Enduring deficits in memory and neuronal pathology after blast-induced traumatic brain injury.
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ABSTRACT:
SUBMITTER: Sajja VS
PROVIDER: S-EPMC4633584 | biostudies-other | 2015
REPOSITORIES: biostudies-other
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Project description:Blast exposure has been identified to be the most common cause for traumatic brain injury (TBI) in soldiers. Over the years, rodent models to mimic blast exposures and the behavioral outcomes observed in veterans have been developed extensively. However, blast tube design and varying experimental parameters lead to inconsistencies in the behavioral outcomes reported across research laboratories. This review aims to curate the behavioral outcomes reported in rodent models of blast TBI using shockwave tubes or open field detonations between the years 2008–2019 and highlight the important experimental parameters that affect behavioral outcome. Further, we discuss the role of various design parameters of the blast tube that can affect the nature of blast exposure experienced by the rodents. Finally, we assess the most common behavioral tests done to measure cognitive, motor, anxiety, auditory, and fear conditioning deficits in blast TBI (bTBI) and discuss the advantages and disadvantages of these tests.
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Project description:Long-term molecular changes in the brain resulting from blast exposure may be mediated by epigenetic changes, such as deoxyribonucleic acid (DNA) methylation, that regulate gene expression. Aberrant regulation of gene expression is associated with behavioral abnormalities, where DNA methylation bridges environmental signals to sustained changes in gene expression. We assessed DNA methylation changes in the brains of rats exposed to three 74.5 kPa blast overpressure events, conditions that have been associated with long-term anxiogenic manifestations weeks or months following the initial exposures. Rat frontal cortex eight months post-exposure was used for cell sorting of whole brain tissue into neurons and glia. We interrogated DNA methylation profiles in these cells using Expanded Reduced Representation Bisulfite Sequencing. We obtained data for millions of cytosines, showing distinct methylation profiles for neurons and glia and an increase in global methylation in neuronal versus glial cells (p<10(-7)). We detected DNA methylation perturbations in blast overpressure-exposed animals, compared with sham blast controls, within 458 and 379 genes in neurons and glia, respectively. Differentially methylated neuronal genes showed enrichment in cell death and survival and nervous system development and function, including genes involved in transforming growth factor β and nitric oxide signaling. Functional validation via gene expression analysis of 30 differentially methylated neuronal and glial genes showed a 1.2 fold change in gene expression of the serotonin N-acetyltransferase gene (Aanat) in blast animals (p<0.05). These data provide the first genome-based evidence for changes in DNA methylation induced in response to multiple blast overpressure exposures. In particular, increased methylation and decreased gene expression were observed in the Aanat gene, which is involved in converting serotonin to the circadian hormone melatonin and is implicated in sleep disturbance and depression associated with traumatic brain injury.
| S-EPMC4532898 | biostudies-literature
Project description:Mild to moderate traumatic brain injury (TBI) due to blast exposure is frequently diagnosed in veterans returning from the wars in Iraq and Afghanistan. However, it is unclear whether neural damage resulting from blast TBI differs from that found in TBI due to blunt-force trauma (e.g., falls and motor vehicle crashes). Little is also known about the effects of blast TBI on neural networks, particularly over the long term. Because impairment in working memory has been linked to blunt-force TBI, the present functional magnetic resonance imaging (fMRI) study sought to investigate whether brain activation in response to a working memory task would discriminate blunt-force from blast TBI. Twenty-five veterans (mean age = 29.8 years, standard deviation = 6.01 years, 1 female) who incurred TBI due to blast an average of 4.2 years prior to enrollment and 25 civilians (mean age = 27.4 years, standard deviation = 6.68 years, 4 females) with TBI due to blunt-force trauma performed the Sternberg Item Recognition Task while undergoing fMRI. The task involved encoding 1, 3, or 5 items in working memory. A group of 25 veterans (mean age = 29.9 years, standard deviation = 5.53 years, 0 females) and a group of 25 civilians (mean age = 27.3 years, standard deviation = 5.81 years, 0 females) without history of TBI underwent identical imaging procedures and served as controls. Results indicated that the civilian TBI group and both control groups demonstrated a monotonic relationship between working memory set size and activation in the right caudate during encoding, whereas the blast TBI group did not (p < 0.05, corrected for multiple comparisons using False Discovery Rate). Blast TBI was also associated with worse performance on the Sternberg Item Recognition Task relative to the other groups, although no other group differences were found on neuropsychological measures of episodic memory, inhibition, and general processing speed. These results could not be attributed to caudate atrophy or the presence of PTSD symptoms. Our results point to a specific vulnerability of the caudate to blast injury. Changes in activation during the Sternberg Item Recognition Task, and potentially other tasks that recruit the caudate, may serve as biomarkers for blast TBI.
