Multi-Focal Neuronal Ultrastructural Abnormalities and Synaptic Alterations in Mice after Low-Intensity Blast Exposure

Konan, Landry; Song, Hailong; Pentecost, Genevieve; Fogwe, Delvise T.; Ndam, Tina; Cui, Jiankun; Johnson, Catherine E.; Grant, De Ana G.; White, Tommi; Chen, Mei; Xia, Weiming; Černak, Ibolja; DePalma, Ralph G.

doi:10.1089/neu.2018.6260

Cited by 27 publications

(38 citation statements)

References 61 publications

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“…Semple et al showed (by dendritic lengths, branching, and Sholl intersections) that male mice were more sensitive to CCI induced reductions in prefrontal cortex layer III pyramidal neurons and dentate gyrus granule cells 40 and these morphological changes were reflected in spatial memory deficits and hyperactivity in similarly treated mice in their study. In another recent blast TBI mouse model, Konan et al observed decreased synapse density within the cortex, which mirror our results indicating a reduction in the dendritic arbor within the cortex 41 . In a previous study using the same blast TBI mouse model, myelinated axonal damage and mitochondrial abnormalities were also observed 42 .…”

Section: Discussionsupporting

confidence: 91%

Effect of mild blast-induced TBI on dendritic architecture of the cortex and hippocampus in the mouse

Ratliff

Mervis

Citron

et al. 2020

Sci Rep

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Traumatic brain injury (TBI) has been designated as a signature injury of modern military conflicts. Blast trauma, in particular, has come to make up a significant portion of the TBIs which are sustained in warzones. Though most TBIs are mild, even mild TBI can induce long term effects, including cognitive and memory deficits. In our study, we utilized a mouse model of mild blast-related TBI (bTBI) to investigate TBI-induced changes within the cortex and hippocampus. We performed rapid Golgi staining on the layer IV and V pyramidal neurons of the parietal cortex and the CA1 basilar tree of the hippocampus and quantified dendritic branching and distribution. We found decreased dendritic branching within both the cortex and hippocampus in injured mice. Within parietal cortex, this decreased branching was most evident within the middle region, while outer and inner regions resembled that of control mice. This study provides important knowledge in the study of how the shockwave associated with a blast explosion impacts different brain regions. Brain trauma is one of the largest causes of death and disability in the United States, accounting for about 30% of all injury deaths 1. Traumatic brain injury (TBI) occurs when sufficient external force is imposed on the head resulting in brain damage. TBI varies in severity, with the most common form being mild (mTBI), which accounts for approximately 80% of the cases in the United States 2. While more severe TBI involve a mix of neuronal cell death and axonal degradation, mild TBIs can produce more subtle morphological changes within the cells of the brain and consequent cognitive deficits for which there are no consistently effective treatments. In addition to this, laboratory and clinical evaluations of mTBI patients (i.e. CT scan, MRI) often fail to reveal any clear and consistent morphological changes to the brain, thus making proper diagnosis difficult 3,4. Primary mechanical changes due to impact are generally followed by several biologic processes that occur in the minutes and days following mTBI 5 , resulting in secondary brain injuries, including inflammation in the brain, giving rise to elevated intracranial pressure 6. Physical symptoms of mTBI typically include headaches, nausea, dizziness and weakness; in addition to this there are a number of cognitive symptoms such as amnesia and problems with short term memory, as well as emotional symptoms such as depression or anxiety. Traumatic brain injury has become an increasingly common affliction among military personnel in recent conflicts. Among U.S. Forces, there have been approximately 384,000 brain injuries sustained since 2000 7. Blast-related TBIs make up a significant portion of these injuries 8,9 , accounting for numerous long term cognitive deficits in veterans who have been exposed to blasts. In the Iraq and Afghanistan wars, mTBI has been identified as a signature injury with an estimated 10-20% of veterans having been affected 10. In 2017, over 83,000 military personnel were diagnosed and treated for TBI ...

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Section: Discussionsupporting

confidence: 91%

Effect of mild blast-induced TBI on dendritic architecture of the cortex and hippocampus in the mouse

Ratliff

Mervis

Citron

et al. 2020

Sci Rep

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“…The “ground-bounce” effect occurs when the explosion detonates above ground level and the shockwave hits the ground prior to impacting the subject ( 41 , 47 ). This model has provided reliable and consistent findings demonstrated in previous studies ( 20 , 41 , 43 , 48 – 50 ). Briefly, anesthetized mice were placed on platforms in naturally forward-facing prone position, and the LIB exposure was generated by detonating 350 grams of military-grade C4 explosive in open field.…”

Section: Investigating Injurious Blast Forcessupporting

confidence: 89%

“…A hypothesis concerning the biologically damaging effects of the blast-body interaction posits that as blast-induced pressure waves travel through brain tissue there is excitation of the phonon continuum in brain water followed by decomposition into specific low-frequency acoustic wave oscillations ( 51 ). These oscillations surpass the tensile strength of water in the brain, resulting in rupture of subcellular structures at nanometer levels ( 20 , 41 , 51 ).…”

