Differential behavioral and histopathological responses to graded cortical impact injury in mice.

Controlled cortical impact (CCI) injury, a model of contusive brain injury in humans, is being used with increasing frequency in mice to investigate post-traumatic cell damage and death and to evaluate treatment strategies. Because cellular injury mechanisms and therapeutic approaches may depend on the severity of the initial insult, it is important to utilize a model in which outcomes are sensitive to injury severity. Adult male C57Bl/6 mice were anesthetized and subjected to sham injury (n = 23) or CCI injury at either 0.5 mm (n = 22) or 1.0 mm (n = 22) depth of impact at a velocity of 5 m/sec. At 2 days, brain-injured mice exhibited significant memory (p < 0.05) and motor function (p < 0.001) deficits compared to sham-injured mice; furthermore, mice subjected to an impact of 1.0 mm were significantly more impaired in both outcome measures than those injured at 0.5 mm (p < 0.05). The cortical lesion increased in size between 24 h and 7 days in both injury groups, but was significantly larger in the 1.0 mm group. Hippocampal cell loss was observed in the hilar and CA3 regions in both groups, and in the CA1 and dentate granule cell layers in the 1.0 mm group. Regional patterns of IgG extravasation and reactive astrocytosis were similar in the two injured groups, but changes were more persistent in the 1.0 mm group. Both levels of injury resulted in acute loss of neuronal MAP-2 immunoreactivity in the cortex and sub-region specific changes in the hippocampus. Thus, increasing the depth of impact led to similar structural alterations in neurons, astrocytes and the vasculature, but resulted in greater behavioral deficits and cortical and hippocampal cell death.