Blast related traumatic brain injury (TBI) has been a major cause of injury in the wars in Iraq and Afghanistan. A striking feature of the mild TBI (mTBI) cases has been the prominent association with post-traumatic stress disorder (PTSD). However, because of the overlapping symptoms, distinction between the two disorders has been difficult. We studied a rat model of mTBI in which adult male rats were exposed to repetitive blast injury while under anesthesia. Blast exposure induced a variety of PTSD-related behavioral traits that were present many months after the blast exposure, including increased anxiety, enhanced contextual fear conditioning, and an altered response in a predator scent assay. We also found elevation in the amygdala of the protein stathmin 1, which is known to influence the generation of fear responses. Because the blast overpressure injuries occurred while animals were under general anesthesia, our results suggest that a blastrelated mTBI exposure can, in the absence of any psychological stressor, induce PTSD-related traits that are chronic and persistent. These studies have implications for understanding the relationship of PTSD to mTBI in the population of veterans returning from the wars in Iraq and Afghanistan.

Mild traumatic brain injury (mTBI) resulting from exposure to improvised explosive devices (IEDs) has fueled a requirement to develop animals models that mirror this condition using exposure to blast overpressure (BOP). En route to developing a model of repeated exposure to BOP we sought to initially characterize the effects of acute BOP exposure in rodents, focusing specifically on the levels of BOP exposure that produced clinical mTBI symptoms. We first measured BOP effects on gross motor function on a balance beam. Separate groups of unanesthetized rats were exposed (in different orientations) to 36.6, 74.5, and 116.7 kPa BOP exposure inside a pneumatically driven shock tube. Results demonstrated that rats exposed to 116.7 kPa demonstrated transient alterations or loss of consciousness indicated by a transient loss of righting and by increased latencies on the balance beam. The 116.7 kPa exposure was the threshold for overt pathology for acute BOP exposure with approximately 30% of rats presenting with evidence of subdural hemorrhage and cortical contusions. All animals exposed to 116.7 kPa BOP manifested evidence of significant pulmonary hemorrhage. Anterograde memory deficits were observed in rats exposed to 74.5 kPa facing the BOP wave and rats exposed to 116.7 kPa in the lateral (side) orientation. We next assessed repeated exposure to either lateral or frontal 36.6 kPa BOP in anesthetized rats, once per day for 12 days. Results showed that repeated exposure in the frontal, but not side, orientation to the BOP wave produced a transitory learning deficit on a Morris water maze task as shown by significantly longer latencies to reach the submerged platform in the second and third blocks of a four block session. Implications of these data are discussed in relation to the manifestation of mTBI in military personnel exposed to IEDs. Finally, we suggest that there are multiple types of long-term brain injury from blast exposure.

BackgroundBlast-related traumatic brain injury (TBI) has been a significant cause of injury in the military operations of Iraq and Afghanistan, affecting as many as 10-20% of returning veterans. However, how blast waves affect the brain is poorly understood. To understand their effects, we analyzed the brains of rats exposed to single or multiple (three) 74.5 kPa blast exposures, conditions that mimic a mild TBI.ResultsRats were sacrificed 24 hours or between 4 and 10 months after exposure. Intraventricular hemorrhages were commonly observed after 24 hrs. A screen for neuropathology did not reveal any generalized histopathology. However, focal lesions resembling rips or tears in the tissue were found in many brains. These lesions disrupted cortical organization resulting in some cases in unusual tissue realignments. The lesions frequently appeared to follow the lines of penetrating cortical vessels and microhemorrhages were found within some but not most acute lesions.ConclusionsThese lesions likely represent a type of shear injury that is unique to blast trauma. The observation that lesions often appeared to follow penetrating cortical vessels suggests a vascular mechanism of injury and that blood vessels may represent the fault lines along which the most damaging effect of the blast pressure is transmitted.

BackgroundBlast-related traumatic brain injury (TBI) is a common cause of injury in the military operations in Iraq and Afghanistan. How the primary blast wave affects the brain is not well understood. The aim of the present study was to examine whether blast exposure affects the cerebral vasculature in a rodent model. We analyzed the brains of rats exposed to single or multiple (three) 74.5 kPa blast exposures, conditions that mimic a mild TBI. Rats were sacrificed 24 hours or between 6 and 10 months after exposure. Blast-induced cerebral vascular pathology was examined by a combination of light microscopy, immunohistochemistry, and electron microscopy.ResultsWe describe a selective vascular pathology that is present acutely at 24 hours after injury. The vascular pathology is found at the margins of focal shear-related injuries that, as we previously showed, typically follow the patterns of penetrating cortical vessels. However, changes in the microvasculature extend beyond the margins of such lesions. Electron microscopy revealed that microvascular pathology is found in regions of the brain with an otherwise normal neuropil. This initial injury leads to chronic changes in the microvasculature that are still evident many months after the initial blast exposure.ConclusionsThese studies suggest that vascular pathology may be a central mechanism in the induction of chronic blast-related injury.

