Progressive Histopathological Damage Occurring Up to One Year after Experimental Traumatic Brain Injury Is Associated with Cognitive Decline and Depression-Like Behavior

Abstract

Increasing clinical and experimental evidence suggests that traumatic brain injury (TBI) is associated with progressive histopathological damage. The aim of the current study was to characterize the time course of motor function, memory performance, and depression-like behavior up to 1 year after experimental TBI, and to correlate these changes to histopathological outcome. Male C57BL/6N mice underwent controlled cortical impact (CCI) or sham operation, and histopathological outcome was evaluated 15 min, 24 h, 1 week, or 1, 3, 6, or 12 months thereafter (<i>n</i> = 12 animals per time point). Motor function, depression-like behavior, and memory function were evaluated concomitantly, and magnetic resonance imaging (MRI) was repeatedly performed. Naïve mice (<i>n</i> = 12) served as an unhandled control group. Injury volume almost doubled within 1 year after CCI (<i>p</i> = 0.008) and the ipsilateral hemisphere became increasingly atrophic (<i>p</i> < 0.0001). Progressive tissue loss was observed in the corpus callosum (<i>p</i> = 0.007) and the hippocampus (<i>p</i> = 0.004) together with hydrocephalus formation (<i>p</i> < 0.0001). Motor function recovered partially after TBI, but 6 months after injury progressive depression-like behavior (<i>p</i> < 0.0001) and loss of memory function (<i>p</i> < 0.0001) were observed. The present study demonstrates that delayed histopathological damage that occurs over months after brain injury is followed by progressive depression and memory loss, changes also observed after TBI in humans. Hence, experimental TBI models in mice replicate long-term sequelae of brain injury such as post-traumatic dementia and depression.