title: The pathophysiology underlying repetitive mild traumatic brain injury in a novel mouse model of chronic traumatic encephalopathy.
abstract: BACKGROUND
  An animal model of chronic traumatic encephalopathy (CTE) is essential for further understanding the pathophysiological link between repetitive head injury and the development of chronic neurodegenerative disease. We previously described a model of repetitive mild traumatic brain injury (mTBI) in mice that encapsulates the neurobehavioral spectrum characteristic of patients with CTE. We aimed to study the pathophysiological mechanisms underlying this animal model.
  
  
  METHODS
  Our previously described model allows for controlled, closed head impacts to unanesthetized mice. Briefly, 12-week-old mice were divided into three groups: Control, single, and repetitive mTBI. Repetitive mTBI mice received six concussive impacts daily, for 7 days. Mice were then subsequently sacrificed for macro- and micro-histopathologic analysis at 7 days, 1 month, and 6 months after the last TBI received. Brain sections were immunostained for glial fibrillary acidic protein (GFAP) for astrocytes, CD68 for activated microglia, and AT8 for phosphorylated tau protein.
  
  
  RESULTS
  Brains from single and repetitive mTBI mice lacked macroscopic tissue damage at all time-points. Single mTBI resulted in an acute rea ctive astrocytosis at 7 days and increased phospho-tau immunoreactivity that was present acutely and at 1 month, but was not persistent at 6 months. Repetitive mTBI resulted in a more marked neuroinflammatory response, with persistent and widespread astrogliosis and microglial activation, as well as significantly elevated phospho-tau immunoreactivity to 6-months.
  
  
  CONCLUSIONS
  The neuropathological findings in this new model of repetitive mTBI resemble some of the histopathological hallmarks of CTE, including increased astrogliosis, microglial activation, and hyperphosphorylated tau protein accumulation.
authors.affiliation: Division of Neurosurgery, Rochester Regional Health System, Rochester, New York, USA.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Petraglia
authors.affiliation: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Plog
authors.affiliation: Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Dayawansa
authors.affiliation: Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Dashnaw
authors.affiliation: Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Czerniecka
authors.affiliation: Division of Neurological Surgery, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA.
authors.forename: Corey T
authors.initials: CT
authors.lastname: Walker
authors.affiliation: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Ollivier
authors.initials: O
authors.lastname: Hyrien
authors.affiliation: Department of Anesthesiology and Peri-operative Medicine, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Iliff
authors.affiliation: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Rashid
authors.initials: R
authors.lastname: Deane
authors.affiliation: Department of Neurosurgery, Baylor Scott and White Health System, Temple, Texas, USA.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Huang
authors.affiliation: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Maiken
authors.initials: M
authors.lastname: Nedergaard
keywords: Animal model; chronic traumatic encephalopathy; concussion; pathophysiology; repetitive