Traumatic brain injury (TBI) can cause a broad array of behavioral problems including cognitive and emotional deficits. Human studies comparing neurobehavioral outcomes after TBI suggest that cognitive impairments increase with injury severity, but emotional problems such as anxiety and depression do not. To determine whether cognitive and emotional impairments increase as a function of injury severity we exposed mice to sham, mild, moderate, or severe controlled cortical impact (CCI) and evaluated performance on a variety of neurobehavioral tests in the same animals before assessing lesion volume as a histological measure of injury severity. Increasing cortical impact depth successfully produced lesions of increasing severity in our model. We found that cognitive impairments in the Morris water maze increased with injury severity, as did the degree of contralateral torso flexion, a measure of unilateral striatal damage. TBI also caused deficits in emotional behavior as quantified in the forced swim test, elevated-plus maze, and prepulse inhibition of acoustic startle, but these deficits were not dependent on injury severity. Stepwise regression analyses revealed that Morris water maze performance and torso flexion predicted the majority of the variability in lesion volume. In summary, we find that cognitive deficits increase in relation to injury severity, but emotional deficits do not. Our data suggest that the threshold for emotional changes after experimental TBI is low, with no variation in behavioral deficits seen between mild and severe brain injury.

Neuropathological studies of human traumatic brain injury (TBI) cases have described amyloid plaques acutely after a single severe TBI, and tau pathology after repeat mild TBI (mTBI). This has helped drive the hypothesis that a single moderate to severe TBI increases the risk of developing late-onset Alzheimer’s disease (AD), while mTBI increases the risk of developing chronic traumatic encephalopathy (CTE). In this review we critically assess this position—examining epidemiological and case-control human studies, neuropathological evidence, and preclinical studies. Epidemiological studies emphasize that TBI is associated with the increased risk of developing multiple types of dementia, not just AD-type dementia, and that TBI can also trigger other neurodegenerative conditions such as Parkinson’s disease. Further, human post-mortem studies on either single TBI and repeat mTBI can show combinations of amyloid, tau, TDP-43, and Lewy body pathology indicating that the neuropathology of TBI is best described as a ‘polypathology’. Preclinical studies confirm that multiple proteins associated with the development of neurodegenerative disease accumulate in the brain after TBI. The chronic sequelae of both single TBI and repeat mTBI share common neuropathological features and clinical symptoms of classically defined neurodegenerative disorders. However, while the spectrum of chronic cognitive and neurobehavioral disorders that occur following repeat mTBI are viewed as the symptoms of CTE, the spectrum of chronic cognitive and neurobehavioral symptoms that occur after a single TBI is considered to represent distinct neurodegenerative diseases such as AD. These data support the suggestion that the multiple manifestations of TBI-induced neurodegenerative disorders be classified together as traumatic encephalopathy or trauma-induced neurodegeneration, regardless of the nature or frequency of the precipitating TBI.