Section: Investigating Injurious Blast Forcesmentioning

confidence: 99%

“…Our previous gross anatomical and microscopic studies of primary blast injury have shown absence of macroscopic and cell damage, including necrosis or hemorrhages in the brain after LIB exposure ( 19 , 41 ). However, transmission electron microscopy (TEM) clearly delineated nanoscale neuropathology, including ultrastructural myelin sheath defects, abnormalities of myelinated axons, asymmetric synapses, neuronal soma, and dendrites ( 20 , 41 , 50 ). These nanoscale intracellular changes were anticipated based on the calculations of blast-induced phonon decay in brain water ( 51 ).…”

Section: Investigating Injurious Blast Forcesmentioning

confidence: 99%

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Perspectives on Primary Blast Injury of the Brain: Translational Insights Into Non-inertial Low-Intensity Blast Injury

et al. 2022

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Most traumatic brain injuries (TBIs) during military deployment or training are clinically “mild” and frequently caused by non-impact blast exposures. Experimental models were developed to reproduce the biological consequences of high-intensity blasts causing moderate to severe brain injuries. However, the pathophysiological mechanisms of low-intensity blast (LIB)-induced neurological deficits have been understudied. This review provides perspectives on primary blast-induced mild TBI models and discusses translational aspects of LIB exposures as defined by standardized physical parameters including overpressure, impulse, and shock wave velocity. Our mouse LIB-exposure model, which reproduces deployment-related scenarios of open-field blast (OFB), caused neurobehavioral changes, including reduced exploratory activities, elevated anxiety-like levels, impaired nesting behavior, and compromised spatial reference learning and memory. These functional impairments associate with subcellular and ultrastructural neuropathological changes, such as myelinated axonal damage, synaptic alterations, and mitochondrial abnormalities occurring in the absence of gross- or cellular damage. Biochemically, we observed dysfunctional mitochondrial pathways that led to elevated oxidative stress, impaired fission-fusion dynamics, diminished mitophagy, decreased oxidative phosphorylation, and compensated cell respiration-relevant enzyme activity. LIB also induced increased levels of total tau, phosphorylated tau, and amyloid β peptide, suggesting initiation of signaling cascades leading to neurodegeneration. We also compare translational aspects of OFB findings to alternative blast injury models. By scoping relevant recent research findings, we provide recommendations for future preclinical studies to better reflect military-operational and clinical realities. Overall, better alignment of preclinical models with clinical observations and experience related to military injuries will facilitate development of more precise diagnosis, clinical evaluation, treatment, and rehabilitation.

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“…There have also been a limited number of studies published in rodents as well as larger animals (e.g. primates and swine) using open field settings with exposure to detonated explosives which truly begin to reproduce the real life settings of military and civilian blast exposures 10,[13][14][15][16][17][18] . While open field environments are the most realistic, there are difficulties in carrying out open field studies including but not limited to: large amounts of required explosives and securing an accessible location where such studies can occur 10 .…”

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confidence: 99%

Explosive-driven double-blast exposure: molecular, histopathological, and behavioral consequences

Murphy

Iacono

Pan

et al. 2020

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Traumatic brain injury generated by blast may induce long-term neurological and psychiatric sequelae. We aimed to identify molecular, histopathological, and behavioral changes in rats 2 weeks after explosive-driven double-blast exposure. Rats received two 30-psi (~ 207-kPa) blasts 24 h apart or were handled identically without blast. All rats were behaviorally assessed over 2 weeks. At Day 15, rats were euthanized, and brains removed. Brains were dissected into frontal cortex, hippocampus, cerebellum, and brainstem. Western blotting was performed to measure levels of total-Tau, phosphorylated-Tau (pTau), amyloid precursor protein (APP), GFAP, Iba1, αII-spectrin, and spectrin breakdown products (SBDP). Kinases and phosphatases, correlated with tau phosphorylation were also measured. Immunohistochemistry for pTau, APP, GFAP, and Iba1 was performed. pTau protein level was greater in the hippocampus, cerebellum, and brainstem and APP protein level was greater in cerebellum of blast vs control rats (p < 0.05). GFAP, Iba1, αII-spectrin, and SBDP remained unchanged. No immunohistochemical or neurobehavioral changes were observed. The dissociation between increased pTau and APP in different regions in the absence of neurobehavioral changes 2 weeks after double blast exposure is a relevant finding, consistent with human data showing that battlefield blasts might be associated with molecular changes before signs of neurological and psychiatric disorders manifest.

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Multi-Focal Neuronal Ultrastructural Abnormalities and Synaptic Alterations in Mice after Low-Intensity Blast Exposure

Cited by 27 publications

References 61 publications

Effect of mild blast-induced TBI on dendritic architecture of the cortex and hippocampus in the mouse

Effect of mild blast-induced TBI on dendritic architecture of the cortex and hippocampus in the mouse

Perspectives on Primary Blast Injury of the Brain: Translational Insights Into Non-inertial Low-Intensity Blast Injury

Explosive-driven double-blast exposure: molecular, histopathological, and behavioral consequences

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