Blast-induced Mild Traumatic Brain Injury Research Articles

Influence of trace elements changes in the cerebellum on the rat’s behavior in elevated plus maze in the early period of mild blast-induced traumatic brain injury

The aim of the current study was to determine whether there are changes in brain trace elements of rats with blast-induced trauma and if these changes affect behavior in the elevated plus maze. Materials and methods. The study was carried out on 126 sexually mature male Wistar and were divided into 3 groups: Experimental – exposed to a shock wave 26.4 ± 3.6 kPa (n = 42); Sham (n = 42), the animals of which were subjected to inhalation anesthesia with halothane and fixation in a horizontal position; and Intact (n = 42). Behavior was study in elevated plus maze. The duration of presence in the open and closed arms, the number of stands, the duration of grooming was recorded in all groups of rats for 3 minutes. After, the animals were euthanized with halothane, followed by removal of the brain. The cerebellum was completely separated for spectral analysis using energy dispersive X-ray fluorescence analysis (EDRFA) on the analyzer EXPERT 3 XL. Results. Results showed significant changes of cognitive activity in experimental group which are indicate functional disorders of the cerebellum in the form of maladaptation in space with subsequent inhibition of motor centers. Cu/Fe ratio was decreased in the 14th and 21st days and increased in the 28th. Cu/Zn ratio was decreased on the 14th day. Zn/Fe ratio was higher on the 14th and 28th days. The existence of correlations between changes in trace elements and behavioral disorders in experimental rats was established. Conclusions. In the early period of blast-induced traumatic brain injury, cerebellar dysfunction in the form of spatial maladaptation with subsequent depression of motor centers was observed in the experimental rats Correlation analysis showed the presence of different strengths and directions of relationships between the ratios of Cu/Fe, Cu/Zn and Zn/Fe in the cerebellum and behavioral indicators in the elevated plus maze (duration of stay in open and closed arms, grooming and vertical motor activity) of experimental rats.

LOCOMOTOR ACTIVITY OF RATS WITH BLAST-INDUCED TRAUMATIC BRAIN INJURY IN A COMPLEX MAZE

Aim – to investigate the peculiarities of rats with blast-induced brain injury movement in the complex maze.Material and methods. The study was carried out on 15 sexually mature Wistar rats. All animals were randomly divided into 3 groups: experimental group (n=5), which was anesthetized and exposed to an air shock wave with an overpressure of 26-36 kPa; sham group (n=5), which was only anesthetized, and intact group (n=5). The study of locomotor activity was performed using a complex maze for 5 consecutive days, starting on the 1st day after the simulation of blast-induced brain injury. The route of rat`s movement through the maze of three groups was graphically depicted and visually analyzed.Results of the study. The complex maze is considered to be complicated due to the presence of a central zone and T-shaped branches to the right and left, ending with feeders. The complication of the situation and task lead to fear with rapid adaptation of healthy rats. However, if the brain functions are impaired, the experimental animal loses its physiological ability to adapt and shows signs of anxiety. The analysis of the images of the movement paths showed that on the 1st day of training, the rats of the experimental group moved more actively, despite the fact that the animals did not yet know that food was waiting for them. They performed monotonous movements and went to the side sectors more often. On 2nd day, the experimental rats were more active and explored the maze more stereotypically than intact animals. On 3rd and 4th days, clear signs of spatial memory impairment in the experimental group were found in terms of lengthening the path to the feeder. On the 5th day, it was found that the experimental rats were still poorly oriented in the maze, with a monotonous examination of the side sectors.Conclusions. Thus, mild blast-induced traumatic brain injury leads to persistent impairment of spatial memory, as well as behavioral disorders in the form of anxiety. The rats of the experimental group demonstrated stereotypical locomotor activity, as evidenced by the examination of the lateral sectors of the complex maze. At the same time, the memory for food reinforcement was well developed and retained.