BackgroundTraumatic Brain Injury (TBI) is a major cause of disability and mortality, to which there is currently no comprehensive treatment. Blood Brain Barrier (BBB) dysfunction is well documented in human TBI patients, yet the molecular mechanisms that underlie this neurovascular unit (NVU) pathology remains unclear. The apolipoprotein-E (apoE) protein has been implicated in controlling BBB integrity in an isoform dependent manner, via suppression of Cyclophilin A (CypA)–Matrix metallopeptidase-9 (MMP-9) signaling cascades, however the contribution of this pathway in TBI-induced BBB permeability is not fully investigated.MethodsWe exposed C57Bl/6 mice to controlled cortical impact and assessed NVU and BBB permeability responses up to 21 days post-injury. We pharmacologically probed the role of the CypA-MMP-9 pathway in BBB permeability after TBI using Cyclosporin A (CsA, 20 mg/kg). Finally, as the apoE4 protein is known to be functionally deficient compared to the apoE3 protein, we used humanized APOE mice as a clinically relevant model to study the role of apoE on BBB injury and repair after TBI.ResultsIn C57Bl/6 mice there was an inverse relationship between soluble apoE and BBB permeability, such that damaged BBB stabilizes as apoE levels increase in the days following TBI. TBI mice displayed acute pericyte loss, increased MMP-9 production and activity, and reduced tight-junction expression. Treatment with the CypA antagonist CsA in C57Bl/6 mice attenuates MMP-9 responses and enhances BBB repair after injury, demonstrating that MMP-9 plays an important role in the timing of spontaneous BBB repair after TBI. We also show that apoe mRNA is present in both astrocytes and pericytes after TBI.We report that APOE3 and APOE4 mice have similar acute BBB responses to TBI, but APOE3 mice display faster spontaneous BBB repair than APOE4 mice. Isolated microvessel analysis reveals delayed pericyte repopulation, augmented and sustained MMP-9 expression at the NVU, and impaired stabilization of Zonula Occludens-1, Occludin and Claudin-5 expression at tight junctions in APOE4 mice after TBI compared to APOE3 mice.ConclusionsThese data confirm apoE as an important modulator of spontaneous BBB stabilization following TBI, and highlights the APOE4 allele as a risk factor for poor outcome after TBI.

Soluble amyloid-beta (Aβ) oligomers are hypothesized to be the pathogenic species in Alzheimer's disease (AD), and increased levels of oligomers in the brain subsequent to traumatic brain injury (TBI) may exacerbate secondary injury pathways and underlie increased risk of developing AD in later life. To determine whether TBI causes Aβ aggregation and oligomerization in the brain, we exposed triple transgenic AD model mice to controlled cortical impact injury and measured levels of soluble, insoluble, and oligomeric Aβ by enzyme-linked immunosorbent assay (ELISA) at 1, 3, and 7 days postinjury. TBI rapidly increased levels of both soluble and insoluble Aβ40 and Aβ42 in the injured cortex at 1 day postinjury. We confirmed previous findings that identified damaged axons as a major site of Aβ accumulation using both immunohistochemistry and biochemistry. We also report that soluble Aβ oligomers were significantly increased in the injured cortex, as demonstrated by both ELISA and Western blot. Interestingly, the mouse brain is able to rapidly clear trauma-induced Aβ, with both soluble and insoluble Aβ species returning to sham levels by 7 days postinjury. In conclusion, we demonstrate that TBI causes acute accumulation and aggregation of Aβ in the brain, including the formation of low- and high-molecular-weight Aβ oligomers. The formation and aggregation of Aβ into toxic species acutely after injury may play a role in secondary injury cascades after trauma and, chronically, may contribute to increased risk of developing AD in later life.

BackgroundSpinal cord injury (SCI) induces secondary tissue damage that is associated with inflammation. We have previously demonstrated that inflammation-related gene expression after SCI occurs in two waves - an initial cluster that is acutely and transiently up-regulated within 24 hours, and a more delayed cluster that peaks between 72 hours and 7 days. Here we extend the microarray analysis of these gene clusters up to 6 months post-SCI.MethodsAdult male rats were subjected to mild, moderate or severe spinal cord contusion injury at T9 using a well-characterized weight-drop model. Tissue from the lesion epicenter was obtained 4 hours, 24 hours, 7 days, 28 days, 3 months or 6 months post-injury and processed for microarray analysis and protein expression.ResultsAnchor gene analysis using C1qB revealed a cluster of genes that showed elevated expression through 6 months post-injury, including galectin-3, p22PHOX, gp91PHOX, CD53 and progranulin. The expression of these genes occurred primarily in microglia/macrophage cells and was confirmed at the protein level using both immunohistochemistry and western blotting. As p22PHOX and gp91PHOX are components of the NADPH oxidase enzyme, enzymatic activity and its role in SCI were assessed and NADPH oxidase activity was found to be significantly up-regulated through 6 months post-injury. Further, treating rats with the nonspecific, irreversible NADPH oxidase inhibitor diphenylene iodinium (DPI) reduced both lesion volume and expression of chronic gene cluster proteins one month after trauma.ConclusionsThese data demonstrate that inflammation-related genes are chronically up-regulated after SCI and may contribute to further tissue loss.

