Effects of acute restraint-induced stress on glucocorticoid receptors and brain-derived neurotrophic factor after mild traumatic brain injury.

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.

Heightening of the stress response during the first weeks after a mild traumatic brain injury.

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.

Repeat traumatic brain injury in the juvenile rat is associated with increased axonal injury and cognitive impairments.

Among the enormous population of head-injured children and young adults are a growing subpopulation who experience repeat traumatic brain injury (RTBI). The most common cause of RTBI in this age group is sports-related concussions, and athletes who have experienced a head injury are at greater risk for subsequent TBI, with consequent long-term cognitive dysfunction. While several animal models have been proposed to study RTBI, they have been shown to either produce injuries too severe, were conducted in adults, involved craniotomy, or failed to show behavioral deficits. A closed head injury model for postnatal day 35 rats was established, and single and repeat TBI (1-day interval) were examined histologically for axonal injury and behaviorally by the novel object recognition (NOR) task. The results from the current study demonstrate that an experimental closed head injury in the rodent with low mortality rates and absence of gross pathology can produce measurable cognitive deficits in a juvenile age group. The introduction of a second injury 24 h after the first impact resulted in increased axonal injury, astrocytic reactivity and increased memory impairment in the NOR task. The histological evidence demonstrates the potential usefulness of this RTBI model for studying the impact and time course of RTBI as it relates to the pediatric and young adult population. This study marks the first critical step in experimentally addressing the consequences of concussions and the cumulative effects of RTBI in the developing brain.

Acute neuroprotection to pilocarpine-induced seizures is not sustained after traumatic brain injury in the developing rat.

Following CNS injury there is a period of vulnerability when cells will not easily tolerate a secondary insult. However recent studies have shown that following traumatic brain injury (TBI), as well as hypoxic-ischemic injuries, the CNS may experience a period of protection termed "preconditioning." While there is literature characterizing the properties of vulnerability and preconditioning in the adult rodent, there is an absence of comparable literature in the developing rat. To determine if there is a window of vulnerability in the developing rat, post-natal day 19 animals were subjected to a severe lateral fluid percussion injury followed by pilocarpine (Pc)-induced status epilepticus at 1, 6 or 24 h post TBI. During the first 24 h after TBI, the dorsal hippocampus exhibited less status epilepticus-induced cell death than that normally seen following Pc administration alone. Instead of producing a state of hippocampal vulnerability to activation, TBI produced a state of neuroprotection. However, in a second group of animals evaluated 20 weeks post injury, double-injured animals were statistically indistinguishable in terms of seizure threshold, mossy fiber sprouting and cell survival when compared to those treated with Pc alone. TBI, therefore, produced a temporary state of neuroprotection from seizure-induced cell death in the developing rat; however, this ultimately conferred no long-term protection from altered hippocampal circuit rearrangements, enhanced excitability or later convulsive seizures.

Traumatic brain injury results in disparate regions of chondroitin sulfate proteoglycan expression that are temporally limited.

Axonal injury is a major hallmark of traumatic brain injury (TBI), and it seems likely that therapies directed toward enhancing axon repair could potentially improve functional outcomes. One potential target is chondroitin sulfate proteoglycans (CSPGs), which are major axon growth inhibitory molecules that are generally, but not always, up-regulated after central nervous system injury. The current study was designed to determine temporal changes in cerebral cortical mRNA or protein expression levels of CSPGs and to determine their regional localization and cellular association by using immunohistochemistry in a controlled cortical impact model of TBI. The results showed significant increases in versican mRNA at 4 and 14 days after TBI but no change in neurocan, aggrecan, or phosphacan. Semiquantitative Western blot (WB) analysis of cortical CSPG protein expression revealed a significant ipsilateral decrease of all CSPGs at 1 day after TBI. Lower CSPG protein levels were sustained until at least 14 days, after which the levels began to normalize. Immunohistochemistry data confirm previous reports of regional increases in CSPG proteins after CNS injury, seen primarily within the developing glial scar after TBI, but also corroborate the WB data by revealing wide areas of pericontusional tissue that are deficient in both extracellular and perineuronal net-associated CSPGs. Given the evidence that CSPGs are largely inhibitory to axonal growth, we interpret these data to indicate a potential for regional spontaneous plasticity after TBI. If this were the case, the gradual normalization of CSPG proteins over time postinjury would suggest that this may be temporally as well as regionally limited.

Voluntary exercise or amphetamine treatment, but not the combination, increases hippocampal brain-derived neurotrophic factor and synapsin I following cortical contusion injury in rats.

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.

Essential protective roles of reactive astrocytes in traumatic brain injury.

