Abstract
Mild traumatic brain injury (mTBI) results in broad neurological symptoms and an increased risk of being diagnosed with a neurodegenerative disease later in life. While the immediate oxidative stress response and post-mortem pathology of the injured brain has been well studied, it remains unclear how early pathogenic changes may drive persistent symptoms and confer susceptibility to neurodegeneration. In this study we have used a mouse model of repeated mTBI (rmTBI) to identify early gene expression changes at 24 h or 7 days post-injury (7 dpi). At 24 h post-injury, gene expression of rmTBI mice shows activation of the DNA damage response (DDR) towards double strand DNA breaks, altered calcium and cell–cell signalling, and inhibition of cell death pathways. By 7 dpi, rmTBI mice had a gene expression signature consistent with induction of cellular senescence, activation of neurodegenerative processes, and inhibition of the DDR. At both timepoints gliosis, microgliosis, and axonal damage were evident in the absence of any gross lesion, and by 7 dpi rmTBI also mice had elevated levels of IL1β, p21, 53BP1, DNA2, and p53, supportive of DNA damage-induced cellular senescence. These gene expression changes reflect establishment of processes usually linked to brain aging and suggests that cellular senescence occurs early and most likely prior to the accumulation of toxic proteins. These molecular changes were accompanied by spatial learning and memory deficits in the Morris water maze. To conclude, we have identified DNA damage-induced cellular senescence as a repercussion of repeated mild traumatic brain injury which correlates with cognitive impairment. Pathways involved in senescence may represent viable treatment targets of post-concussive syndrome. Senescence has been proposed to promote neurodegeneration and appears as an effective target to prevent long-term complications of mTBI, such as chronic traumatic encephalopathy and other related neurodegenerative pathologies.
Highlights
Mild traumatic brain injury is common and can cause a broad range of debilitating symptoms, including headaches, fatigue, irritability, sleep disturbances, depression and anxiety, and attention deficits [61, 94, 101]
We suggest that activation of the DNA damage response (DDR) occurs in the 24 h period following Mild traumatic brain injury (mTBI), which drives changes consistent with cellular senescence and early neurodegeneration by 7d post-injury
RmTBI mice spent significantly longer searching for the hidden platform compared to shams at 1 week post-injury with a main effect of injury (p = 0.0001, repeated measures ANOVA), a main effect of training day (p = 0.047, repeated measures ANOVA) and a significant interaction between injury status and training day (p = 0.001, repeated measures ANOVA) indicating that while the shams improved their performance over time whereas the repeated mTBI (rmTBI) mice did not (Fig. 2b)
Summary
Mild traumatic brain injury (mTBI) is common and can cause a broad range of debilitating symptoms, including headaches, fatigue, irritability, sleep disturbances, depression and anxiety, and attention deficits [61, 94, 101]. Brain changes following mTBI are still under investigation, it is established that immediately following mTBI there is a significant increase of oxidative stress [52, 140]. This can lead to widespread DNA damage [28]. Accumulation of DNA damage has been reported in various models of mTBI [3, 123, 151] and our lab has previously shown evidence of double-strand. If the DDR becomes persistently activated in the face of persistent DNA damage, cellular senescence pathways may be activated. Senescent cells accumulate with age [23, 157, 175], neurodegenerative disease and cognitive decline [15], neuropsychiatric disorders [33], and have recently been discovered to accumulate after TBI [3, 123, 131, 132, 151]
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