EXPLORATORY ACTIVITY OF RATS IN THE ACUTE PERIOD OF MILD BLAST-INDUCED TRAUMATIC BRAIN INJURY

The relevance of this work is related to the widespread use of explosive devices in military conflicts. More common and "invisible" is mild blast-induced brain injury. This can manifest through anxiety, emotional dysregulation, and spatial memory impairments. However, significant variability exists in modeling blast-induced traumatic brain injury and spatial memory assessment methods. This study aimed to investigate the exploratory activity of rats during the acute phase of mild blast-induced traumatic brain injury modelled by using a newly developed device.
 The study carried out on 18 sexually mature male Wistar rats weighing 220-270 g. The selected rats were divided into three groups: an experimental group (n=6), animals were modeled with blast-induced trauma by generating an air shock wave with an overpressure of 26.4±3.6 kPa, sham group (n=6), animals were subjected only to inhalation anesthesia with halothane and fixed in a horizontal position, and an intact group (n=6). The exploratory activity was recorded by the iPhoneXR camera; the route of movement through the maze of rats from three groups was graphically depicted and visually analyzed, as well as the number of entries into the "false shelters" was counted and the performance of experimental, sham and intact rats was compared. On the 1st day of the post-traumatic period, the experimental rats explored a greater number of "false shelters", by 72% (p<0.01) compared to intact animals and by 65% (p<0.05) compared to control animals. On the 3rd day, this activity was higher by 53% (p<0.05) compared to intact and by 67% (p<0.05) compared to control rats. On day 7, experimental rats explored more, by 86% (p<0.01) compared to intact rats and also by 86% (p<0.01) compared to control animals. The obtained results indicate an increase in the exploratory activity of rats in the acute period of mild blast-induced brain injury.

Changes of rat’s brain vesseles after air shock wave exposure

Mild blast-induced traumatic brain injury is common among the military, resulting in cognitive impairment, reduced socialization, which leads to disability and, as a result, a deterioration in the quality of life. It is considered that blood-brain barrier disruption and microvascular dysfunction are the key to this type of injury. The purpose of study was to study changes in brain vessels after air shock wave exposure. The study was carried out on 48 mature male Wistar rats, which were randomly divided into 2 groups: an experimental group, in which animals were subjected to inhalation anesthesia using halothane and exposed to a shock wave with an overpressure of 26.4±3.6 kPa, and a Sham group. After simulation of injury on days 1st, 3rd, 7th, 14th, and 21st, the rats were euthanized and the brain was removed and after all subjected to standard histological procedures and stained with hematoxylin and eosin. For immunohistochemical studies, as primary antibodies were used eNOS. The finished preparations were examined by light microscopy and photographed. Disorders of the cerebral vessels in experimental rats were detected from day 1st of the posttraumatic period. It was found that the blast wave led to vascular rupture, as well as increased vascular permeability with diapedesis of red blood cells and cerebral edema for up to 21st days. Focal violations of the vascular wall integrity in cortical and hippocampal hemocapillaries, venular link of the submembrane vessels; changes in the morphology of the metabolic vessels endothelium; uneven blood filling of the brain vessels were of major importance. These changes indicate that increased eNOS expression leads to dilation of cerebral vessels, which is a compensatory mechanism in response to injury to improve cerebral blood circulation. However, eNOS is not involved in vasodilation, which we observed up to 21st day post-trauma.

The state of antioxidant system and emotional status in rats with mild blast-induced traumatic brain injury

