Lateral Fluid Percussion Traumatic Brain Injury Research Articles

Divergent Spatial Learning, Enhanced Neuronal Transcription, and Blood-Brain Barrier Disruption Develop During Recovery from Post-Injury Sleep Fragmentation.

Traumatic brain injury (TBI) causes pathophysiology that may significantly decrease quality of life over time. A major propagator of this response is chronic, maladaptive neuroinflammation, which can be exacerbated by stressors such as sleep fragmentation (SF). This study determined whether post-TBI SF had lasting behavioral and inflammatory effects even with a period of recovery. To test this, male and female mice received a moderate lateral fluid percussion TBI or sham surgery. Half the mice were left undisturbed, and half were exposed to daily SF for 30 days. All mice were then undisturbed between 30 and 60 days post-injury (DPI), allowing mice to recover from SF (SF-R). SF-R did not impair global Barnes maze performance. Nonetheless, TBI SF-R mice displayed retrogression in latency to reach the goal box within testing days. These nuanced behavioral changes in TBI SF-R mice were associated with enhanced expression of neuronal processing/signaling genes and indicators of blood-brain barrier (BBB) dysfunction. Aquaporin-4 (AQP4) expression, a marker of BBB integrity, was differentially altered by TBI and TBI SF-R. For example, TBI enhanced cortical AQP4 whereas TBI SF-R mice had the lowest cortical expression of perivascular AQP4, dysregulated AQP4 polarization, and the highest number of CD45+ cells in the ipsilateral cortex. Altogether, post-TBI SF caused lasting, divergent behavioral responses associated with enhanced expression of neuronal transcription and BBB disruption even after a period of recovery from SF. Understanding lasting impacts from post-TBI stressors can better inform both acute and chronic post-injury care to improve long-term outcome post-TBI.

Sex-Specific and Dose-Dependent Effects of Drag-Reducing Polymers on Microcirculation and Tissue Oxygenation in Rats After Traumatic Brain Injury.

Traumatic brain injury (TBI) ultimately leads to a reduction in the cerebral metabolic rate for oxygen due to ischemia. Previously, we showed that 2ppm i.v. of drag-reducing polymers (DRP) improve hemodynamic and oxygen delivery to tissue in a rat model of mild-to-moderate TBI. Here we evaluated sex-specific and dose-dependent effects of DRP on microvascular CBF (mvCBF) and tissue oxygenation in rats after moderate TBI. In vivo two-photon laser scanning microscopy over the rat parietal cortex was used to monitor the effects of DRP on microvascular perfusion, tissue oxygenation, and blood-brain barrier (BBB) permeability. Lateral fluid-percussion TBI (1.5 ATA, 100ms) was induced after baseline imaging and followed by 4h of monitoring. DRP was injected at 1, 2, or 4ppm within 30 min after TBI. Differences between groups were determined using a two-way ANOVA analysis for multiple comparisons and post hoc testing using the Mann-Whitney U test. Moderate TBI progressively decreased mvCBF, leading to tissue hypoxia and BBB degradation in the pericontusion zone (p<0.05). The i.v. injection of DRP increased near-wall flow velocity and flow rate in arterioles, leading to an increase in the number of erythrocytes entering capillaries, enhancing capillary perfusion and tissue oxygenation while protecting BBB in a dose-dependent manner without significant difference between males and females (p<0.01). TBI resulted in an increase in intracranial pressure (20.1±3.2mmHg, p<0.05), microcirculatory redistribution to non-nutritive microvascular shunt flow, and stagnation of capillary flow, all of which were dose-dependently mitigated by DRP. DRP at 4ppm was most effective, with a non-significant trend to better outcomes in female rats.

Animal welfare assessment after severe traumatic brain injury in rats.

