated recovery of beam-walking ability, reduced volume of necrosis and less spontaneous activity compared to animals receiving only contusions. Animals receiving seven ECSs after contusion had an even smaller volume of necrosis and also reduced spontaneous activity compared to the two ECS group and to controls receiving contusions alone. However, for recovery of beam-walking ability, the seven ECS group did not differ from control rats receiving only contusions. The results are discussed in terms of the effects of seizures on catcholamines, gamma-amino butyric acid, cerebral blood flow and possible effects on remote functional depression after brain injury.

Corticorubral (CR) connections are reorganized after the red nucleus is deafferented by neonatal hemispherectomy. Our objective was to determine if the new decussating CR axons establish synaptic junctions with their target neurons. The ultrastructure of CR axonal terminal arbors was identified by the anterograde transport and histochemical labeling of wheat germ agglutinin lectin-bound horseradish peroxidase injected unilaterally into the pericruciate neocortex of adult cats that received unilateral neonatal hemispherectomy (HEMI cases) and normal adult cats (control cases). The regional organization of undecussated and decussated CR arbors was nearly equivalent in the HEMI cases. The fine structure of both connections was uniform. Asymmetrical synaptic junctions were observed in frequent axodendritic and infrequent axosomatic boutons en passage and boutons terminaux. The undecussated arbors formed the principal connection in the control cases. However, the fine structures of the decussated and undecussated arbors were comparable and matched the arrangements in the HEMI cases. We conclude that developmental deafferentation redirects CR axons to provide stable synaptic afferents to new targets. The reinnervation is homotypical in terms of regional and fine structure organization. It is likely to be an important factor in chemically mediated neurotransmission that contributes to the sparing/recovery of function after brain damage.