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  1. Article ; Online: Repetitive head trauma, chronic traumatic encephalopathy and tau: Challenges in translating from mice to men.

    Ojo, Joseph O / Mouzon, Benoit C / Crawford, Fiona

    Experimental neurology

    2016  Volume 275 Pt 3, Page(s) 389–404

    Abstract: Chronic traumatic encephalopathy (CTE) is a neurological and psychiatric condition marked by preferential perivascular foci of neurofibrillary and glial tangles (composed of hyperphosphorylated-tau proteins) in the depths of the sulci. Recent ... ...

    Abstract Chronic traumatic encephalopathy (CTE) is a neurological and psychiatric condition marked by preferential perivascular foci of neurofibrillary and glial tangles (composed of hyperphosphorylated-tau proteins) in the depths of the sulci. Recent retrospective case series published over the last decade on athletes and military personnel have added considerably to our clinical and histopathological knowledge of CTE. This has marked a vital turning point in the traumatic brain injury (TBI) field, raising public awareness of the potential long-term effects of mild and moderate repetitive TBI, which has been recognized as one of the major risk factors associated with CTE. Although these human studies have been informative, their retrospective design carries certain inherent limitations that should be cautiously interpreted. In particular, the current overriding issue in the CTE literature remains confusing in regard to appropriate definitions of terminology, variability in individual pathologies and the potential case selection bias in autopsy based studies. There are currently no epidemiological or prospective studies on CTE. Controlled preclinical studies in animals therefore provide an alternative means for specifically interrogating aspects of CTE pathogenesis. In this article, we review the current literature and discuss difficulties and challenges of developing in-vivo TBI experimental paradigms to explore the link between repetitive head trauma and tau-dependent changes. We provide our current opinion list of recommended features to consider for successfully modeling CTE in animals to better understand the pathobiology and develop therapeutics and diagnostics, and critical factors, which might influence outcome. We finally discuss the possible directions of future experimental research in the repetitive TBI/CTE field.
    MeSH term(s) Animals ; Brain Injury, Chronic/etiology ; Brain Injury, Chronic/metabolism ; Brain Injury, Chronic/pathology ; Craniocerebral Trauma/complications ; Craniocerebral Trauma/metabolism ; Craniocerebral Trauma/pathology ; Disease Models, Animal ; Humans ; Mice ; Translational Medical Research/methods ; Translational Medical Research/trends ; tau Proteins/metabolism
    Chemical Substances tau Proteins
    Language English
    Publishing date 2016-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 207148-4
    ISSN 1090-2430 ; 0014-4886
    ISSN (online) 1090-2430
    ISSN 0014-4886
    DOI 10.1016/j.expneurol.2015.06.003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Chronic Hippocampal Abnormalities and Blunted HPA Axis in an Animal Model of Repeated Unpredictable Stress.

    Algamal, Moustafa / Ojo, Joseph O / Lungmus, Carlyn P / Muza, Phillip / Cammarata, Constance / Owens, Margaret J / Mouzon, Benoit C / Diamond, David M / Mullan, Michael / Crawford, Fiona

    Frontiers in behavioral neuroscience

    2018  Volume 12, Page(s) 150

    Abstract: Incidence of post-traumatic stress disorder (PTSD) ranges from 3 to 30% in individuals exposed to traumatic events, with the highest prevalence in groups exposed to combat, torture, or rape. To date, only a few FDA approved drugs are available to treat ... ...