Severe traumatic brain injury (TBI) is a multifactorial injury process involving respiratory, cardiovascular and immune functions in addition to the brain. Thus, live animal models are needed to study the molecular, cellular and systemic mechanisms of TBI. The ethical use of laboratory animals requires that the benefits of approaches be carefully weighed against potential harm to animals. Welfare assessments adapted to severe TBI research are lacking. Here, we introduce a scoresheet to describe and monitor potential distress in animals, which includes general welfare (body weight, general appearance and spontaneous behaviour) and TBI-specific indices (respiratory function, pain, locomotor impairment, wound healing). Implementation of this scoresheet in Sprague-Dawley rats subjected to severe lateral fluid percussion TBI revealed a period of suffering limited to four days, followed by a recovery to normal welfare scores within 10-15 days, with females showing a worse impact than males. The scores indicate that animal suffering in this model is transitory compared with TBI consequences in humans. The scoresheet allows for the implementation of refinement measures including (1) analgesia during the initial period following TBI and (2) humane endpoints set (30% weight loss, score ≥90 and/or respiratory problems). This animal scoresheet tailored to TBI research provides a basis for further refinement of animal research paradigms aimed at understanding or treating the sequelae of severe TBI.

Abstracts from The 39th Annual Symposium of the National Neurotrauma Society, including the AANS/CNS Joint Section on Neurotrauma and Critical Care

Abstracts from The 39^th Annual Symposium of the National Neurotrauma Society, including the AANS/CNS Joint Section on Neurotrauma and Critical Care

Sleep fragmentation engages stress-responsive circuitry, enhances inflammation and compromises hippocampal function following traumatic brain injury

Traumatic brain injury (TBI) impairs the ability to restore homeostasis in response to stress, indicating hypothalamic-pituitary-adrenal (HPA)-axis dysfunction. Many stressors result in sleep disturbances, thus mechanical sleep fragmentation (SF) provides a physiologically relevant approach to study the effects of stress after injury. We hypothesize SF stress engages the dysregulated HPA-axis after TBI to exacerbate post-injury neuroinflammation and compromise recovery. To test this, male and female mice were given moderate lateral fluid percussion TBI or sham-injury and left undisturbed or exposed to daily, transient SF for 7- or 30-days post-injury (DPI). Post-TBI SF increases cortical expression of interferon- and stress-associated genes characterized by inhibition of the upstream regulator NR3C1 that encodes glucocorticoid receptor (GR). Moreover, post-TBI SF increases neuronal activity in the hippocampus, a key intersection of the stress-immune axes. By 30 DPI, TBI SF enhances cortical microgliosis and increases expression of pro-inflammatory glial signaling genes characterized by persistent inhibition of the NR3C1 upstream regulator. Within the hippocampus, post-TBI SF exaggerates microgliosis and decreases CA1 neuronal activity. Downstream of the hippocampus, post-injury SF suppresses neuronal activity in the hypothalamic paraventricular nucleus indicating decreased HPA-axis reactivity. Direct application of GR agonist, dexamethasone, to the CA1 at 30 DPI increases GR activity in TBI animals, but not sham animals, indicating differential GR-mediated hippocampal action. Electrophysiological assessment revealed TBI and SF induces deficits in Schaffer collateral long-term potentiation associated with impaired acquisition of trace fear conditioning, reflecting dorsal hippocampal-dependent cognitive deficits. Together these data demonstrate that post-injury SF engages the dysfunctional post-injury HPA-axis, enhances inflammation, and compromises hippocampal function. Therefore, external stressors that disrupt sleep have an integral role in mediating outcome after brain injury.

Lateral Fluid Percussion Injury Causes Sex-Specific Deficits in Anterograde but Not Retrograde Memory.