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Project description:Explosive blast-induced traumatic brain injury (blast-TBI) in military personnel is a leading cause of injury and persistent neurological abnormalities, including chronic pain. We previously demonstrated that chronic pain after spinal cord injury results from central sensitization in the posterior thalamus (PO). The presence of persistent headaches and back pain in veterans with blast-TBI suggests a similar involvement of thalamic sensitization. Here, we tested the hypothesis that pain after blast-TBI is associated with abnormal increases in activity of neurons in PO thalamus. We developed a novel model with two unique features: (1) blast-TBI was performed in awake, un-anesthetized rats, to simulate the human experience and to eliminate confounds of anesthesia and surgery inherent in other models; (2) only the cranium, rather than the entire body, was exposed to a collimated blast wave, with the blast wave striking the posterior cranium in the region of the occipital crest and foramen magnum. Three weeks after blast-TBI, rats developed persistent, ongoing spontaneous pain. Contrary to our hypothesis, we found no significant differences in the activity of PO neurons, or of neurons in the spinal trigeminal nucleus. There were also no significant changes in gliosis in either of these structures. This novel model will allow future studies on the pathophysiology of chronic pain after blast-TBI.
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Project description: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.
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Project description:Recent wars in Iraq and Afghanistan have accounted for an estimated 270,000 blast exposures among military personnel. Blast traumatic brain injury (TBI) is the 'signature injury' of modern warfare. Blood brain barrier (BBB) disruption following blast TBI can lead to long-term and diffuse neuroinflammation. In this study, we investigate for the first time the role of bryostatin-1, a specific protein kinase C (PKC) modulator, in ameliorating BBB breakdown. Thirty seven Sprague-Dawley rats were used for this study. We utilized a clinically relevant and validated blast model to expose animals to moderate blast exposure. Groups included: control, single blast exposure, and single blast exposure + bryostatin-1. Bryostatin-1 was administered i.p. 2.5 mg/kg after blast exposure. Evan's blue, immunohistochemistry, and western blot analysis were performed to assess injury. Evan's blue binds to albumin and is a marker for BBB disruption. The single blast exposure caused an increase in permeability compared to control (t?=?4.808, p?<?0.05), and a reduction back toward control levels when bryostatin-1 was administered (t?=?5.113, p?<?0.01). Three important PKC isozymes, PKC?, PKC?, and PKC?, were co-localized primarily with endothelial cells but not astrocytes. Bryostatin-1 administration reduced toxic PKC? levels back toward control levels (t?=?4.559, p?<?0.01) and increased the neuroprotective isozyme PKC? (t?=?6.102, p?<?0.01). Bryostatin-1 caused a significant increase in the tight junction proteins VE-cadherin, ZO-1, and occludin through modulation of PKC activity. Bryostatin-1 ultimately decreased BBB breakdown potentially due to modulation of PKC isozymes. Future work will examine the role of bryostatin-1 in preventing chronic neurodegeneration following repetitive neurotrauma.