Astrocytes respond to traumatic brain injury (TBI) by altered gene expression, hypertrophy and proliferation that occur in a gradated fashion in relation to the severity of the injury. Both beneficial and detrimental effects have been attributed to reactive astrocytes, but their roles after brain injury are not well understood. To investigate these roles, we determined the effects on cortical tissue of ablating reactive astrocytes after contusion injury generated by controlled cortical impact (CCI) of different severities in transgenic mice that express a glial fibrillary acidic protein-herpes simplex virus-thymidine kinase transgene. Treatment of these mice with the antiviral agent, ganciclovir, conditionally ablates proliferating reactive astrocytes. Moderate or severe CCI were generated with a precisely regulated pneumatic piston, and forebrain tissue was evaluated using immunohistochemistry and quantitative morphometry. Moderate CCI in control mice triggered extensive and persisting reactive astrogliosis, with most neurons being preserved, little inflammation and an 18% loss of cortical tissue beneath the impact site. Ablation of reactive astrocytes after moderate CCI in transgenic mice caused substantial neuronal degeneration and inflammation, with a significantly greater 60% loss of cortical tissue. Severe CCI in control mice caused pronounced neuronal degeneration and loss of about 88% of cortical tissue that was not significantly altered by ablating reactive astrocytes in transgenic mice. Thus, ablation of dividing reactive astrocytes exacerbated cortical degeneration after moderate CCI, but did not alter cortical degeneration after severe CCI. These findings indicate that the reactive astrocytes play essential roles in preserving neural tissue and restricting inflammation after moderate focal brain injury.

Age-dependent reduction of cortical contusion volume by ketones after traumatic brain injury.

Although the adult brain primarily metabolizes glucose, the evidence from the starvation literature has demonstrated that the adult brain retains some potential to revert to ketone metabolism. This attribute has been exploited recently to shift the adult brain toward ketone metabolism after traumatic brain injury (TBI), resulting in increased cerebral uptake and oxidation of exogenously administered ketones and improved cerebral energy. The ability to utilize ketones as an alternative substrate decreases with cerebral maturation, suggesting that the younger brain has a greater ability to metabolize this substrate and may be more receptive to this therapy. It was hypothesized that the administration of ketones after TBI in the developing brain will decrease lesion size in an age-dependent manner. Postnatal day (PND) 17, 35, 45, and 65 rats were placed on either a standard or ketogenic (KG) diet after controlled cortical impact (CCI) injury. PND35 and PND45 KG-fed animals showed a 58% and 39% reduction in cortical contusion volume, respectively, at 7 days post-injury. The KG diet had no effect on contusion volume in PND17 and PND65 injured rats. Both PND35 and PND45 KG-fed groups revealed fewer Fluoro-Jade-positive cells in the cortex and hippocampus at 6 hr and showed earlier decreases in plasma lactate compared to standard-fed animals. The age-dependent ketogenic neuroprotection is likely related to age-related differences in cerebral metabolism of ketones and suggests that alternative substrate therapy has potential applications for younger head-injured patients.

Injury-induced alterations in N-methyl-D-aspartate receptor subunit composition contribute to prolonged 45calcium accumulation following lateral fluid percussion.

Cells that survive traumatic brain injury are exposed to changes in their neurochemical environment. One of these changes is a prolonged (48 h) uptake of calcium which, by itself, is not lethal. The N-methyl-D-aspartate receptor (NMDAR) is responsible for the acute membrane flux of calcium following trauma; however, it is unclear if it is involved in a flux lasting 2 days. We proposed that traumatic brain injury induced a molecular change in the NMDAR by modifying the concentrations of its corresponding subunits (NR1 and NR2). Changing these subunits could result in a receptor being more sensitive to glutamate and prolong its opening, thereby exposing cells to a sustained flux of calcium. To test this hypothesis, adult rats were subjected to a lateral fluid percussion brain injury and the NR1, NR2A and NR2B subunits measured within different regions. Although little change was seen in NR1, both NR2 subunits decreased nearly 50% compared with controls, particularly within the ipsilateral cerebral cortex. This decrease was sustained for 4 days with levels returning to control values by 2 weeks. However, this decrease was not the same for both subunits, resulting in a decrease (over 30%) in the NR2A:NR2B ratio indicating that the NMDAR had temporarily become more sensitive to glutamate and would remain open longer once activated. Combining these regional and temporal findings with 45calcium autoradiographic studies revealed that the degree of change in the subunit ratio corresponded to the extent of calcium accumulation. Finally, utilizing a combination of NMDAR and NR2B-specific antagonists it was determined that as much at 85% of the long term NMDAR-mediated calcium flux occurs through receptors whose subunits favor the NR2B subunit. These data indicate that TBI induces molecular changes within the NMDAR, contributing to the cells' post-injury vulnerability to glutamatergic stimulation.