Cognitive impairment is a common symptom after traumatic brain injury (TBI). Memory, in particular, is often disrupted during chronic post-injury recovery. To understand the sex-specific effects of brain injury on retrograde and anterograde memory, we examined paired associate learning (PAL), spatial learning and memory, and fear memory after lateral fluid percussion TBI. We hypothesized that male and female mice would display unique memory deficits after TBI. PAL task acquisition was initiated via touchscreen operant conditioning 22 weeks before sham injury or TBI. Post-injury PAL testing occurred 7 weeks post-injury. Barnes maze and fear conditioning were completed at 14- and 15-weeks post-injury, respectively. Contrary to our expectations, behavioral outcomes were not primarily influenced by TBI. Instead, sex-specific differences were observed in all tasks which exposed task-specific trends in male TBI mice. Male mice took longer to complete the PAL task, but this was not affected by TBI and did not compromise the ability to make a correct choice. Latency to reach the goal box decreased across testing days in Barnes maze, but male TBI mice lagged in improvement compared to all other groups. Use of two learning indices revealed that male TBI mice were deficient in transferring information from 1 day to the next. Finally, acquisition and contextual retention of fear memory were similar between all groups. Cued retention of the tone-shock pairing was influenced by both injury and sex. Male sham mice displayed the strongest cued retention of fear memory, evidenced by increased freezing behavior across the test trial. In contrast, male TBI mice displayed reduced freezing behavior with repetitive tone exposure. An inverse relationship in freezing behavior to tone exposure was detected between female sham and TBI mice, although the difference was not as striking. Together, these studies show that retrograde memory is intact after lateral TBI. However, male mice are more vulnerable to post-injury anterograde memory deficits. These behaviors were not associated with gross pathological change near the site injury or in subcortical brain regions associated with memory formation. Future studies that incorporate pre- and post-injury behavioral analysis will be integral in defining sex-specific memory impairment after TBI.

Sleep Disruption Exacerbates and Prolongs the Inflammatory Response to Traumatic Brain Injury.

Traumatic brain injury (TBI) alters stress responses, which may influence neuroinflammation and behavioral outcome. Sleep disruption (SD) is an understudied post-injury environmental stressor that directly engages stress-immune pathways. Thus, we predicted that maladaptive changes in the hypothalamic-pituitary-adrenal (HPA) axis after TBI compromise the neuroendocrine response to SD and exacerbate neuroinflammation. To test this, we induced lateral fluid percussion TBI or sham injury in female and male C57BL/6 mice aged 8-10 weeks that were then left undisturbed or exposed to 3 days of transient SD. At 3 days post-injury (DPI) plasma corticosterone (CORT) was reduced in TBI compared with sham mice, indicating altered HPA-mediated stress response to SD. This response was associated with approach-avoid conflict behavior and exaggerated cortical neuroinflammation. Post-injury SD specifically enhanced neutrophil trafficking to the injured brain in conjunction with dysregulated aquaporin-4 (AQP4) polarization. Delayed and persistent effects of post-injury SD were determined 4 days after SD concluded at 7 DPI. SD prolonged anxiety-like behavior regardless of injury and was associated with increased cortical Iba1 labeling in both sham and TBI mice. Strikingly, TBI SD mice displayed an increased number of CD45+ cells near the site of injury, enhanced cortical glial fibrillary acidic protein (GFAP) immunolabeling, and persistent expression of Trem2 and Tlr4 7 DPI compared with TBI mice. These results support the hypothesis that post-injury SD alters stress-immune pathways and inflammatory outcomes after TBI. These data provide new insight to the dynamic interplay between TBI, stress, and inflammation.

Alteration of FDG uptake by performing novel object recognition task in a rat model of Traumatic Brain Injury

Traumatic Brain Injury (TBI) affects approximately 2.5 million people in the United States, of which 80% are considered to be mild (mTBI). Previous studies have shown that cerebral glucose uptake and metabolism are altered after brain trauma and functional metabolic deficits observed following mTBI are associated with changes in cognitive performance. Imaging of glucose uptake using [18F] Fluorodeoxyglucose (FDG) based Positron Emission Tomography (PET) with anesthesia during the uptake period demonstrated limited variability in results, but may have depressed uptake. Anesthesia has been found to interfere with blood glucose levels, and hence, FDG uptake. Conversely, forced cognitive testing during uptake may increase glucose demand in targeted regions, such as hippocampus, allowing for better differentiation of outcomes. Therefore, the objective of this study was to investigate the influence of a directed cognitive function task during the FDG uptake period on uptake measurements both in naïve rats and at 2 days after mild lateral fluid percussion (mLFP) TBI. Adult male Sprague Dawley rats underwent FDG uptake with either cognitive testing with the Novel Object Recognition (NOR) test or No Novel Object (NNO), followed by PET scans at baseline (prior to injury) and at 2days post mLFP. At baseline, FDG uptake in the right hippocampus was elevated in rats completing the NOR in comparison to the NNO (control group). Further, the NNO group rats demonstrated a greater fold change in the FDG uptake between baseline and post injury scans than the NOR group. Overall, these data suggest that cognitive activity during FDG uptake affects the regional uptake pattern in the brain, increasing uptake at baseline and suppressing the effects of injury.