    Abstract Incidence of post-traumatic stress disorder (PTSD) ranges from 3 to 30% in individuals exposed to traumatic events, with the highest prevalence in groups exposed to combat, torture, or rape. To date, only a few FDA approved drugs are available to treat PTSD, which only offer symptomatic relief and variable efficacy. There is, therefore, an urgent need to explore new concepts regarding the biological responses causing PTSD. Animal models are an appropriate platform for conducting such studies. Herein, we examined the chronic behavioral and neurobiological effects of repeated unpredictable stress (RUS) in a mouse model. 12 weeks-old C57BL/6J male mice were exposed to a 21-day RUS paradigm consisting of exposures to a predator odor (TMT) whilst under restraint, unstable social housing, inescapable footshocks and social isolation. Validity of the model was assessed by comprehensive examination of behavioral outcomes at an acute timepoint, 3 and 6 months post-RUS; and molecular profiling was also conducted on brain and plasma samples at the acute and 6 months timepoints. Stressed mice demonstrated recall of traumatic memories, passive stress coping behavior, acute anxiety, and weight gain deficits when compared to control mice. Immunoblotting of amygdala lysates showed a dysregulation in the p75NTR/ProBDNF, and glutamatergic signaling in stressed mice at the acute timepoint. At 6 months after RUS, stressed mice had lower plasma corticosterone, reduced hippocampal CA1 volume and reduced brain-derived neurotrophic factor levels. In addition, glucocorticoid regulatory protein FKBP5 was downregulated in the hypothalamus of stressed mice at the same timepoint, together implicating an impaired hypothalamus-pituitary-adrenal-axis. Our model demonstrates chronic behavioral and neurobiological outcomes consistent with those reported in human PTSD cases and thus presents a platform through which to understand the neurobiology of stress and explore new therapeutic interventions.
    Language English
    Publishing date 2018-07-20
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2452960-6
    ISSN 1662-5153
    ISSN 1662-5153
    DOI 10.3389/fnbeh.2018.00150
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Ultrastructural Changes in the White and Gray Matter of Mice at Chronic Time Points After Repeated Concussive Head Injury.

    Ojo, Joseph O / Bachmeier, Corbin / Mouzon, Benoit C / Tzekov, Radouil / Mullan, Michael / Davies, Heather / Stewart, Michael G / Crawford, Fiona

    Journal of neuropathology and experimental neurology

    2015  Volume 74, Issue 10, Page(s) 1012–1035

    Abstract: Mild traumatic brain injury is a risk factor for neurodegenerative disease. We recently developed a model of repetitive concussive injury in mice that we have extensively characterized from 24 hours to 24 months after injury. Animals show evidence of ... ...

    Abstract Mild traumatic brain injury is a risk factor for neurodegenerative disease. We recently developed a model of repetitive concussive injury in mice that we have extensively characterized from 24 hours to 24 months after injury. Animals show evidence of progressive spatial memory deficits, thinning of the corpus callosum, axonal injury, and neuroglial activation. Here, we extended our neuropathologic characterization to the ultrastructural level in both a qualitative and a quantitative study. We focused on chronic (3 and 6 months) postinjury time points when the earliest stages of degenerative secondary changes were previously observed. In both C57BL/6 and hTau mice, we found white matter damage typified by axonal degeneration, microglial phagocytosis, and increased neuroglial cell density. In the cerebral cortex, we observed evidence of synaptic degeneration, dark neurons, altered dendritic microfilaments, subtle changes to the microvasculature, a mild augmentation of age-related features such as lipofuscin deposition, and electron-dense inclusions in microglial and perivascular cells. The majority of these ultrastructural features seemed to be more prominent at 3 versus 6 months after injury. Similar patterns were observed in C57BL/6 and hTau mice. These findings further support the relevance of our concussive injury model to the consequences of repetitive mild traumatic brain injury in humans.
    MeSH term(s) Animals ; Brain Injuries/pathology ; Disease Models, Animal ; Gray Matter/ultrastructure ; Mice ; Mice, Inbred C57BL ; Microscopy, Electron, Transmission ; White Matter/ultrastructure
    Language English
    Publishing date 2015-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3088-0
    ISSN 1554-6578 ; 0022-3069
    ISSN (online) 1554-6578
    ISSN 0022-3069
    DOI 10.1097/NEN.0000000000000247
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Negative Impact of Female Sex on Outcomes from Repetitive Mild Traumatic Brain Injury in hTau Mice Is Age Dependent: A Chronic Effects of Neurotrauma Consortium Study.

