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A mouse model of human repetitive mild traumatic brain injury.

ABSTRACT: A novel method for the study of repetitive mild traumatic brain injury (rmTBI) that models the most common form of head injury in humans is presented. Existing animal models of TBI impart focal, severe damage unlike that seen in repeated and mild concussive injuries, and few are configured for repetitive application. Our model is a modification of the Marmarou weight drop method and allows repeated head impacts to lightly anesthetized mice. A key facet of this method is the delivery of an impact to the cranium of an unrestrained subject allowing rapid acceleration of the free-moving head and torso, an essential characteristic known to be important for concussive injury in humans, and a factor that is missing from existing animal models of TBI. Our method does not require scalp incision, emplacement of protective skull helmets or surgery and the procedure can be completed in 1-2 min. Mice spontaneously recover the righting reflex and show no evidence of seizures, paralysis or impaired behavior. Skull fractures and intracranial bleeding are very rare. Minor deficits in motor coordination and locomotor hyperactivity recover over time. Histological analyses reveal mild astrocytic reactivity (increased expression of GFAP) and increased phospho-tau but a lack of blood-brain-barrier disruption, edema and microglial activation. This new animal model is simple and cost-effective and will facilitate characterization of the neurobiological and behavioral consequences of rmTBI. It is also ideal for high throughput screening of potential new therapies for mild concussive injuries as experienced by athletes and military personnel.

SUBMITTER: Kane MJ

PROVIDER: S-EPMC3221913 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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A mouse model of human repetitive mild traumatic brain injury.

Kane Michael J MJ Angoa-Pérez Mariana M Briggs Denise I DI Viano David C DC Kreipke Christian W CW Kuhn Donald M DM

Journal of neuroscience methods 20110912 1

A novel method for the study of repetitive mild traumatic brain injury (rmTBI) that models the most common form of head injury in humans is presented. Existing animal models of TBI impart focal, severe damage unlike that seen in repeated and mild concussive injuries, and few are configured for repetitive application. Our model is a modification of the Marmarou weight drop method and allows repeated head impacts to lightly anesthetized mice. A key facet of this method is the delivery of an impact ...[more]

PMID: 21930157

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Project description:Clinical studies examining the interaction between traumatic brain injury (TBI) and stress-related disorders (e.g., post-traumatic stress disorder) are often complicated by methodological constraints, such as heterogeneity in injury type and severity, time post-trauma, and predisposing risk factors. Developing relevant animal models whereby many variables can be efficiently controlled is thus essential to understanding this elusive relationship. Here, we use our repeated unpredictable stress (RUS) paradigm, in combination with our established mouse model of repetitive mild TBI (r-mTBI), to assess the impact of repeated exposures to these paradigms on behavioral and neurobiological measures. C57BL/6J male mice were exposed to RUS and r-mTBI at 3 and 6 months of age followed by batteries of behavioral testing. Mice were euthanized 10 days and 3 months post-exposure, with brain and plasma samples collected for molecular profiling. The RUS paradigm involved exposure to a predator odor (trimethylthiazoline; TMT) while under restraint, daily unstable social housing, five inescapable footshocks on separate days, and chronic social isolation. Animals receiving r-mTBI (?×?5) and stress were exposed to a single closed-head injury 1?h after each footshock. Stress-alone mice showed significant weight loss, recall of traumatic memories, and anxiety-like and passive stress-coping behavior when compared with control mice. However, in stress+r-mTBI animals, the changes in cued fear memory, anxiety, and stress-coping tests were diminished, possibly due to TBI-induced hyperactivity. We also report complex brain molecular and neuropathological findings. Stress and r-mTBI, either individually or comorbidly, were associated with a chronic reduction in dendritic spine GluN2A/GluN2B ratio in the hippocampus. While stress augmented the r-mTBI-dependent astrogliosis in the corpus callosum, it mitigated r-mTBI-induced increases in hippocampal pro-brain-derived neurotrophic factor. We anticipate that our model will be a good platform to untangle the complex comorbid pathophysiology in stress disorders and r-mTBI.

