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.
Highlights
Traumatic brain injury (TBI) is a major global health concern, and the CDC has estimated that over 1.5 million people experience a TBI each year in the US
Neuronal injury is closely tied to astrogliosis, and we and others have previously shown that bioluminescence intensity in the GFAP-luc mice correlates significantly with astrogliosis assessed by immunohistochemistry and with neural injury in brain injury models of excitotoxicity and experimental autoimmune encephalomyelitis [22, 23]
We show that animals subjected to three repetitive mTBI with an inter-impact interval of 24 h displayed long-term (6 months after injury) cognitive impairment, accompanied by prominent pathological changes
Summary
Traumatic brain injury (TBI) is a major global health concern, and the CDC has estimated that over 1.5 million people experience a TBI each year in the US. While most mTBI patients recover without significant long-term consequences, 7– 30% (even up to 60% in some reports) of individuals are estimated to suffer from a post-concussive syndrome that comprises physical, cognitive, and emotional symptoms [4, 5]. These long-lasting symptoms include memory impairments, difficulty in concentration, depression, apathy, and anxiety [4, 5]. Because these symptoms are usually observed in the absence of significant structural damage, patients sustaining mTBI are difficult to diagnose [6], and routine clinical and laboratory evaluations of mTBI patients often fail to show clear morphological brain defects
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