| S-EPMC5000781 | biostudies-literature
Project description:Blast-induced traumatic brain injury (bTBI) has been linked to a multitude of delayed-onset neurodegenerative and neuropsychiatric disorders, but complete understanding of their pathogenesis remains elusive. To develop mechanistic relationships between bTBI and post-blast neurological sequelae, it is imperative to characterize the initiating traumatic mechanical events leading to eventual alterations of cell, tissue, and organ structure and function. This paper presents a wireless sensing system capable of monitoring the intracranial brain deformation in real-time during the event of a bTBI. The system consists of an implantable soft magnet and an external head-mounted magnetic sensor that is able to measure the field in three dimensions. The change in the relative position of the soft magnet WITH respect to the external sensor as the result of the blast wave induces changes in the magnetic field. The magnetic field data in turn is used to extract the temporal and spatial motion of the brain under the blast wave in real-time. The system has temporal and spatial resolutions of 5??s and 10??m. Following the characterization and validation of the sensor system, we measured brain deformations in a live rodent during a bTBI.
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Project description:Delayed memory deficits are common for patients with mild traumatic brain injury (mTBI), according to a recent systematic review of meta-analyses (Karr et al., 2014). However, there has been little work to identify different cognitive processes that may be underpinning these delayed memory deficits for mTBI. Frontal cortex is important for delayed memory, and is implicated in the pathophysiology of mTBI; moreover, frontal lobes are typically considered the locus of executive abilities. To further explore these relationships, we sought to partly explain delayed memory deficits after mTBI by examining behavioral indicators of executive function. Results showed that sub-acute as well as chronic mTBI patients performed worse than controls on the delayed memory trial of the Hopkins Verbal Learning Test-Revised (Brandt & Benedict, 2001), recalling approximately 18% and 15% fewer words, respectively. Furthermore, worse delayed memory performance was associated with less use of the cognitive strategy of semantic clustering, and with lower scores for the executive function composite from a standardized neuropsychological battery (NIH EXAMINER; Kramer et al., 2014). In contrast, serial clustering, a memory organizational strategy thought to be less dependent on executive function, did not show strong relationships to clinical status or delayed memory performance. This exploratory work suggests novel hypotheses to be tested in future, confirmatory studies, including that general executive functions and/or semantic clustering will mediate delayed memory deficits following mTBI.
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Project description:Mild traumatic brain injury (TBI) involves widespread axonal injury and activation of microglia, which initiates secondary processes that worsen the TBI outcome. The upregulation of cannabinoid type-2 receptors (CB2) when microglia become activated allows CB2-binding drugs to selectively target microglia. CB2 inverse agonists modulate activated microglia by shifting them away from the harmful pro-inflammatory M1 state toward the helpful reparative M2 state and thus can stem secondary injury cascades. We previously found that treatment with the CB2 inverse agonist SMM-189 after mild TBI in mice produced by focal cranial blast rescues visual deficits and the optic nerve axon loss that would otherwise result. We have further shown that raloxifene, which is Food and Drug Administration (FDA)-approved as an estrogen receptor modulator to treat osteoporosis, but also possesses CB2 inverse agonism, yields similar benefit in this TBI model through its modulation of microglia. As many different traumatic events produce TBI in humans, it is widely acknowledged that diverse animal models must be used in evaluating possible therapies. Here we examine the consequences of TBI created by blunt impact to the mouse head for visual function and associated pathologies and assess raloxifene benefit. We found that mice subjected to impact TBI exhibited decreases in contrast sensitivity and the B-wave of the electroretinogram, increases in light aversion and resting pupil diameter, and optic nerve axon loss, which were rescued by daily injection of raloxifene at 5 or 10 mg/ml for 2 weeks. Raloxifene treatment was associated with reduced M1 activation and/or enhanced M2 activation in retina, optic nerve, and optic tract after impact TBI. Our results suggest that the higher raloxifene dose, in particular, may be therapeutic for the optic nerve by enhancing the phagocytosis of axonal debris that would otherwise promote inflammation, thereby salvaging less damaged axons. Our current work, together with our prior studies, shows that microglial activation drives secondary injury processes after both impact and cranial blast TBI and raloxifene mitigates microglial activation and visual system injury in both cases. The results thus provide a strong basis for phase 2 human clinical trials evaluating raloxifene as a TBI therapy.
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Project description: Not available
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