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Apoptotic and behavioral sequelae of mild brain trauma in mice

Authors

  • David Tweedie,

    1. Drug Design and Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, Baltimore, Maryland
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    • David Tweedie and Anat Milman contributed equally to this work as first authors.

  • Anat Milman,

    1. Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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    • David Tweedie and Anat Milman contributed equally to this work as first authors.

  • Harold W. Holloway,

    1. Drug Design and Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, Baltimore, Maryland
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  • Yazhou Li,

    1. Drug Design and Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, Baltimore, Maryland
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  • Brandon K. Harvey,

    1. Neural Protection and Regeneration Section, Molecular Neuropsychiatry Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland
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  • Hui Shen,

    1. Neural Protection and Regeneration Section, Molecular Neuropsychiatry Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland
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  • Paul J. Pistell,

    1. Laboratory of Experimental Gerontology, Intramural Research Program, National Institute on Aging, Baltimore, Maryland
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  • Debomoy K. Lahiri,

    1. Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana
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  • Barry J. Hoffer,

    1. Cellular Neurobiology Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland
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    • Barry J. Hoffer, Yun Wang, Chaim G. Pick, and Nigel H. Greig contributed equally to this work as senior authors.

  • Yun Wang,

    1. Neural Protection and Regeneration Section, Molecular Neuropsychiatry Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland
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    • Barry J. Hoffer, Yun Wang, Chaim G. Pick, and Nigel H. Greig contributed equally to this work as senior authors.

  • Chaim G. Pick,

    1. Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Nigel H. Greig

    Corresponding author
    1. Drug Design and Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, Baltimore, Maryland
    • Drug Design and Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, Baltimore, Maryland
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    • Barry J. Hoffer, Yun Wang, Chaim G. Pick, and Nigel H. Greig contributed equally to this work as senior authors.


Abstract

Mild traumatic brain injury (mTBI) is a not uncommon event in adolescents and young adults. Although it does not result in clear morphological brain defects, it is associated with long-term cognitive, emotional, and behavioral problems. Herein, we characterized the biochemical and behavioral changes associated with experimental mTBI in mice that may act as either targets or surrogate markers for interventional therapy. Specifically, mTBI was induced by 30-g and 50-g weight drop, and at 8 and 72 hr thereafter markers of cellular apoptosis—caspase-3, Bax, apoptosis-inducing factor (AIF), and cytochrome-c (Cyt-c)—were quantified by Western blot analysis in hippocampus ipsilateral to the impact. Levels of amyloid-β precursor protein (APP) were also measured, and specific behavioral tests—passive avoidance, open field, and forced swimming (Porsolt) paradigms—were undertaken to assess learning, emotionality, and emotional memory. In the absence of hemorrhage or infarcts, as assessed by triphenyltetrazolium chloride staining, procaspase-3 and Bax levels were markedly altered following mTBI at both times. No cleaved caspase-3 was detected, and levels of AIF and Cyt-c, but not APP, were significantly changed at 72 hr. Mice subjected to mTBI were indistinguishable from controls by neurological examination at 1 and 24 hr, and by passive avoidance/open field at 72 hr, but could be differentiated in the forced swimming paradigm. In general, this model mimics the diffuse effects of mTBI on brain function associated with the human condition and highlights specific apoptotic proteins and a behavioral paradigm as potential markers for prospective interventional strategies. © 2007 Wiley-Liss, Inc.

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