The Effect of Injury Severity on Behavior: A Phenotypic Study of Cognitive and Emotional Deficits after Mild, Moderate, and Severe Controlled Cortical Impact Injury in Mice

Washington, Patricia M.; Forcelli, Patrick A.; Wilkins, Tiffany; Zapple, David N.; Parsadanian, Maia; Burns, Mark P.

doi:10.1089/neu.2012.2456

Cited by 191 publications

(169 citation statements)

References 41 publications

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“…The bone over cortex was removed, exposing a 3.5-mm region on one side. The impact was delivered by a computer-controlled head impactor (Precision Systems, Fairfax Station, VA) using a 3-mm flat circular impactor tip at a speed of 4 m/s and a depth of 1.5 mm below the cortical surface for 0.1 s. The parameter set was to provide a moderate contusive brain injury in mice (31,32). Sham-injured animals received craniotomy only.…”

Section: Methodsmentioning

confidence: 99%

Essential Roles of Neutral Ceramidase and Sphingosine in Mitochondrial Dysfunction Due to Traumatic Brain Injury

Novgorodov

Riley

et al. 2014

Journal of Biological Chemistry

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Background: A cardinal feature of many neurological disorders is mitochondrial dysfunction. Results: Knocking down neutral ceramidase reduces mitochondrial sphingosine, preserves mitochondrial function, and improves brain function recovery after trauma. Conclusion: Activation of the sphingosine-generating pathway plays a significant role in promoting mitochondrial injury. Significance: This is the first direct evidence of endogenous sphingosine involvement in regulation of mitochondrial function.

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Section: Methodsmentioning

confidence: 99%

Essential Roles of Neutral Ceramidase and Sphingosine in Mitochondrial Dysfunction Due to Traumatic Brain Injury

Novgorodov

Riley

et al. 2014

Journal of Biological Chemistry

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“…24 Briefly, the water maze apparatus consisted of a 4-foot diameter pool (San Diego Instruments, San Diego, CA) filled with water maintained at Synaptic/White Matter Changes after rmTBI…”

Section: Morris Water Mazementioning

confidence: 99%

“…The elevated plus maze was used to assay anxiety-like behavior 21 days after injury, as previously described, 24 with modifications. The apparatus (San Diego Instruments) consists of a 26-inch long cross-shaped platform made of nonporous white plastic and elevated 15 inches above the ground.…”

Section: Elevated Plus Mazementioning

confidence: 99%

Dendritic Spine Loss and Chronic White Matter Inflammation in a Mouse Model of Highly Repetitive Head Trauma

Winston

Noël

Neustadtl

et al. 2016

The American Journal of Pathology

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Mild traumatic brain injury (mTBI) is an emerging risk for chronic behavioral, cognitive, and neurodegenerative conditions. Athletes absorb several hundred mTBIs each year; however, rodent models of repeat mTBI (rmTBI) are often limited to impacts in the single digits. Herein, we describe the effects of 30 rmTBIs, examining structural and pathological changes in mice up to 365 days after injury. We found that single mTBI causes a brief loss of consciousness and a transient reduction in dendritic spines, reflecting a loss of excitatory synapses. Single mTBI does not cause axonal injury, neuroinflammation, or cell death in the gray or white matter. Thirty rmTBIs with a 1-day interval between each mTBI do not cause dendritic spine loss; however, when the interinjury interval is increased to 7 days, dendritic spine loss is reinstated. Thirty rmTBIs cause white matter pathology characterized by positive silver and Fluoro-Jade B staining, and microglial proliferation and activation. This pathology continues to develop through 60 days, and is still apparent at 365 days, after injury. However, rmTBIs did not increase b-amyloid levels or tau phosphorylation in the 3xTg-AD mouse model of Alzheimer disease. Our data reveal that single mTBI causes a transient loss of synapses, but that rmTBIs habituate to repetitive injury within a short time period. rmTBI causes the development of progressive white matter pathology that continues for months after the final impact. (Am J Pathol 2016, 186: 552e567; http://dx.doi.org/ 10.1016/j.ajpath.2015 Athletes participating in contact sports are at high risk of exposure to large numbers of concussive and subconcussive mild traumatic brain injuries (mTBIs). Recent studies using head impact telemetry systems have begun to reveal how many head impacts an individual football player can receive in the process of playing his or her sport. In a study of high school football players, the number of helmet impacts >20 g recorded in a single season ranged from a low of 226 (average, 4.7 per session) to a high of 1855 (average, 38.6 per session). 1 Most of these impacts do not result in the clinical diagnosis of a concussion; however, it is not known if the cumulative effects of these impacts can result in increased damage to the brain. mTBI has been extensively modeled in mice and rats. 2 Most of these rodent models use fewer than five mTBIs, and report adverse events, including intracerebral bleeding, skull fractures, severe axonal injury, neuronal cell death, and increased mortality.

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“…21 Three-month-old male C57/ Bl6J mice were anesthetized with isoflurane (induction at 3-4% and maintenance at 1-2%) evaporated in oxygen and administered through a nose mask. The mice were placed on a custom-made stereotaxic frame with a built-in heating bed that maintains body temperature at 37°C.…”

Section: Injurymentioning

confidence: 99%

Controlled Cortical Impact Results in an Extensive Loss of Dendritic Spines that Is Not Mediated by Injury-Induced Amyloid-Beta Accumulation

Winston

Chellappa

Wilkins

et al. 2013

Journal of Neurotrauma

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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.

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The Effect of Injury Severity on Behavior: A Phenotypic Study of Cognitive and Emotional Deficits after Mild, Moderate, and Severe Controlled Cortical Impact Injury in Mice

Cited by 191 publications

References 41 publications

Essential Roles of Neutral Ceramidase and Sphingosine in Mitochondrial Dysfunction Due to Traumatic Brain Injury

Essential Roles of Neutral Ceramidase and Sphingosine in Mitochondrial Dysfunction Due to Traumatic Brain Injury

Dendritic Spine Loss and Chronic White Matter Inflammation in a Mouse Model of Highly Repetitive Head Trauma

Controlled Cortical Impact Results in an Extensive Loss of Dendritic Spines that Is Not Mediated by Injury-Induced Amyloid-Beta Accumulation

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