Alterations of Parenchymal Microstructure, Neuronal Connectivity, and Cerebrovascular Resistance at Adolescence after Mild-to-Moderate Traumatic Brain Injury in Early Development.

Traumatic brain injury (TBI) is a leading cause of morbidity in children. To investigate outcome of early developmental TBI during adolescence, a rat model of fluid percussion injury was developed, where previous work reported deficits in sensorimotor behavior and cortical blood flow at adolescence.1 Based on the nonlocalized outcome, we hypothesized that multiple neurophysiological components of brain function, namely neuronal connectivity, synapse/axonal microstructural integrity, and neurovascular function, are altered and magnetic resonance imaging (MRI) methods could be used to determine regional alterations. Adolescent outcomes of developmental TBI were studied 2 months after injury, using functional MRI (fMRI) and diffusion tensor imaging (DTI). fMRI-based resting-state functional connectivity (RSFC), representing neural connectivity, was significantly altered between sham and TBI. RSFC strength decreased in the cortex, hippocampus, and thalamus, accompanied by decrease in spatial extent of their corresponding RSFC networks and interhemispheric asymmetry. Cerebrovascular reactivity to arterial CO2 changes diminished after TBI across both hemispheres, with a more pronounced decrease in the ipsilateral hippocampus, thalamus, and motor cortex. DTI measures of fractional anisotropy and apparent diffusion coefficient, reporting on axonal and microstructural integrity of the brain, indicated similar interhemispheric asymmetry, with highest change in the ipsilateral hippocampus and regions adjoining the ipsilateral thalamus, hypothalamus, and amygdala. TBI-induced corpus callosal microstructural alterations indicated measurable changes in interhemispheric structural connectivity. Hippocampus, thalamus, and select cortical regions were most consistently affected in multiple imaging markers. The multi-modal MRI results demonstrate cortical and subcortical alterations in neural connectivity, cerebrovascular resistance, and parenchymal microstructure in the adolescent brain, indicating the highly diffuse and persistent nature of the lateral fluid percussion TBI early in development.

Optical Depolarization of DCX-Expressing Cells Promoted Cognitive Recovery and Maturation of Newborn Neurons via the Wnt/β-Catenin Pathway.

Electrical excitability by membrane depolarization is crucial for survival and maturation of newborn cells in the dentate gyrus of the hippocampus. However, traditional technology for membrane depolarization lacks temporal and spatial precision. Optogenetics can be used to activate channelrhodopsin-2 (ChR2), allowing cationic current to depolarize genetically targeted cells. In this study, we used ChR2-EGFP driven by doublecortin (DCX) to promote survival and maturation of newborn cells in the dentate gyrus after traumatic brain injury (TBI). C57BL/6 mice underwent lateral fluid percussion TBI. TBI mice were transfected with a lentivirus carrying the DCX-ChR2-EGFP gene. We observed that not only immature neurons but also type-2b intermediate progenitor (IPs) and neuroblasts expressed DCX-EGFP, indicating that DCX-expressing newborn cells could provide a long time window for electrical activity regulation. Quantitative results showed that the number of EGFP-expressing cells began to rise at 3 days after TBI and peaked at 9 days after TBI. By optical depolarization of DCX-EGFP-expressing cells between 3 and 12 days, we observed significantly improved cognitive deficits after TBI with enhanced survival and maturation of newborn cells in the dentate gyrus. We also investigated the role of optical depolarization in neural stem cells transfected with a lentivirus carrying the ChR2-DCX-EGFP gene in vitro. By administrating verapamil to block L-type calcium channels, we verified that the up-regulation of MAP2, NeuN, Neurog2, NeuroD1 and GluR2 in newborn cells was mediated by ChR2-elicted depolarization. By using β-catenin inhibitor Dkk1, we demonstrated that optical depolarization of DCX-EGFP-expressing cells facilitated survival and maturation probably through the Wnt/β-catenin signaling cascade.