The aim was to evaluate the markers of emotional status and the antioxidant system activity in rats with blast-induced traumatic brain injury. Materials and methods. The study carried out on 85 sexually mature male Wistar rats in compliance with the current legislation on humane treatment of animals. The selected rats were randomly divided into three groups: I – study in the Barnes maze; II – study in the Open Field test; and III – study of glutathione reductase activity in a solution of rat erythrocyte’s hemolysate. In each of these groups, three groups were formed: Experimental – exposed to a shock wave with an overpressure of 26.4 ± 3.6 kPa; the Sham – subjected only to halothane and fixation; and the Intact group. Results. Showed a disturbance in the emotional status and the oxidative stress development in rats with blast-induced trauma. The time of experimental rats freezing in the Barnes maze increased by 69 % (p < 0.01) on 28th day compared to 1st day, indicating the development of fear and negative emotionality. Changes in the defecation acts number indicate the development of anxiety in the acute period (1–3 days), followed by a depression-like state. The glutathione reductase activity in experimental rats was significantly higher compared to sham and intact rats, but gradually decreased inside in the experimental group. The results of the correlation analysis indicate the presence of weak relationships between the freezing time and the glutathione reductase activity. The positive relationship of a strong degree was found between the number of defecation acts and glutathione reductase on 1st day and a negative relationship of a strong degree was found on 7th day. Conclusions. We suppose that oxidative stress is a link, but not the leading one, in the pathogenesis of emotional disturbance in rats with blast-induced brain injury.

Mitigation ofHearing Damage With Liraglutide Treatment inChinchillas After Repeated Blast Exposures at Mild-TBI.

Although hearing protection devices (HPDs) have been widely used during training and combat, over one million veterans experience service-connected hearing loss. Hearing damage has been reported to be associated with blast-induced mild traumatic brain injury (mTBI) and there is a lack of understanding and treatment. Liraglutide is a glucagon-like peptide-1 receptor agonist and a potential treatment for TBI-induced memory deficits. This study aims to investigate the function of the liraglutide to prevent damage and facilitate hearing restoration in chinchillas exposed to multiple high-intensity, mTBI-level blasts. Chinchillas were divided into three treatment groups: blast control, pre-blast drug treatment, and post-blast drug treatment. On day 1, the chinchilla ears were protected by HPDs and exposed to three blasts with peak pressure levels of 15-25 psi. The auditory brainstem response (ABR), distortion product otoacoustic emission (DPOAE), and middle latency response (MLR) were recorded pre- and post-blast on day 1 and on days 4, 7, 14, and 28. Substantial acute damage was observed and progressively recovered in chinchillas after the blast exposures. The pre-blast treatment group exhibited the lowest elevation of the ABR threshold and reduction of the wave I amplitude on day 1 after blasts. The liraglutide treatment insignificantly facilitated the recovery of the DPOAE levels and ABR thresholds on days 14 and 28. The pre-blast treatment chinchillas showed reduced MLR amplitudes on days 4 and 7. This study indicated that the pre-blast liraglutide administration provided damage protection against blasts in addition to the HPDs. Current evidence suggests that the effect of liraglutide is more prominent in the early phase of the experiment.

Reduction of epinephrine in the lumbar spinal cord following repetitive blast-induced traumatic brain injury in rats.

Abstract Traumatic brain injury-induced unfavorable outcomes in human patients have independently been associated with dysregulated levels of monoamines, especially epinephrine, although few preclinical studies have examined the epinephrine level in the central nervous system after traumatic brain injury. Epinephrine has been shown to regulate the activities of spinal motoneurons as well as increase the heart rate, blood pressure, and blood flow to the hindlimb muscles. Therefore, the purpose of the present study was to determine the impact of repeated blast-induced traumatic brain injury on the epinephrine levels in several function-specific central nervous system regions in rats. Following three repeated blast injuries at three-day intervals, the hippocampus, motor cortex, locus coeruleus, vestibular nuclei, and lumbar spinal cord were harvested at post-injury day eight and processed for epinephrine assays using a high-sensitive electrochemical detector coupled with high-performance liquid chromatography. Our results showed that the epinephrine levels were significantly decreased in the lumbar spinal cord tissues of blast-induced traumatic brain injury animals compared to the levels detected in age- and sex-matched sham controls. In other function-specific central nervous system regions, although the epinephrine levels were slightly altered following blast-induced traumatic brain injury, they were not statistically significant. These results suggest that blast injury-induced significant downregulation of epinephrine in the lumbar spinal cord could negatively impact the motor and cardiovascular function. This is the first report to show altered epinephrine levels in the spinal cord following repetitive mild blast-induced traumatic brain injury.

