title: Long-term cognitive impairments and pathological alterations in a mouse model of repetitive mild traumatic brain injury.
abstract: Mild traumatic brain injury (mTBI, also referred to as concussion) accounts for the majority of all traumatic brain injuries. The consequences of repetitive mTBI have become of particular concern for individuals engaged in certain sports or in military operations. Many mTBI patients suffer long-lasting neurobehavioral impairments. In order to expedite pre-clinical research and therapy development, there is a need for animal models that reflect the long-term cognitive and pathological features seen in patients. In the present study, we developed and characterized a mouse model of repetitive mTBI, induced onto the closed head over the left frontal hemisphere with an electromagnetic stereotaxic impact device. Using GFAP-luciferase bioluminescence reporter mice that provide a readout of astrocyte activation, we observed an increase in bioluminescence relative to the force delivered by the impactor after single impact and cumulative effects of repetitive mTBI. Using the injury parameters established in the reporter mice, we induced a repetitive mTBI in wild-type C57BL/6J mice and characterized the long-term outcome. Animals received repetitive mTBI showed a significant impairment in spatial learning and memory when tested at 2 and 6 months after injury. A robust astrogliosis and increased p-Tau immunoreactivity were observed upon post-mortem pathological examinations. These findings are consistent with the deficits and pathology associated with mTBI in humans and support the use of this model to evaluate potential therapeutic approaches.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Stanford, CA , USA ; Center for Tissue Regeneration, Repair and Restoration, VA Palo Alto Health Care System , Palo Alto, CA , USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Stanford, CA , USA ; Center for Tissue Regeneration, Repair and Restoration, VA Palo Alto Health Care System , Palo Alto, CA , USA.
authors.forename: Andy
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Stanford, CA , USA ; Center for Tissue Regeneration, Repair and Restoration, VA Palo Alto Health Care System , Palo Alto, CA , USA.
authors.forename: Saul
authors.initials: S
authors.lastname: Villeda
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Stanford, CA , USA ; Center for Tissue Regeneration, Repair and Restoration, VA Palo Alto Health Care System , Palo Alto, CA , USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Stanford, CA , USA ; Center for Tissue Regeneration, Repair and Restoration, VA Palo Alto Health Care System , Palo Alto, CA , USA.
authors.forename: Zhaoqing
authors.initials: Z
authors.lastname: Ding
authors.affiliation: Center for Tissue Regeneration, Repair and Restoration, VA Palo Alto Health Care System , Palo Alto, CA , USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Lindsey
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Stanford, CA , USA ; Center for Tissue Regeneration, Repair and Restoration, VA Palo Alto Health Care System , Palo Alto, CA , USA.
authors.forename: Gregor
authors.initials: G
authors.lastname: Bieri
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Stanford, CA , USA ; Center for Tissue Regeneration, Repair and Restoration, VA Palo Alto Health Care System , Palo Alto, CA , USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Castellano
authors.affiliation: Center for Tissue Regeneration, Repair and Restoration, VA Palo Alto Health Care System , Palo Alto, CA , USA.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Beaupre
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Stanford, CA , USA ; Center for Tissue Regeneration, Repair and Restoration, VA Palo Alto Health Care System , Palo Alto, CA , USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Wyss-Coray
keywords: astrogliosis; bioluminescence; long-term; mild traumatic brain injury; neurobehavior