Traumatic Brain Injury in hTau Model Mice: Enhanced Acute Macrophage Response and Altered Long-Term Recovery.

Traumatic brain injury (TBI) induces widespread neuroinflammation and accumulation of microtubule associated protein tau (MAPT): two key pathological features of tauopathies. This study sought to characterize the microglial/macrophage response to TBI in genomic-based MAPT transgenic mice in a Mapt knockout background (called hTau). Two-month-old hTau and age-matched control male and female mice received a single lateral fluid percussion TBI or sham injury. Separate groups of mice were aged to an acute (3 days post-injury [DPI]) or chronic (135 DPI) post-injury time point. As judged by tissue immunostaining for macrophage markers, microglial/macrophage response to TBI was enhanced at 3 DPI in hTau mice compared with control TBI and sham mice. However, MAPT phosphorylation increased in hTau mice regardless of injury group. Flow cytometric analysis revealed distinct populations of microglia and macrophages within all groups at 135 DPI. Unexpectedly, microglial reactivity was significantly reduced in hTau TBI mice compared with all other groups. Instead, hTau TBI mice showed a persistent macrophage response. In addition, TBI enhanced MAPT pathology in the temporal cortex and hippocampus of hTau TBI mice compared with controls 135 DPI. A battery of behavioral tests revealed that TBI in hTau mice resulted in compromised use of spatial search strategies to complete a water maze task, despite lack of motor or visual deficits. Collectively, these data indicate that the presence of wild-type human tau alters the microglial/macrophage response to a single TBI, induces delayed, region-specific MAPT pathology, and alters cognitive recovery; however, the causal relationship between these events remains unclear. These results highlight the potential significance of communication between MAPT and microglia/macrophages following TBI, and emphasize the role of neuroinflammation in post-injury recovery.

Inhibition of Src Family Kinases Protects Hippocampal Neurons and Improves Cognitive Function after Traumatic Brain Injury

Traumatic brain injury (TBI) is often associated with intracerebral and intraventricular hemorrhage. Thrombin is a neurotoxin generated at bleeding sites fater TBI and can lead to cell death and subsequent cognitive dysfunction via activation of Src family kinases (SFKs). We hypothesize that inhibiting SFKs can protect hippocampal neurons and improve cognitive memory function after TBI. To test these hypotheses, we show that moderate lateral fluid percussion (LFP) TBI in adult rats produces bleeding into the cerebrospinal fluid (CSF) in both lateral ventricles, which elevates oxyhemoglobin and thrombin levels in the CSF, activates the SFK family member Fyn, and increases Rho-kinase 1(ROCK1) expression. Systemic administration of the SFK inhibitor, PP2, immediately after moderate TBI blocks ROCK1 expression, protects hippocampal CA2/3 neurons, and improves spatial memory function. These data suggest the possibility that inhibiting SFKs after TBI might improve clinical outcomes.

Traumatic Brain Injury Causes a Tacrolimus-Sensitive Increase in Non-Convulsive Seizures in a Rat Model of Post-Traumatic Epilepsy.