Trace elements changes in the forebrain and their influence on the rats behavior in elevated plus maze in acute period of mild blast-induced traumatic brain injury

The relevance of the study is related to the high frequency of blast-induced brain injury in both military and civilian populations, which is caused by the use of various types of explosives in military conflicts, including in Ukraine today. Changes of biometals in the acute period of a mild blast-induced traumatic brain injury, including forebrain that participates in the implementation of various behavioral and cognitive processes, remain unexplained. The study was carried out on 54 sexually mature male Wistar rats, which were divided into 3 groups: experimental (influenced by a baroacoustic wave with an excess pressure of 26-36 kPa, previously anesthetized with halothane and softly fixed), sham (under the influence of halothane and fixation), intact. Behavior was studied in an elevated plus maze. Biometals in the forebrain were determined using energy dispersive X-ray fluorescence analysis. Standard deviation, Mann-Whitney U test (р<0.01, р<0.05), Spearman's correlation coef­ficient (r, р<0.01) were statistically calculated. According to the results of the study, behavioral changes in the elevated plus maze were found in the rats of the experimental group, which indicate the absence of fear on day 1 and 3 and the increase of anxiety on day 7 of the post-traumatic period. Spectral analysis of the forebrain showed significant (р<0.01) changes in the Cu/Fe, Cu/Zn and Zn/Fe ratios, which are the result of iron accumulation due to disruption of the blood-brain barrier. The obtained changes in the ratio of biometals lead to the development of anxiety, which is confirmed by correlation analysis. This indicates that the imbalance of biometals is an important secondary factor in the pathogenesis of blast-induced brain traumatic injury, which is important to consider for diagnosis, treatment and prevention of complications.

Visceral hypersensitivity induced by mild traumatic brain injury via the corticotropin-releasing hormone receptor: An animal model.

Mild blast-induced traumatic brain injury (bTBI) induces various gut symptoms resembling human irritable bowel syndrome (IBS) as one of mental and behavioral disorders. However, the underlying mechanisms remain unclear. We investigated whether the extremely localized brain impact extracranially induced by laser-induced shock wave (LISW) evoked IBS-like phenomenon including visceral hypersensitivity and intestinal hyperpermeability in rats. The rats were subjected to LISW on the scalp to shock the entire brain. Visceral hypersensitivity was evaluated by the threshold pressure of abdominal withdrawal reflex (AWR) using a colorectal distension test. Permeability was evaluated by the concentration of penetrating FITC-dextran from intestine and the mRNA expression levels of tight junction family proteins. Involvement of corticotropin-releasing factor receptor (CRFR) 1 and 2 was examined by evaluating mRNA expression and modulating CRFR function with agonist, recombinant CRF (10 μg/kg), and antagonist, astressin (33 μg/kg). High-throughput sequencing of the gut microbiota was performed by MiSeqIII instrument and QIIME tool. The thresholds of the AWR were significantly lowered after LISW. Permeability was increased in small intestine by LISW along with decreased expression of tight junction ZO-1. LISW significantly increased CRFR1 expression and decreased CRFR2 expression. Visceral hypersensitivity was significantly aggravated by CRFR agonist and suppressed by CRFR antagonist. The α- and β-diversity of the fecal microbiota was altered after LISW. LISW provoked visceral hypersensitivity, small intestinal hyperpermeability, altered expression of CRFRs and changes in the microbiota, suggesting that genuine bTBI caused by LISW can induce a pathophysiology comparable to that of human IBS.

