Regional Neurodegeneration and Gliosis Are Amplified by Mild Traumatic Brain Injury Repeated at 24-Hour Intervals

Abstract

Most traumatic brain injuries (TBIs) that occur every year are classified as ‘mild’. Individuals involved in high-risk activities may sustain multiple mild TBIs. We evaluated the acute physiological and histopathological consequences of mild TBI in a mouse model, comparing sham injury, single impact, or 5 impacts at a 24- or 48-hour inter-injury interval. A single closed skull impact resulted in bilateral gliosis in the hippocampus and entorhinal cortex that was proportional to impact depth. Midline impact, at a depth just above the threshold to induce transient unconsciousness, produced occasional axonal injury and degenerating neurons accompanied by astrogliosis in the entorhinal cortex and cerebellum. Mild TBI repeated every 24 hours resulted in bilateral hemorrhagic lesions in the entorhinal cortex along with significantly increased neurodegeneration and microglial activation despite diminished durations of apnea and unconsciousness with subsequent impacts. Astrogliosis and diffusely distributed axonal injury were also observed bilaterally in the cerebellum and the brainstem. When the interval between mild TBIs was increased to 48 hours, the pathological consequences were comparable to a single TBI. Together, these data suggest that in mice the brain remains at increased risk for damage for 24 hours after mild TBI despite reduced acute physiological responses to subsequent mild impacts.

Dendritic Spine Loss and Chronic White Matter Inflammation in a Mouse Model of Highly Repetitive Head Trauma

“…Recently, preclinical studies of rmTBI suggest that impacts sustained within vulnerable time periods will amplify brain pathology, 51 and result in cognitive and behavioral deficits 5,36,52 up to a year after injury. 26,48 Conversely, increasing the recovery time between impacts can improve cognitive outcome and attenuate brain pathology after rmTBI.…”

Repeated mild traumatic brain injury: potential mechanisms of damage

“…While astrocyte responses typically increase with mTBI severity, number, and decreased inter-injury interval, 150,151 there is variability in reported time courses of response. A single mTBI can lead to a rapidly resolving 151 or mildly progressive 53,150 astrogliosis in a closed-head CCI model.…”

“…However, 2 injuries delivered at 24-h intervals result in prominent acute microglial responses that persist in white matter until 7 wk. 56 Interestingly, when 4 mTBIs are given, exacerbated microglial hypertrophy and increased immunoreactivity are observed at acute 150 and subacute, 57 but not chronic 70 …”

“…54 Although not measuring BBB disruption directly, 5 mild CCI TBIs delivered at either 24-or 48-h intervals revealed major histocompatibility complex class II-associated antigen-labeled macrophages in hemorrhagic lesions. 150 Other repeated mTBI studies revealed no BBB compromise in CCI, 59 WD, 65 or Kimwipe/aluminum foil models, 71,72 although all analyses were conducted at acute time points.…”

“…54,56,65,70 One repeated mTBI study reported significant acute neuronal death in the entorhinal cortex and around hemorrhagic lesions, following 5 CCI mTBI given at 24 h intervals. 150 Findings were deemed an outcome of both injury number and inter-injury interval, as a 48-h interval prevented neurodegeneration 150 ; however, a study using similar injury parameters and experimental design did not report neurodegenerative changes. 151 While a threshold for injury severity exists, the typical absence of overt neuronal cell death at both acute and chronic time points suggests that neuronal dysfunction and diffuse axonal injury are greater contributors to the progressive nature and chronic sequelae of mTBI and repeated mTBI than death of neurons; little is known regarding the death of glial cells following repeated mTBI.…”