Increased cerebral uptake and oxidation of exogenous betaHB improves ATP following traumatic brain injury in adult rats.

There is growing evidence of the brain's ability to increase its reliance on alternative metabolic substrates under conditions of energy stress such as starvation, hypoxia and ischemia. We hypothesized that following traumatic brain injury (TBI), which results in immediate changes in energy metabolism, the adult brain increases uptake and oxidation of the alternative substrate beta-hydroxybutyrate (betaHB). Arterio-venous differences were used to determine global cerebral uptake of betaHB and production of 14CO2 from [14C]3-betaHB 3 h after controlled cortical impact (CCI) injury. Quantitative bioluminescence was used to assess regional changes in ATP concentration. As expected, adult sham and CCI animals with only endogenously available betaHB showed no significant increase in cerebral uptake of betaHB or 14CO2 production. Increasing arterial betaHB concentrations 2.9-fold with 3 h of betaHB infusion failed to increase cerebral uptake of betaHB or 14CO2 production in adult sham animals. Only CCI animals that received a 3-h betaHB infusion showed an 8.5-fold increase in cerebral uptake of betaHB and greater than 10.7-fold increase in 14CO2 production relative to sham betaHB-infused animals. The TBI-induced 20% decrease in ipsilateral cortical ATP concentration was alleviated by 3 h of betaHB infusion beginning immediately after CCI injury.

Voluntary exercise following traumatic brain injury: brain-derived neurotrophic factor upregulation and recovery of function.

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.

PET investigation of post-traumatic cerebral blood volume and blood flow.

Hemodynamic changes following traumatic brain injury (TBI) may reflect cellular damage leading to secondary injury. The purpose of this study was to investigate the regional hemodynamic parameters acutely after TBI among regions in and around contusions. Sixteen patients (11 male, 5 female) showing evidence of contusion on CT and 18 normal volunteers (12 male, 6 female) underwent positron emission tomography (PET) with O-15 CO and O-15 H2O to estimate cerebral blood volume (CBV) and cerebral blood flow (CBF), respectively. A flow to volume ratio (FVR = CBF/CBV) was also calculated as an index of vasodilatation. The hemodynamic parameters were compared among contusion, pericontusion, and remote areas. Globally, hemodynamic parameters did not differ between patients and normal volunteers, and did not correlate with intracranial pressure (ICP). Regionally, contusional and pericontusional areas showed significantly lower CBF and FVR compared with normal volunteers, while CBV did not differ significantly. The correlation between CBF and CBV was significant (r = 0.37, p < 0.01). Remote areas did not show a significant difference in any of the PET parameters. In conclusion, regional brain edema is likely to occur in contusion and pericontusion areas, while some of the contusional tissue may show vascular engorgement.

Delayed increase in extracellular glycerol with post-traumatic electrographic epileptic activity: support for the theory that seizures induce secondary injury.

Early post-traumatic seizures occur commonly and may have adverse clinical consequences. In order to determine the significance of post-traumatic seizures, we performed a prospective assessment of the consequences of epileptic activity by assessing the change in extracellular glycerol levels. Glycerol is a marker of cellular membrane breakdown. Thirteen patients underwent combined electroencephalography (EEG) and cerebral microdialysis monitoring. Two patients had seizures on EEG with associated delayed elevations of glycerol associated with the seizure activity. Higher mean levels of glycerol were present in those patients with seizures compared to those without seizures (p < 0.001). Preliminary evidence suggests that post-traumatic seizures lead to additional membrane injury as reflected by elevated extracellular glycerol levels.

alpha-Phenyl-tert-N-butyl nitrone (PBN) improves functional and morphological outcome after cortical contusion injury in the rat.