    Ferguson, Scott A / Mouzon, Benoit C / Lynch, Cillian / Lungmus, Carlyn / Morin, Alexander / Crynen, Gogce / Carper, Benjamin / Bieler, Gayle / Mufson, Elliott J / Stewart, William / Mullan, Michael / Crawford, Fiona

    Frontiers in aging neuroscience

    2017  Volume 9, Page(s) 416

    Abstract: Traumatic brain injury (TBI) is a serious public health concern which strikes someone every 15 s on average in the US. Even mild TBI, which comprise as many as 75% of all TBI cases, carries long term consequences. The effects of age and sex on long term ... ...

    Abstract Traumatic brain injury (TBI) is a serious public health concern which strikes someone every 15 s on average in the US. Even mild TBI, which comprise as many as 75% of all TBI cases, carries long term consequences. The effects of age and sex on long term outcome from TBI is not fully understood, but due to the increased risk for neurodegenerative diseases after TBI it is important to understand how these factors influence the outcome from TBI. This study examined the neurobehavioral and neuropathological effects of age and sex on the outcome 15 days following repetitive mild traumatic brain injury (r-mTBI) in mice transgenic for human tau (hTau). These mice express the six human isoforms of tau but do not express endogenous murine tau and they develop tau pathology and memory impairment in an age-dependent manner. After 5 mild impacts, aged female mice showed motor impairments that were absent in aged male mice, as well as younger animals. Conversely, aged female sham mice outperformed all other groups of aged mice in a Barnes maze spatial memory test. Pathologically, increases in IBA-1 and GFAP staining typically seen in this model of r-mTBI showed the expected increases with both injury and age, but phosphorylated tau stained with CP13 in the hippocampus (reduced in female sham mice compared to males) and PHF1 in the cortex (reduced in female TBI mice compared to male TBI mice) showed the only histological signs of sex-dependent differences in these mice.
    Language English
    Publishing date 2017-12-22
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2558898-9
    ISSN 1663-4365
    ISSN 1663-4365
    DOI 10.3389/fnagi.2017.00416
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Lifelong behavioral and neuropathological consequences of repetitive mild traumatic brain injury.

    Mouzon, Benoit C / Bachmeier, Corbin / Ojo, Joseph O / Acker, Christopher M / Ferguson, Scott / Paris, Daniel / Ait-Ghezala, Ghania / Crynen, Gogce / Davies, Peter / Mullan, Michael / Stewart, William / Crawford, Fiona

    Annals of clinical and translational neurology

    2017  Volume 5, Issue 1, Page(s) 64–80

    Abstract: Objective: Exposure to repetitive concussion, or mild traumatic brain injury (mTBI), has been linked with increased risk of long-term neurodegenerative changes, specifically chronic traumatic encephalopathy (CTE). To date, preclinical studies largely ... ...

    Abstract Objective: Exposure to repetitive concussion, or mild traumatic brain injury (mTBI), has been linked with increased risk of long-term neurodegenerative changes, specifically chronic traumatic encephalopathy (CTE). To date, preclinical studies largely have focused on the immediate aftermath of mTBI, with no literature on the lifelong consequences of mTBI in these models. This study provides the first account of lifelong neurobehavioral and histological consequences of repetitive mTBI providing unique insight into the constellation of evolving and ongoing pathologies with late survival.
    Methods: Male C57BL/6J mice (aged 2-3 months) were exposed to either single or repetitive mild TBI or sham procedure. Thereafter, animals were monitored and assessed at 24 months post last injury for measures of motor coordination, learning deficits, cognitive function, and anxiety-like behavior prior to euthanasia and preparation of the brains for detailed neuropathological and protein biochemical studies.
    Results: At 24 months survival animals exposed to r-mTBI showed clear evidence of learning and working memory impairment with a lack of spatial memory and vestibule-motor vestibulomotor deficits compared to sham animals. Associated with these late behavioral deficits there was evidence of ongoing axonal degeneration and neuroinflammation in subcortical white matter tracts. Notably, these changes were also observed after a single mTBI, albeit to a lesser degree than repetitive mTBI.
    Interpretation: In this context, our current data demonstrate, for the first time, that rather than an acute, time limited event, mild TBI can precipitate a lifelong degenerative process. These data therefore suggest that successful treatment strategies should consider both the acute and chronic nature of mTBI.
    Language English
    Publishing date 2017-12-14
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2740696-9
    ISSN 2328-9503
    ISSN 2328-9503
    DOI 10.1002/acn3.510
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Chronic neuropathological and neurobehavioral changes in a repetitive mild traumatic brain injury model.