Epilepsy is a significant but potentially preventable complication of traumatic brain injury (TBI). Previous research in animal models of acquired epilepsy has implicated the calcium-sensitive phosphatase, calcineurin. In addition, our lab recently found that calcineurin activity in the rat hippocampus increases acutely after lateral TBI. Here we use a calcineurin inhibitor test whether an acute increase in calcineurin activity is necessary for the development of late post-traumatic seizures. Adult rats were administered the calcineurin inhibitor Tacrolimus (5mg/kg; i.p.) 1 hour after lateral fluid percussion TBI and then monitored by video-electrocorticography (video-ECoG) for spontaneous seizure activity 5 weeks or 33 weeks later. At 5 weeks post-TBI, we observed epileptiform activity on the video-ECoG of brain injured rats but no seizures. By 33 weeks post-TBI though, nearly all injured rats exhibited spontaneous seizures, including convulsive seizures which were infrequent but lasted minutes (18% of injured rats), and non-convulsive seizures which were frequent but lasted tens of seconds (94% of injured rats). We also identified non-convulsive seizures in a smaller subset of control and sham TBI rats (56%), reminiscent of idiopathic seizures described in other rats strains. Non-convulsive seizures in the brain injured rats, however, were four-times more frequent and two-times longer lasting than in their uninjured littermates. Interestingly, rats administered Tacrolimus acutely after TBI showed significantly fewer non-convulsive seizures than untreated rats, but a similar degree of cortical atrophy. The data thus indicate that administration of Tacrolimus acutely after TBI suppressed non-convulsive seizures months later.

Acute Alcohol Intoxication Prolongs Neuroinflammation without Exacerbating Neurobehavioral Dysfunction following Mild Traumatic Brain Injury

Traumatic brain injury (TBI) represents a leading cause of death and disability among young persons with ∼1.7 million reported cases in the United States annually. Although acute alcohol intoxication (AAI) is frequently present at the time of TBI, conflicting animal and clinical reports have failed to establish whether AAI significantly impacts short-term outcomes after TBI. The objective of this study was to determine whether AAI at the time of TBI aggravates neurobehavioral outcomes and neuroinflammatory sequelae post-TBI. Adult male Sprague-Dawley rats were surgically instrumented with gastric and vascular catheters before a left lateral craniotomy. After recovery, rats received either a primed constant intragastric alcohol infusion (2.5 g/kg+0.3 g/kg/h for 15 h) or isocaloric/isovolumic dextrose infusion followed by a lateral fluid percussion TBI (∼1.4 J, ∼30 ms). TBI induced apnea and a delay in righting reflex. AAI at the time of injury increased the TBI induced delay in righting reflex without altering apnea duration. Neurological and behavioral dysfunction was observed at 6 h and 24 h post-TBI, and this was not exacerbated by AAI. TBI induced a transient upregulation of cortical interleukin (IL)-6 and monocyte chemotactic protein (MCP)-1 mRNA expression at 6 h, which was resolved at 24 h. AAI did not modulate the inflammatory response at 6 h but prevented resolution of inflammation (IL-1, IL-6, tumor necrosis factor-α, and MCP-1 expression) at 24 h post-TBI. AAI at the time of TBI did not delay the recovery of neurological and neurobehavioral function but prevented the resolution of neuroinflammation post-TBI.

Propofol Limits Microglial Activation after Experimental Brain Trauma through Inhibition of Nicotinamide Adenine Dinucleotide Phosphate Oxidase