alpha-Phenyl-tert-N-butyl nitrone (PBN), a potent reactive oxygen species (ROS) scavenger, has shown robust neuroprotective properties in several models of acute brain injury, although not previously evaluated in traumatic brain injury (TBI). In this study, we assessed the potential efficacy of PBN in a weight drop model producing a controlled cortical contusion. Sham operation, mild or severe injury was induced in intubated and ventilated rats and functional and morphological outcome was used as end-points at two weeks post-injury. In the trauma groups, saline or PBN (30 mg/kg) was injected as an intravenous bolus 30 minutes prior to injury. At day 11-15 post-injury, cognitive disturbance was assessed using the Morris Water Maze (MWM) and estimation of lesion volume and hemispheric loss of tissue was made. No change in MWM performance were found in either of the mildly traumatized groups as compared to uninjured controls. In contrast, a significant decrease in total mean latency and increase in path length in the severely traumatized rats were found. PBN-treatment significantly improved MWM performance as compared to saline treatment at the severe injury level (p < 0.05). The mild injury level caused a discrete atrophy of the ipsilateral cortex with no effect of PBN treatment. The severe injury caused a substantial loss of ipsilateral hemispheric tissue and a large cortical cavitation. PBN pre-treatment significantly reduced the lesion volume and reduced hemispheric loss of tissue at this injury level (p < 0.05). Our results support the involvement of ROS in the injury process contributing to the tissue loss and cognitive disturbance after TBI. The potential clinical utility of PBN will have to be assessed using a post-injury dosing regime.

Age-dependency of 45calcium accumulation following lateral fluid percussion: acute and delayed patterns.

This study was designed to determine the regional and temporal profile of 45calcium (45Ca2+) accumulation following mild lateral fluid percussion (LFP) injury and how this profile differs when traumatic brain injury occurs early in life. Thirty-six postnatal day (P) 17, thirty-four P28, and 17 adult rats were subjected to a mild (approximately 2.75 atm) LFP or sham injury and processed for 45Ca2+ autoradiography immediately, 6 h, and 1, 2, 4, 7, and 14 days after injury. Optical densities were measured bilaterally within 16 regions of interest. 45Ca2+ accumulation was evident diffusely within the ipsilateral cerebral cortex immediately after injury (18-64% increase) in all ages, returning to sham levels by 2-4 days in P17s, 1 day in P28s, and 4 days in adults. While P17s showed no further 45Ca2+ accumulation, P28 and adult rats showed an additional delayed, focal accumulation in the ipsilateral thalamus beginning 2-4 days postinjury (12-49% increase) and progressing out to 14 days (26-64% increase). Histological analysis of cresyl violet-stained, fresh frozen tissue indicated little evidence of neuronal loss acutely (in all ages), but considerable delayed cell death in the ipsilateral thalamus of the P28 and adult animals. These data suggest that two temporal patterns of 45Ca2+ accumulation exist following LFP: acute, diffuse calcium flux associated with the injury-induced ionic cascade and blood brain barrier breakdown and delayed, focal calcium accumulation associated with secondary cell death. The age-dependency of posttraumatic 45Ca2+ accumulation may be attributed to differential biomechanical consequences of the LFP injury and/or the presence or lack of secondary cell death.

Metabolic recovery following human traumatic brain injury based on FDG-PET: time course and relationship to neurological disability.

OBJECTIVE: Utilizing [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET), we assessed the temporal pattern and the correlation of functional and metabolic recovery following human traumatic brain injury. DESIGN AND SUBJECTS: Fifty-four patients with injury severity ranging from mild to severe were studied. Thirteen of these patients underwent both an acute and delayed FDG-PET study. RESULTS: Analysis of the pooled global cerebral metabolic rate of glucose (CMRglc) values revealed that the intermediate metabolic reduction phase begins to resolve approximately one month following injury, regardless of injury severity. The correlation, in the 13 patients studied twice, between the extent of change in neurologic disability, assessed by the Disability Rating Scale (DRS), and the change in CMRglc from the early to late period was modest (r = -0.42). Potential explanations for this rather poor correlation are discussed. A review of the pertinent literature regarding the use of PET and related imaging modalities, including single photon emission tomography (SPECT) for the assessment of patients following traumatic brain injury is given. CONCLUSION: The dynamic profile of CMRglc that changes following traumatic brain injury is seemingly stereotypic across a broad range and severity of injury types. Quantitative FDG-PET cannot be used as a surrogate technique for estimating degree of global functional recovery following traumatic brain injury.

Mapping cerebral glucose metabolism during spatial learning: interactions of development and traumatic brain injury.

Previous studies have demonstrated that, compared to adults, postnatal day 17 (P17) and P28 rats show remarkable cognitive recovery in the Morris water maze (MWM) following fluid percussion injury (FPI). This observed age-at-trauma effect could result from either younger animals solving the MWM task using noninjured neural circuitry or an inability of adult and P28 brains to activate appropriate neural networks due to trauma-induced neurological dysfunction. To address these possibilities, we compared "activated" brain regions during normal MWM acquisition and following FP injury. To generate "activated" images of the brain while animals were performing the MWM task, qualitative [14C]2-deoxy-D-glucose was conducted on days 2, 5, and 14 during training in sham and injured adult, P28, and P17 rats. When maturational changes in cerebral glucose metabolism are taken into account, the results suggests similar activity changes in the cerebral cortex and lacunosum moleculare of CA1 during acquisition in all age groups, suggesting that the developmental rates of MWM learning do not correspond to different patterns of activated cerebral metabolism. Injured P17s, showing no latency deficits, revealed activated cerebral metabolic patterns similar to noninjured P17 animals. In P28 and adult cases, animals exhibited cognitive deficits and their metabolic studies indicated that the cortical-hippocampal pattern of activation was disrupted by marked injury-induced metabolic depression, which primarily affected the ipsilateral hemisphere and lasted for as long as 14 days in adult animals.