Insulin is a hormone typically associated with pancreatic release and blood sugar regulation. The brain was long thought to be "insulin-independent," but research has shown that insulin receptors (IR) are expressed on neurons, microglia and astrocytes, among other cells. The effects of insulin on cells within the central nervous system are varied, and can include both metabolic and non-metabolic functions. Emerging data suggests that insulin can improve neuronal survival or recovery after trauma or during neurodegenerative diseases. Further, data suggests a strong antiinflammatory component of insulin, which may also play a role in both neurotrauma and neurodegeneration. As a result, administration of exogenous insulin, either via systemic or intranasal routes, is an increasing area of focus in research in neurotrauma and neurodegenerative disorders. This review will explore the literature to date on the role of insulin in neurotrauma and neurodegeneration, with a focus on traumatic brain injury (TBI), spinal cord injury (SCI), Alzheimer's disease (AD) and Parkinson's disease (PD).

Microglia are the macrophages of the central nervous system (CNS), which function to monitor and maintain homeostasis. Microglial activation occurs after CNS injury, infection or disease. Prolonged microglial activation is detrimental to the CNS as they produce nitric oxide (NO), reactive oxygen species (ROS) and pro-inflammatory cytokines, resulting in neuronal cell dysfunction and death. Microglial activation is implicated in the neurological deficits following traumatic brain injury (TBI) and Alzheimer’s disease. Intranasal insulin administration is a promising treatment of Alzheimer’s disease and TBI. However, the exact effect of insulin on microglia is currently unclear. The goal of this study was therefore to examine the effect of insulin administration on activated microglia. The microglial cell line BV2 were exposed to a pro-inflammatory stimulus, lipopolysaccharide (LPS), followed by insulin administration. Outcome measures were conducted at 24 hours after treatment. In vitro assays quantified NO and ROS production. Western blot, immunocytochemistry and phagocytosis assay further examined the effect of insulin on microglial activity. Insulin treatment significantly reduced NO, ROS and TNFα production and increased phagocytic activity. Insulin treatment also significantly reduced iNOS expression, but had no significant effect on any other M1 or M2 macrophage polarization marker examined. These data suggest that insulin has very specific effects to reduce pro-inflammatory or chemoattractant properties of microglia, and this may be one mechanism by which insulin has beneficial effects in CNS injury or neurodegenerative conditions.

Blast-induced traumatic brain injury (TBI) has been a major cause of morbidity and mortality in the conflicts in Iraq and Afghanistan. How the primary blast wave affects the brain is not well understood. In particular, it is unclear whether blast injures the brain through mechanisms similar to those found in non-blast closed impact injuries (nbTBI). The β-amyloid (Aβ) peptide associated with the development of Alzheimer’s disease is elevated acutely following TBI in humans as well as in experimental animal models of nbTBI. We examined levels of brain Aβ following experimental blast injury using enzyme-linked immunosorbent assays for Aβ 40 and 42. In both rat and mouse models of blast injury, rather than being increased, endogenous rodent brain Aβ levels were decreased acutely following injury. Levels of the amyloid precursor protein (APP) were increased following blast exposure although there was no evidence of axonal pathology based on APP immunohistochemical staining. Unlike the findings in nbTBI animal models, levels of the β-secretase, β-site APP cleaving enzyme 1, and the γ-secretase component presenilin-1 were unchanged following blast exposure. These studies have implications for understanding the nature of blast injury to the brain. They also suggest that strategies aimed at lowering Aβ production may not be effective for treating acute blast injury to the brain.

Current clinical research into mild traumatic brain injury (mTBI) has focused on white matter changes as identified by advanced MRI based imaging techniques. However, perivascular tau accumulation in the brains of individuals diagnosed with mTBI suggests that the vasculature plays a key role in the pathology. This study used a rat model to examine whether the endothelial glycocalyx, a layer of the vasculature responsible for sensing luminal shear forces, is damaged by exposure to repeated low intensity blast, and whether this layer is associated with observed behavioral deficits. The blast exposure used consisted of 12, 40 kPa blast exposures conducted with a minimum of 24 h between blasts. We found that repeated blast exposure reduced glycocalyx length and density in various brain regions indicating damage. This blast exposure paradigm was associated with a mild performance decrement in the Morris water maze (MWM) which assesses learning and memory. Administration of hyaluronidase, an enzyme that binds to and degrades hyaluronan (a major structural component of the glycocalyx) prior to blast exposure reduced the observed behavioral deficits and induced a thickening of the glycocalyx layer. Taken together these findings demonstrate that the endothelial glycocalyx degradation following repeated blast is associated with behavioral decrements which can be prevented by treatment with hyaluronidase.