Microglial activation is implicated in delayed tissue damage after traumatic brain injury (TBI). Activation of microglia causes up-regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, with the release of reactive oxygen species and cytotoxicity. Propofol appears to have antiinflammatory actions. The authors evaluated the neuroprotective effects of propofol after TBI and examined in vivo and in vitro whether such actions reflected modulation of NADPH oxidase. Adult male rats were subjected to moderate lateral fluid percussion TBI. Effect of propofol on brain microglial activation and functional recovery was assessed up to 28 days postinjury. By using primary microglial and BV2 cell cultures, the authors examined propofol modulation of lipopolysaccharide and interferon-γ-induced microglial reactivity and neurotoxicity. Propofol improved cognitive recovery after TBI in novel object recognition test (48 ± 6% for propofol [n = 15] vs. 30 ± 4% for isoflurane [n = 14]; P = 0.005). The functional improvement with propofol was associated with limited microglial activation and decreased cortical lesion volume and neuronal loss. Propofol also attenuated lipopolysaccharide- and interferon-γ-induced microglial activation in vitro, with reduced expression of inducible nitric oxide synthase, nitric oxide, tumor necrosis factor-α, interlukin-1β, reactive oxygen species, and NADPH oxidase. Microglial-induced neurotoxicity in vitro was also markedly reduced by propofol. The protective effect of propofol was attenuated when the NADPH oxidase subunit p22 was knocked down by small interfering RNA. Moreover, propofol reduced the expression of p22 and gp91, two key components of NADPH oxidase, after TBI. The neuroprotective effects of propofol after TBI appear to be mediated, in part, through the inhibition of NADPH oxidase.

Mild Traumatic Brain Injury Results in Depressed Cerebral Glucose Uptake: An 18FDG PET Study

Moderate to severe traumatic brain injury (TBI) in humans and rats induces measurable metabolic changes, including a sustained depression in cerebral glucose uptake. However, the effect of a mild TBI on brain glucose uptake is unclear, particularly in rodent models. This study aimed to determine the glucose uptake pattern in the brain after a mild lateral fluid percussion (LFP) TBI. Briefly, adult male rats were subjected to a mild LFP and positron emission tomography (PET) imaging with (18)F-fluorodeoxyglucose ((18)FDG), which was performed prior to injury and at 3 and 24 h and 5, 9, and 16 days post-injury. Locomotor function was assessed prior to injury and at 1, 3, 7, 14, and 21 days after injury using modified beam walk tasks to confirm injury severity. Histology was performed at either 10 or 21 days post-injury. Analysis of function revealed a transient impairment in locomotor ability, which corresponds to a mild TBI. Using reference region normalization, PET imaging revealed that mild LFP-induced TBI depresses glucose uptake in both the ipsilateral and contralateral hemispheres in comparison with sham-injured and naïve controls from 3 h to 5 days post-injury. Further, areas of depressed glucose uptake were associated with regions of glial activation and axonal damage, but no measurable change in neuronal loss or gross tissue damage was observed. In conclusion, we show that mild TBI, which is characterized by transient impairments in function, axonal damage, and glial activation, results in an observable depression in overall brain glucose uptake using (18)FDG-PET.

Acute lower urinary tract dysfunction (LUTD) following traumatic brain injury (TBI) in rats

The aim of this study was to assess experimental traumatic brain injury (TBI)-induced lower urinary tract dysfunction (LUTD) by monitoring systemic and urodynamic parameters using an implantable telemetry system. A single lateral fluid percussion TBI (FP-TBI; 3.4 atm) was administered to 10 female rats. Pressure micro-catheters were implanted in the abdominal aorta and bladder dome for simultaneous data recording. Hemodynamic and urodynamic variables recorded 24 hr before and 24 hr after injury were analyzed and compared. TBI in the acute phase resulted in LUTD affecting bladder emptying, characterized by failure of voiding reflex, high capacity bladder, increased voided volume, prolonged intermicturition intervals, and loss of compliance. The dominant symptom was urinary retention (100%) and incontinence (60%). The effects followed a pattern of initial loss of bladder function followed by either altered recovery of reflex micturition or a period of incontinence. With a moderate injury symptoms were temporary in 90% of animals and permanent in 10% of animals. Injury produced only transient hypertension (≤1 hr) with a maximum systolic pressure of 172.64 ± 14.53 mmHg (70% of animals). The results demonstrate that experimental FP-TBI causes temporary bladder dysfunction that in more severe cases becomes permanent. Telemetry recordings revealed a sequence of events following injury that establishes moderate TBI as a risk factor for neurogenic bladder disorder. Results also suggest a correlation between lateral FP-TBI and incontinence.

