NEUROPATHOLOGICAL AND BEHAVIORAL CHANGES FOLLOWING REPEAT MILD TRAUMATIC BRAIN INJURY
Winston, Charisse N.
Burns, Mark P.
Rebeck, G. W,
An estimated 1.7 million Americans will sustain a traumatic brain injury (TBI) every year with approximately two-thirds of those injuries being classified as a mild TBI (mTBI). Injury severity and outcome are affected by a number of factors, which include age, gender, timing between impacts, and genetic vulnerability. The temporary loss of brain function after mTBI can manifest into a variety of emotional, physical, and cognitive impairments and to date, the only effective course of treatment in humans is a period of rest (convalescence). It is unknown how long this recovery period should last, but 25% of mTBI patients still have symptoms at 3 months, and 5-10% at 12 months post injury. The diversity of symptoms that results after mTBI may be explained by loss of dendritic spines in various brain regions. Dendritic spines are tiny protrusions from dendrites that mark the sites for excitatory synaptic transmission. Changes in dendritic spine number are implicated in a number of other neurological disorders such as Alzheimer’s disease (AD), Schizophrenia, and Fragile X.mTBI has been extensively modeled in mice and rats. The majority of these animal models involves less than 5 mTBI, and describes neuropathological changes that are not expected after a human mTBI; including skull fractures, cell death, axonal injury, and edema. Here, we wanted to develop a clinically relevant, extremely mild, highly repetitive injury model that is capable of delivering a higher volume of impacts without causing any discernable injury to mice. The purpose of this study was to determine the acute and chronic effects of r-mTBI on the development of brain pathology, neuronal architecture changes, and functional outcome in mice.Our model resulted in a graded loss of consciousness (LOC) with increased injury severity and no evidence of neuroinflammation, cell death, or axonal injury after single mTBI. We found that dendritic spine loss occurs after a single mTBI, but not r-mTBI. This, plus the work of others suggests that spine loss is a common phenomenon that occurs following all severities of TBI (mild, moderate, and severe). r-mTBI causes significant white matter pathology in the optic tract that persists up to 2m post injury and spontaneously recovers by 12m post injury.Recent preclinical studies of r-mTBI suggest that impacts sustained within vulnerable time periods will amplify brain pathology and result in cognitive and behavioral deficits, up to a year post injury. We found that mice exposed to 30 mTBI over a shorter inter-injury interval (5 consecutive mTBI, 10 sec interval for 6 days) have attenuated brain pathology yet poorer behavioral outcome compared to mice exposed to 30 mTBI over a longer inter-injury interval (1 mTBI, 24h interval for 30 days).Genetic predisposition influences severity and recovery following mTBI. The ϵ4 allele of Apolipoprotien E is the greatest genetic risk factor for the development of Alzheimer’s disease (AD). The ϵ4 allele is synonymous with poorer recovery and death after TBI and the incidence of this gene is increased in those diagnosed with chronic traumatic encephalopathy (CTE). CTE is a progressive degenerative disease that is caused by exposure to r-mTBI. We found that APOE4 increased dendritic spine number and decreased dendritic spine length in a calcineurin-dependent manner following mTBI. APOE4 mice appear to have worse white matter pathology in the optic tract, up to 2m post injury compared to APOE3 mice. Interestingly, the duration of loss of consciousness after r-mTBI in APOE4 mice was significantly reduced, compared to injured APOE3 mice.Collectivity, our data suggests that inter-injury interval and genetic predisposition influence severity and recovery following r-mTBI.
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