Learning ability and spatial memory status in rats during the acute period of mild blast-induced traumatic brain injury

The mild blast-induced brain traumatic injury like a battle fatigue, leads to neurological disability, including due to a violation of spatial memory. The presented work is the result of a blast-induced brain traumatic injury study on a self-developed device. For the experiment, 15 white Wistar rats were used and were divided into 3 groups: rats of Experimental group exposed by air shock wave (26–36 кPа); Sham group (anesthesia with halothane and fixation in a horizontal position) and Intact group. The ability to learning (food reinforcement) and the spatial memory state (time to search for food, vertical locomotor activity) were studied in the complex maze during the first 5 days of the posttraumatic period. To assess the emotional state, we counted the number and observed the quality of grooming acts. All researches were conducted in compliance with modern standards for humane attitude of animals. The results of our study clearly indicate a violation of spatial memory, which was manifested in the time of searching lengthening of the feeder and in the increase of vertical locomotor activity in the rats of the experimental group, while the animals clearly remembered that they were looking for food. The analysis of grooming showed qualitative changes in the form of incomplete and prolonged acts. Such changes indicate the development of anxiety in rats with mild blast-induced traumatic brain injury. This, in turn, led to deterioration of the spatial orientation and memory formation. Thus, the consequence of a mild blast-induced traumatic brain injury in the acute period is changes in the cognitive function of the brain in the form of deterioration of spatial memory, which was aggravated by a disturbance of emotionality in the form of anxiety. At the same time, the memory regarding the presence of food was formed adequately. Keywords: explosion, central nervous system, cognitive function, memory, maze.

The Imbalance of Astrocytic Mitochondrial Dynamics Following Blast-Induced Traumatic Brain Injury.

Mild blast-induced traumatic brain injury (bTBI) is a modality of injury that has been of major concern considering a large number of military personnel exposed to explosive blast waves. bTBI results from the propagation of high-pressure static blast forces and their subsequent energy transmission within brain tissue. Exposure to this overpressure energy causes a diffuse injury that leads to acute cell damage and, if chronic, leads to detrimental long-term cognitive deficits. The literature presents a neuro-centric approach to the role of mitochondria dynamics dysfunction in bTBI, and changes in astrocyte-specific mitochondrial dynamics have not been characterized. The balance between fission and fusion events is known as mitochondrial dynamics. As a result of fission and fusion, the mitochondrial structure is constantly altering its shape to respond to physiological stimuli or stress, which in turn affects mitochondrial function. Astrocytic mitochondria are recognized to play an essential role in overall brain metabolism, synaptic transmission, and neuron protection. Mitochondria are vulnerable to injury insults, leading to the increase in mitochondrial fission, a mechanism controlled by the GTPase dynamin-related protein (Drp1) and the phosphorylation of Drp1 at serine 616 (p-Drp1s616). This site is critical to mediate the Drp1 translocation to mitochondria to promote fission events and consequently leads to fragmentation. An increase in mitochondrial fragmentation could have negative consequences, such as promoting an excessive generation of reactive oxygen species or triggering cytochrome c release. The aim of the present study was to characterize the unique pattern of astrocytic mitochondrial dynamics by exploring the role of DRP1 with a combination of in vitro and in vivo bTBI models. Differential remodeling of the astrocytic mitochondrial network was observed, corresponding with increases in p-Drp1S616 four hours and seven days post-injury. Further, results showed a time-dependent reactive astrocyte phenotype transition in the rat hippocampus. This discovery can lead to innovative therapeutics targets to help prevent the secondary injury cascade after blast injury that involves mitochondria dysfunction.

Abstract 2273: Sex and genotype affect mouse hippocampal gene expression in response to mild blast-induced traumatic brain injury

Abstract 2273: Sex and genotype affect mouse hippocampal gene expression in response to mild blast-induced traumatic brain injury

Blast effects on post-concussive and mental health outcomes: Data from Canadian Armed Forces breachers and snipers