Evaluation of Metric, Topological, and Temporal Ordering Memory Tasks after Lateral Fluid Percussion Injury

Impairments in learning and memory occur in as many as 50% of patients following traumatic brain injury (TBI). Similar impairments occur in rodent models of TBI, and the development of new memory testing procedures provides an opportunity to examine how TBI affects memory processing in specific neural memory systems. Specifically, metric, topological, and temporal ordering tasks are object-based tests for memory of spatial orientation and temporal sequencing working memory developed for use in rodents. Previous studies demonstrated that specific lesions of the dentate gyrus/CA3 of the hippocampus and the parietal cortex resulted in deficits in the metric and topological spatial orientation tasks, respectively. Lesions of the CA1 impaired a rat's ability to recall the temporal order of odors. The purpose of the following study was to determine whether moderate lateral fluid percussion TBI would generate deficits in these working memory tasks, and whether observed deficits were associated with cell loss in the CA2/3 and/or CA1 of the hippocampus. Two weeks following a moderate lateral fluid percussion TBI, adult rats demonstrated significant deficits in both the metric and temporal ordering tasks (p<0.05) but not in the topological task. Stereological analysis identified a significant reduction in neurons in the CA2/3 (p<0.05) but not the CA1 of the hippocampus. These data demonstrate the utility of three object-based tasks to expand our understanding of how different neural memory systems are affected by TBI.

Medial Septal Nucleus Theta Frequency Deep Brain Stimulation Improves Spatial Working Memory after Traumatic Brain Injury

More than 5,000,000 survivors of traumatic brain injury (TBI) live with persistent cognitive deficits, some of which likely derive from hippocampal dysfunction. Oscillatory activity in the hippocampus is critical for normal learning and memory functions, and can be modulated using deep brain stimulation techniques. In this pre-clinical study, we demonstrate that lateral fluid percussion TBI results in the attenuation of hippocampal theta oscillations in the first 6 days after injury, which correlate with deficits in the Barnes maze spatial working memory task. Theta band stimulation of the medial septal nucleus (MSN) results in a transient increase in hippocampal theta activity, and when delivered 1 min prior to training in the Barnes maze, it significantly improves spatial working memory. These results suggest that MSN theta stimulation may be an effective neuromodulatory technique for treatment of persistent learning and memory deficits after TBI.

A CD11d Monoclonal Antibody Treatment Reduces Tissue Injury and Improves Neurological Outcome after Fluid Percussion Brain Injury in Rats

Traumatic brain injury (TBI) is an international health concern often resulting in chronic neurological abnormalities, including cognitive deficits, emotional disturbances, and motor impairments. An anti-CD11d monoclonal antibody that blocks the CD11d/CD18 integrin and vascular cell adhesion molecule (VCAM)-1 interaction following experimental spinal cord injury improves functional recovery, while reducing the intraspinal number of neutrophils and macrophages, oxidative activity, and tissue damage. Since the mechanisms of secondary injury in the brain and spinal cord are similar, we designed a study to evaluate fully the effects of anti-CD11d treatment after a moderate lateral fluid percussion TBI in the rat. Rats were treated at 2 h after TBI with either the anti-CD11d antibody or an isotype-matched control antibody 1B7, and both short (24- to 72-h) and long (4-week) recovery periods were examined. The anti-CD11d integrin treatment reduced neutrophil and macrophage levels in the injured brain, with concomitant reductions in lipid peroxidation, astrocyte activation, amyloid precursor protein accumulation, and neuronal loss. The reduced neuroinflammation seen in anti-CD11d-treated rats correlated with improved performance on a number of behavioral tests. At 24 h, the anti-CD11d group performed significantly better than the 1B7 controls on several water maze measures of spatial cognition. At 4 weeks post-injury the anti-CD11d-treated rats had better sensorimotor function as assessed by the beam task, and reduced anxiety-like behaviors, as evidenced by elevated-plus maze testing, compared to 1B7 controls. These findings suggest that neuroinflammation is associated with behavioral deficits after TBI, and that anti-CD11d antibody treatment is a viable strategy to improve neurological outcomes after TBI.