Project description:Repetitive mild traumatic brain injury (mTBI) is a risk factor for the development of neurodegenerative diseases such as chronic traumatic encephalopathy typified by immunoreactive tau aggregates in the depths of the sulci. However, the underlying neurobiological mechanisms involved have not been largely explored. Phospholipids are important molecules which form membrane lipid bilayers; they are ubiquitous to every cell in the brain, and carry out a host of different functions. Imbalance in phospholipid metabolism, signaling and transport has been documented in some neurological conditions. However, not much is currently known about their roles in repetitive mTBI and how this may confer risk for the development of age-related neurodegenerative diseases. To address this question, we designed a longitudinal study (24 h, 3, 6, 9, and 12 months post-injury) to comprehensively investigate mTBI dependent brain phospholipid profiles compared to sham counterparts. We use our established mouse model of repetitive mTBI that has been extensively characterized up to 1-year post-injury in humanized tau (hTau) mice, which expresses all six human tau isoforms, on a null murine background. Our data indicates a significant increase in sphingomyelin, phosphatidylethanolamine (PE), phosphatidylcholine (PC), and derivative lysoPE and lysoPC at acute and/or sub-acute time points post-injury within the cortex and hippocampus. There was also a parallel increase at early time points in monounsaturated, polyunsaturated and saturated fatty acids. Omega-6 (arachidonic acid) to omega-3 (docosahexaenoic acid) fatty acid ratio for PE and PC species was increased also at 24 h and 3 months post-injury in both hippocampus and cortex. The long-term consequences of these early changes in phospholipids on neuronal and non-neuronal cell function is unclear, and warrants further study. Understanding phospholipid metabolism, signaling and transport following TBI could be valuable; they may offer novel targets for therapeutic intervention not only in TBI but other neurodegenerative diseases.

Project description:Repetitive mild traumatic brain injury (r-mTBI) results in neuropathological and biochemical consequences in the human visual system. Using a recently developed mouse model of r-mTBI, with control mice receiving repetitive anesthesia alone (r-sham) we assessed the effects on the retina and optic nerve using histology, immunohistochemistry, proteomic and lipidomic analyses at 3 weeks post injury. Retina tissue was used to determine retinal ganglion cell (RGC) number, while optic nerve tissue was examined for cellularity, myelin content, protein and lipid changes. Increased cellularity and areas of demyelination were clearly detectable in optic nerves in r-mTBI, but not in r-sham. These changes were accompanied by a ~25% decrease in the total number of Brn3a-positive RGCs. Proteomic analysis of the optic nerves demonstrated various changes consistent with a negative effect of r-mTBI on major cellular processes like depolymerization of microtubules, disassembly of filaments and loss of neurons, manifested by decrease of several proteins, including neurofilaments (NEFH, NEFM, NEFL), tubulin (TUBB2A, TUBA4A), microtubule-associated proteins (MAP1A, MAP1B), collagen (COL6A1, COL6A3) and increased expression of other proteins, including heat shock proteins (HSP90B1, HSPB1), APOE and cathepsin D. Lipidomic analysis showed quantitative changes in a number of phospholipid species, including a significant increase in the total amount of lysophosphatidylcholine (LPC), including the molecular species 16:0, a known demyelinating agent. The overall amount of some ether phospholipids, like ether LPC, ether phosphatidylcholine and ether lysophosphatidylethanolamine were also increased, while the majority of individual molecular species of ester phospholipids, like phosphatidylcholine and phosphatidylethanolamine, were decreased. Results from the biochemical analysis correlate well with changes detected by histological and immunohistochemical methods and indicate the involvement of several important molecular pathways. This will allow future identification of therapeutic targets for improving the visual consequences of r-mTBI.

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A mouse model of human repetitive mild traumatic brain injury.

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A mouse model of human repetitive mild traumatic brain injury.

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