LAY SUMMARY There has been increasing interest in understanding the impact of blast exposure on health and performance in military members and Veterans. This phenomenon has proven difficult to study because personnel diagnosed with blast-induced mild traumatic brain injury (mTBI) typically also exhibit emotional difficulties such as posttraumatic stress disorder (PTSD), likely because the events that led to mTBI in theatre were also emotionally traumatic. In turn, this comorbidity makes it difficult to tease apart symptoms uniquely due to blast-induced mTBI or PTSD. Researchers have therefore explored surrogate settings wherein the effects of blast exposure can be assessed in an operationally realistic, yet scientifically more controlled manner, such as breacher and sniper training. To that aim, researchers administered a measure of post-concussive symptomatology and two mental health scales to breachers and snipers, as well as sex- and age-matched military controls. The breachers and snipers reported greater levels of post-concussive symptoms, but not poorer mental health outcomes. Therefore, post-concussive symptoms and mental health outcomes might be dissociable when the impact of repetitive exposure to low-level blast is assessed in the context of training and operations, rather than following warzone deployment involving primarily high-level blast exposure.

Altered Serotonin 2A (5-HT2A) Receptor Signaling Underlies Mild TBI-Elicited Deficits in Social Dominance.

Various forms of traumatic brain injury (TBI) are a leading cause of disability in the United States, with the generation of neuropsychiatric complications such as depression, anxiety, social dysfunction, and suicidality being common comorbidities. Serotonin (5-HT) signaling is linked to psychiatric disorders; however, the effects of neurotrauma on normal, homeostatic 5-HT signaling within the central nervous system (CNS) have not been well characterized. We hypothesize that TBI alters specific components of 5-HT signaling within the CNS and that the elucidation of specific TBI-induced alterations in 5-HT signaling may identify novel targets for pharmacotherapies that ameliorate the neuropsychiatric complications of TBI. Herein, we provide evidence that closed-head blast-induced mild TBI (mTBI) results in selective alterations in cortical 5-HT2A receptor signaling. We find that mTBI increases in vivo cortical 5-HT2A receptor sensitivity and ex vivo radioligand binding at time points corresponding with mTBI-induced deficits in social behavior. In contrast, in vivo characterizations of 5-HT1A receptor function revealed no effect of mTBI. Notably, we find that repeated pharmacologic activation of 5-HT2A receptors post-injury reverses deficits in social dominance resulting from mTBI. Cumulatively, these studies provide evidence that mTBI drives alterations in cortical 5-HT2A receptor function and that selective targeting of TBI-elicited alterations in 5-HT2A receptor signaling may represent a promising avenue for the development of pharmacotherapies for TBI-induced generation of neuropsychiatric disorders.

Blast-Induced Mild Traumatic Brain Injury Alterations of Corticotropin-Releasing Factor Neuronal Activity in the Mouse Hypothalamic Paraventricular Nucleus.

Blast-induced mild traumatic brain injury (mbTBI) is the most common cause of TBI in US service members and veterans. Those exposed to TBI are at greater risk of developing neuropsychiatric disorders such as posttraumatic stress disorder, anxiety and depressive disorders, and substance use disorders following TBI. Previously, we have demonstrated that mbTBI increases anxiety-like behaviors in mice and dysregulates stress at the level of corticotropin-releasing factor (CRF) neurons in the paraventricular nucleus (PVN). To expand on how mTBI may dysregulate the stress axis centrally, here PVN CRF neuronal activity was evaluated using whole cell-patch clamp recordings in hypothalamic slices from sham and mbTBI adult male CRF:tdTomato mice 7 days post-injury. We found that mbTBI generally did not affect the neuronal excitability and intrinsic membrane properties of PVN CRF neurons; this injury selectively increased the frequency of spontaneous neuronal firing of PVN CRF neurons localized to the dorsal PVN (dPVN) but not ventral PVN (vPVN). Consistently, mbTBI-induced dPVN CRF hyperactivity was associated with pre- and post-synaptic depression of spontaneous GABAergic transmission onto dPVN CRF neurons suggesting that mbTBI-induced GABAergic synaptic dysfunction may underlie dPVN CRF neuronal hyperactivity and increases in dPVN CRF signaling. The present results provide the first evidence for mbTBI-induced alterations in PVN CRF neuronal activity and GABAergic synaptic function that could mediate hypothalamic CRF dysregulation following mbTBI contributing to stress psychopathology associated with blast injury.

