Differential responses to increasing numbers of mild traumatic brain injury in a rodent closed head injury model

Abstract

Following mild traumatic brain injury (mTBI), further mild impacts can exacerbate negative outcomes. To compare chronic damage and deficits following increasing numbers of repeated mTBIs, a closed-head weight-drop model of repeated mTBI was used to deliver 1, 2 or 3 mTBIs to adult female rats at 24 h intervals. Outcomes were assessed at 3 months following the first mTBI. No gross motor, sensory or reflex deficits were identified (p > 0.05), consistent with current literature. Cognitive function assessed using a Morris water maze revealed chronic memory deficits following 1 and 2, but not 3 mTBI compared to shams (p = 0.05). Oxidative damage to DNA was assessed immunohistochemically in the dentate hilus of the hippocampus and splenium of the corpus callosum; no changes were observed. IBA1 positive microglia were increased in size in the cortex following 1 mTBI and in the corpus callosum following 2 mTBI compared to shams (p = 0.05); no changes were observed in the dentate hilus. GFAP positive astrocyte immunoreactivity was assessed in all three brain regions and no chronic changes were observed. Integrity of myelin ultrastructure in the corpus callosum was assessed using transmission electron microscopy. G ratio was decreased following 2 mTBIs compared to shams (p = 0.05) at post-hoc level only. The changing patterns of damage and deficits following increasing numbers of mTBI may reflect dynamic responses to small numbers of mTBIs or a conditioning effect such that increasing numbers of mild traumatic brain injuries do not necessarily result in worsening pathology.