title: Repetitive mild traumatic brain injury with impact acceleration in the mouse: Multifocal axonopathy, neuroinflammation, and neurodegeneration in the visual system.
abstract: Repetitive mild traumatic brain injury (mTBI) is implicated in chronic neurological illness. The development of animal models of repetitive mTBI in mice is essential for exploring mechanisms of these chronic diseases, including genetic vulnerability by using transgenic backgrounds. In this study, the rat model of impact acceleration (IA) was redesigned for the mouse cranium and used in two clinically relevant repetitive mTBI paradigms. We first determined, by using increments of weight dropped from 1m that the 40g weight was most representative of mTBI and was not associated with fractures, brain contusions, anoxic-ischemic injury, mortality, or significant neurological impairments. Quantitative evaluation of traumatic axonal injury (TAI) in the optic nerve/tract, cerebellum and corpus callosum confirmed that weight increase produced a graded injury. We next evaluated two novel repetitive mTBI paradigms (1 time per day or 3 times per day at days 0, 1, 3, and 7) and compared the resulting TAI, neuronal cell death, and neuroinflammation to single hit mTBI at sub-acute (7days) and chronic time points (10weeks) post-injury. Both single and repetitive mTBI caused TAI in the optic nerve/tract, cerebellum, corticospinal tract, lateral lemniscus and corpus callosum. Reactive microglia with phagocytic phenotypes were present at injury sites. Severity of axonal injury corresponded to impact load and frequency in the optic nerve/tract and cerebellum. Both single and repeat injury protocols were associated with retinal ganglion cell loss and optic nerve degeneration; these outcomes correlated with impact load and number/frequency. No phosphorylated tau immunoreactivity was detected in the brains of animals subjected to repetitive mTBI. Our findings establish a new model of repetitive mTBI model featured by TAI in discrete CNS tracts, especially the visual system and cerebellum. Injury in retina and optic nerve provides a sensitive measure of severity of mTBI, thus enabling further studies on mechanisms and experimental therapeutics. Our model can also be useful in exploring mechanisms of chronic neurological disease caused by repetitive mTBI in wild-type and transgenic mice.
authors.affiliation: Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: lxu9@jhmi.edu.
authors.forename: Leyan
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: judy.v.nguyen@gmail.com.
authors.forename: Judy V
authors.initials: JV
authors.lastname: Nguyen
authors.affiliation: Department of Otolaryngology-HNS, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: mlehar@jhmi.edu.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Lehar
authors.affiliation: Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: amen692@gmail.com.
authors.forename: Adarsh
authors.initials: A
authors.lastname: Menon
authors.affiliation: Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: lizrha@gmail.com.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rha
authors.affiliation: Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: jarena2@jhu.edu.
authors.forename: John
authors.initials: J
authors.lastname: Arena
authors.affiliation: Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: jryu4@jhmi.edu.
authors.forename: Jiwon
authors.initials: J
authors.lastname: Ryu
authors.affiliation: Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Hugo W. Moser Research Institute at Kennedy Krieger, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: Marsh-Armstrong@Kennedykrieger.Org.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Marsh-Armstrong
authors.affiliation: Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA 23298, USA. Electronic address: crmarmar@vcu.edu.
authors.forename: Christina R
authors.initials: CR
authors.lastname: Marmarou
authors.affiliation: Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: koliat@jhmi.edu.
authors.forename: Vassilis E
authors.initials: VE
authors.lastname: Koliatsos
mesh_terms: D000054:Acceleration / Q000009:adverse effects*; D000818:Animals; D001369:Axons / Q000473:pathology*; D001930:Brain Injuries / Q000150:complications / Q000473:pathology*; D004195:Disease Models, Animal; D007249:Inflammation / Q000209:etiology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000209:etiology / Q000473:pathology*; D009900:Optic Nerve / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000473:pathology*
keywords: CTE; Concussion; Diffuse axonal injury; Optic nerve; Retinal ganglion cell; Tau; Traumatic axonal injury