Psychosocial impairment following mild blast-induced traumatic brain injury in rats

Traumatic brain injury (TBI) is associated with increased risk for mental health disorders, impacting post-injury quality of life and societal reintegration. TBI is also associated with deficits in psychosocial processing, defined as the cognitive integration of social and emotional behaviors, however little is known about how these deficits manifest and their contributions to post-TBI mental health.In this pre-clinical investigation using rats, a single mild blast TBI (mbTBI) induced impairment of psychosocial processing in the absence of confounding physical polytrauma, post-injury motor deficits, affective abnormalities, or deficits in non-social behavior. Impairment severity correlated with acute upregulations of a known oxidative stress metabolite, 3-hydroxypropylmercapturic acid (3-HPMA), in urine. Resting state fMRI alterations in the acute post-injury period implicated key brain regions known to regulate psychosocial behavior, including orbitofrontal cortex (OFC), which is congruent with our previous report of elevated acrolein, a marker of neurotrauma and 3-HPMA precursor, in this region following mbTBI. OFC of mbTBI-exposed rats demonstrated elevated mRNA expression of metabotropic glutamate receptors 1 and 5 (mGluR1/5) and injection of mGluR1/5-selective agonist in OFC of uninjured rats approximated mbTBI-induced psychosocial processing impairment, demonstrating a novel role for OFC in this psychosocial behavior. Furthermore, OFC may serve as a hotspot for TBI-induced disruption of psychosocial processing and subsequent mental health disorders.

NK1 antagonists attenuate tau phosphorylation after blast and repeated concussive injury

Exposure to repeated concussive traumatic brain injury (TBI) and to blast-induced TBI has been associated with the potential development of the neurodegenerative condition known as chronic traumatic encephalopathy (CTE). CTE is characterized by the accumulation of hyperphosphorylated tau protein, with the resultant tau tangles thought to initiate the cognitive and behavioral manifestations that appear as the condition progresses. However, the mechanisms linking concussive and blast TBI with tau hyperphosphorylation are unknown. Here we show that single moderate TBI, repeated concussive TBI and blast-induced mild TBI all result in hyperphosphorylation of tau via a substance P mediated mechanism. Post-injury administration of a substance P, NK1 receptor antagonist attenuated the injury-induced phosphorylation of tau by modulating the activity of several key kinases including Akt, ERK1/2 and JNK, and was associated with improvement in neurological outcome. We also demonstrate that inhibition of the TRPV1 mechanoreceptor, which is linked to substance P release, attenuated injury-associated tau hyperphosphorylation, but only when it was administered prior to injury. Our results demonstrate that TBI-mediated stimulation of brain mechanoreceptors is associated with substance P release and consequent tau hyperphosphorylation, with administration of an NK1 receptor antagonist attenuating tau phosphorylation and associated neurological deficits. NK1 antagonists may thus represent a pharmacological approach to attenuate the potential development of CTE following concussive and blast TBI.

Behavioral and Myelin-Related Abnormalities after Blast-Induced Mild Traumatic Brain Injury in Mice.

In civilian and military settings, mild traumatic brain injury (mTBI) is a common consequence of impacts to the head, sudden blows to the body, and exposure to high-energy atmospheric shockwaves from blast. In some cases, mTBI from blast exposure results in long-term emotional and cognitive deficits and an elevated risk for certain neuropsychiatric diseases. Here, we tested the effects of mTBI on various forms of auditory-cued fear learning and other measures of cognition in male C57BL/6J mice after single or repeated blast exposure (blast TBI; bTBI). bTBI produced an abnormality in the temporal organization of cue-induced freezing behavior in a conditioned trace fear test. Spatial working memory, evaluated by the Y-maze task performance, was also deleteriously affected by bTBI. Reverse-transcription quantitative real-time polymerase chain reaction (RT-qPCR) analysis for glial markers indicated an alteration in the expression of myelin-related genes in the hippocampus and corpus callosum 1-8 weeks after bTBI. Immunohistochemical and ultrastructural analyses detected bTBI-related myelin and axonal damage in the hippocampus and corpus callosum. Together, these data suggest a possible link between blast-induced mTBI, myelin/axonal injury, and cognitive dysfunction.