    Mouzon, Benoit C / Bachmeier, Corbin / Ferro, Austin / Ojo, Joseph-Olubunmi / Crynen, Gogce / Acker, Christopher M / Davies, Peter / Mullan, Michael / Stewart, William / Crawford, Fiona

    Annals of neurology

    2014  Volume 75, Issue 2, Page(s) 241–254

    Abstract: Objective: Traumatic brain injury (TBI) is a recognized risk factor for later development of neurodegenerative disease. However, the mechanisms contributing to neurodegeneration following TBI remain obscure.: Methods: In this study, we have utilized ... ...

    Abstract Objective: Traumatic brain injury (TBI) is a recognized risk factor for later development of neurodegenerative disease. However, the mechanisms contributing to neurodegeneration following TBI remain obscure.
    Methods: In this study, we have utilized a novel mild TBI (mTBI) model to examine the chronic neurobehavioral and neuropathological outcomes following single and repetitive mTBI at time points from 6 to 18 months following injury.
    Results: Our results reveal that at 6, 12, and 18 months after injury, animals exposed to a single mTBI have learning impairments when compared to their sham controls without exhibiting spatial memory retention deficits. In contrast, animals exposed to repetitive injury displayed persistent cognitive deficits, slower rate of learning, and progressive behavioral impairment over time. These deficits arise in parallel with a number of neuropathological abnormalities, including progressive neuroinflammation and continuing white matter degradation up to 12 months following repetitive injury. Neither single nor repetitive mTBI was associated with elevated brain levels of amyloid beta or abnormal tau phosphorylation at 6 or 12 months after injury.
    Interpretation: Importantly, these data provide evidence that, although a single mTBI produces a clinical syndrome and pathology that remain static in the period following injury, repetitive injuries produce behavioral and pathological changes that continue to evolve many months after the initial injuries. As such, this model recapitulates many aspects described in human studies of TBI, providing a suitable platform on which to investigate the evolving pathologies following mild TBI and potential strategies for therapeutic intervention.
    MeSH term(s) Amyloid beta-Peptides/metabolism ; Animals ; Anxiety/etiology ; Brain Injuries/complications ; Brain Injuries/pathology ; Cognition Disorders/etiology ; Corpus Callosum/pathology ; Disease Models, Animal ; Gene Expression Regulation ; Male ; Maze Learning ; Mice ; Mice, Inbred C57BL ; Movement Disorders/etiology ; Nerve Fibers, Myelinated/pathology ; Peptide Fragments/metabolism ; Retention (Psychology)/physiology ; Rotarod Performance Test ; Time Factors ; tau Proteins/metabolism
    Chemical Substances Amyloid beta-Peptides ; Peptide Fragments ; amyloid beta-protein (1-40) ; tau Proteins
    Language English
    Publishing date 2014-02
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 80362-5
    ISSN 1531-8249 ; 0364-5134
    ISSN (online) 1531-8249
    ISSN 0364-5134
    DOI 10.1002/ana.24064
    Database MEDical Literature Analysis and Retrieval System OnLINE

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