SUSTAINED SENSORY MOTOR AND COGNITIVE DEFICITS WITH NEURONAL APOPTOSIS FOLLOWING CONTROLLED CORTICAL IMPACT BRAIN INJURY IN THE MOUSE/

A mouse model of traumatic brain injury was developed using a device t hat produces controlled cortical impact (CCI), permitting independent manipulation of tissue deformation and impact velocity. The left parie totemporal cortex was subjected to CCI [1 mm tissue deformation and 4. 5 m/s tip velocity (mild), or 6.0 m/s (moderate)] or sham surgery. Inj ured animals showed delayed recovery of pedal withdrawal and righting reflexes compared to sham-operated controls. Significant severity-rela ted deficits in forepaw contraflexion and performance on a rotarod dev ice were evident for up to 7 days. Using a beam walking task to measur e fine motor coordination, pronounced deficits were apparent for at le ast 2 and 4 weeks following mild and moderate CCI, respectively. Cogni tive function was evaluated using the water maze. Impairment of place learning, related to injury severity, was observed in mice trained 7-1 0 days following CCI. Similarly, working memory deficits were evident in a variation of this task when examined 21-23 days postinjury. Mild CCI caused necrosis of subcortical white matter with minimal damage to somatosensory cortex. Moderate CCI produced extensive cortical and su bcortical white matter damage. Triple fluorescence labeling with termi nal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelin g (TUNEL), antineuronal nuclear protein (NeuN), and Hoechst 33258 of p arallel sections showed frequent apoptotic neurons. These findings dem onstrate sustained and reproducible deficits in sensory/motor function and spatial learning in the CCI-injured mouse correlating with injury severity. Mechanisms of neuronal cell death after trauma as well as s trategies for evaluating novel pharmacological treatment strategies ma y be identified using this model.