Quantitative assessment of longitudinal metabolic changes in vivo after traumatic brain injury in the adult rat using FDG-microPET.

With the advent and emerging importance of neurobiology and its relation to behavior, scientists desire the capability to apply noninvasive, quantitative imaging of neuronal activity to small rodents. To this end, the authors' laboratory has developed microPET, a high-resolution positron emission tomography (PET) scanner that is capable of performing in vivo molecular imaging at a resolution sufficient to resolve major structures in the rat brain. The authors report in this article that, in conjunction with 2-[18F]fluoro-2-deoxyglucose (FDG), microPET provides accurate rates of cerebral glucose metabolism (59.7 to 108.5 micromol/100 g x min) in conscious adult rats as validated by within-subject autoradiographic measurements (59.5 to 136.2 micromol/100 g x min; r = 0.88; F[1,46] = 168.0; P < 0.001). By conducting repeated quantitative scanning, the authors demonstrate the sensitivity and accuracy of FDG-microPET to detect within-subject metabolic changes induced by traumatic brain injury. In addition, the authors report that longitudinal recovery from traumatic brain injury-induced metabolic depression, as measured by quantitative FDG-microPET, is significantly correlated (r = 0.65; P < 0.05) to recovery of behavioral dysfunction, as assessed by the Morris Water Maze performance of the same rats, after injury. This is the first study to demonstrate that FDG-microPET is quantitative, reproducible, and sensitive to metabolic changes, introducing a new approach to the longitudinal study of small animal models in neuroscience research.

Cerebral metabolic response to traumatic brain injury sustained early in development: a 2-deoxy-D-glucose autoradiographic study.

Following fluid percussion (FP) traumatic brain injury (TBI), adult rats exhibit dynamic regional changes in cerebral glucose metabolism characterized by an acute (hours) increase and subsequent chronic (weeks) decrease in metabolic rates. The injury-induced hyperglycolysis is the result of ionic fluxes across cell membranes and the degree and extent of metabolic depression is predictive of neurobehavioral deficits. Given that younger animals appear to exhibit similar physiological responses to injury yet show an improved rate of recovery compared to adults, we wanted to determine if this injury-induced dynamic metabolic response to TBI is different if the injury is sustained early in life. Local cerebral metabolic rates for glucose (ICMRglc: micromol/100 g/min) using [14C]2-deoxy-D-glucose were measured immediately, 30 min, 1 day, and 3 days following a mild to moderate level of lateral FP injury in postnatal day 17 (P17) rats. Even though gross morphological damage was not evident, injured pups exhibited ipsilateral hyperglycolysis immediately after injury, predominantly in cortical regions (ranging from 59.2% to 116.5% above controls). This hyperglycolytic state subsided within 30 min, and by 1 day all cerebral structures, except the ipsilateral cerebellar cortex, showed lower rates of glucose metabolism (ranging from 5.7% to 63.0% below controls). This period of posttraumatic metabolic depression resolved within 3 days for all structures measured. Compared to previous adult studies these results suggest that the young rat pup, although exhibiting acute hyperglycolysis, is not subjected to a prolonged period of metabolic depression, which supports the findings that at this level of injury severity, these young animals show remarkable neurological sparing following TBI.

Inhibition of neocortical plasticity during development by a moderate concussive brain injury.

To determine if a moderate traumatic brain injury (TBI) sustained early in life alters the capacity for developmental plasticity, 17-20-day-old rat pups received a lateral fluid percussion and then reared in an enriched environment for 17 days. Compared to sham-injured controls, this moderate TBI prevented the increase in cortical thickness (1.48 vs. 1.68 mm, p < 0.01) as well as the corresponding enhancement in cognitive performance in the Morris Water Maze (39 vs. 25 trials to criterion, p < 0.05). These injured animals exhibited no significant neuronal degeneration and no evidence of neurologic or motor deficits. These findings strongly support the conclusion that a diffuse brain injury is capable of inhibiting both anatomical and cognitive manifestations of experience-dependent developmental plasticity.