18F-FDG PET Combined With MR Spectroscopy Elucidates the Progressive Metabolic Cerebral Alterations After Blast-Induced Mild Traumatic Brain Injury in Rats.

A majority of blast-induced mild traumatic brain injury (mTBI) patients experience persistent neurological dysfunction with no findings on conventional structural MR imaging. It is urgent to develop advanced imaging modalities to detect and understand the pathophysiology of blast-induced mTBI. Fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) could detect neuronal function and activity of the injured brain, while MR spectroscopy provides complementary information and assesses metabolic irregularities following injury. This study aims to investigate the effectiveness of combining 18F-FDG PET with MR spectroscopy to evaluate acute and subacute metabolic cerebral alterations caused by blast-induced mTBI. Thirty-two adult male Sprague–Dawley rats were exposed to a single blast (mTBI group) and 32 rats were not exposed to the blast (sham group), followed by 18F-FDG PET, MRI, and histological evaluation at baseline, 1–3 h, 1 day, and 7 days post-injury in three separate cohorts. 18F-FDG uptake showed a transient increase in the amygdala and somatosensory cortex, followed by a gradual return to baseline from day 1 to 7 days post-injury and a continuous rise in the motor cortex. In contrast, decreased 18F-FDG uptake was seen in the midbrain structures (inferior and superior colliculus). Analysis of MR spectroscopy showed that inflammation marker myo-inositol (Ins), oxidative stress marker glutamine + glutamate (Glx), and hypoxia marker lactate (Lac) levels markedly elevated over time in the somatosensory cortex, while the major osmolyte taurine (Tau) level immediately increased at 1–3 h and 1 day, and then returned to sham level on 7 days post-injury, which could be due to the disruption of the blood–brain barrier. Increased 18F-FDG uptake and elevated Ins and Glx levels over time were confirmed by histology analysis which showed increased microglial activation and gliosis in the frontal cortex. These results suggest that 18F-FDG PET and MR spectroscopy can be used together to reflect more comprehensive neuropathological alterations in vivo, which could improve our understanding of the complex alterations in the brain after blast-induced mTBI.

Original experimental rat model of blast-induced mild traumatic brain injury: a pilot study

ABSTRACT Objective Diagnosing blast-induced mild traumatic brain injury (mTBI) is difficult due to minimal imaging findings. This study aimed to establish a rat model of behavioral abnormality caused by blast-induced mTBI and detect new findings for therapeutic intervention. Methods We used a bench-top blast wave generator with the blast wave exiting through a 20-mm I.D. nozzle aimed at the focused target. The blast wave was directed at the head of male Wistar rats under general anesthesia positioned prone 2.5 cm below the nozzle. Peak shock wave pressure was 646.2 ± 70.3 kPa. Results After blast injury, mTBI rats did not show the findings of brain hemorrhage or contusion macroscopically and on hematoxylin-eosin-stained frozen sections but did show anorexia and weight loss in the early post-injury phase. Behavioral experiments revealed short-term memory impairment at 2 weeks and depression-like behavior at 2 and 6 weeks. Diffusion-weighted ex vivo MRI showed high-intensity areas in layers of the bilateral hippocampus. Immunohistochemical analysis revealed accumulation of reactive microglia and GFAP-positive astrocytes in the same region and loss of NeuN-positive neurons in the hippocampal pyramidal cell layer. Conclusions This model can reflect the pathophysiology of blast-induced mTBI and could potentially be used to develop therapeutic interventions in the future.