The clinical manifestations that occur after traumatic brain injury (TBI) include a wide range of cognitive, emotional, and behavioral deficits. The loss of excitatory synapses could potentially explain why such diverse symptoms occur after TBI, and a recent preclinical study has demonstrated a loss of dendritic spines, the postsynaptic site of the excitatory synapse, after fluid percussion injury. The objective of this study was to determine if controlled cortical impact (CCI) also resulted in dendritic spine retraction and to probe the underlying mechanisms of this spine loss. We used a unilateral CCI and visualized neurons and dendtritic spines at 24 h post-injury using Golgi stain. We found that TBI caused a 32% reduction of dendritic spines in layer II/III of the ipsilateral cortex and a 20% reduction in the dendritic spines of the ipsilateral dentate gyrus. Spine loss was not restricted to the ipsilateral hemisphere, however, with similar reductions in spine numbers recorded in the contralateral cortex (25% reduction) and hippocampus (23% reduction). Amyloid-b (Ab), a neurotoxic peptide commonly associated with Alzheimer disease, accumulates rapidly after TBI and is also known to cause synaptic loss. To determine if Ab contributes to spine loss after brain injury, we administered a c-secretase inhibitor LY450139 after TBI. We found that while LY450139 administration could attenuate the TBI-induced increase in Ab, it had no effect on dendritic spine loss after TBI. We conclude that the acute, global loss of dendritic spines after TBI is independent of c-secretase activity or TBI-induced Ab accumulation.

Traumatic brain injury (TBI) increases brain beta-amyloid (Aβ) in humans and animals. Although the role of Aβ in the injury cascade is unknown, multiple preclinical studies have demonstrated a correlation between reduced Aβ and improved outcome. Therefore, therapeutic strategies that enhance Aβ clearance may be beneficial after TBI. Increased levels of ATP-binding cassette A1 (ABCA1) transporters can enhance Aβ clearance through an apolipoprotein E (apoE)-mediated pathway. By measuring Aβ and ABCA1 after experimental TBI in C57BL/6J mice, we found that Aβ peaked early after injury (1-3 days), whereas ABCA1 had a delayed response (beginning at 3 days). As ABCA1 levels increased, Aβ levels returned to baseline levels-consistent with the known role of ABCA1 in Aβ clearance. To test if enhancing ABCA1 levels could block TBI-induced Aβ, we treated TBI mice with the liver X-receptor (LXR) agonist T0901317. Pre- and post-injury treatment increased ABCA1 levels at 24 h post-injury, and reduced the TBI-induced increase in Aβ. This reduction in Aβ was not due to decreased amyloid precursor protein processing, or a shift in the solubility of Aβ, indicating enhanced clearance. T0901317 also limited motor coordination deficits in injured mice and reduced brain lesion volume. These data indicate that activation of LXR can reduce Aβ accumulation after TBI, and is accompanied by improved functional recovery.

Partial recovery from brain injury due to trauma, hypoxia, or stroke, is ubiquitous and occurs largely through unknown mechanisms. It is now well accepted that injury enhances proliferation of quiescent stem and progenitor cells in specialized niches within the brain. However, whether this injury-induced neurogenesis contributes to recovery after brain injury remains controversial. Recent evidence suggests that hippocampal neural stem/precursor cell activation and subsequent neurogenesis are responsible for at least some aspects of spontaneous recovery following brain injury from a variety of causes. However, other aspects of injury-induced neurogenesis, including its contribution to adverse sequelae such as seizures, are still being investigated. The purpose of this review is to provide an overview of adult hippocampal neurogenesis and how it relates to injury and explain how current mouse technology is allowing for better understanding of whether manipulating this natural process might eventually help inform therapy following brain injury.