title: Sustained sensory/motor and cognitive deficits with neuronal apoptosis following controlled cortical impact brain injury in the mouse.
abstract: A mouse model of traumatic brain injury was developed using a device that produces controlled cortical impact (CCI), permitting independent manipulation of tissue deformation and impact velocity. The left parietotemporal 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. Injured animals showed delayed recovery of pedal withdrawal and righting reflexes compared to sham-operated controls. Significant severity-related deficits in forepaw contraflexion and performance on a rotarod device were evident for up to 7 days. Using a beam walking task to measure fine motor coordination, pronounced deficits were apparent for at least 2 and 4 weeks following mild and moderate CCI, respectively. Cognitive function was evaluated using the water maze. Impairment of place learning, related to injury severity, was observed in mice trained 7-10 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 subcortical white matter damage. Triple fluorescence labeling with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL), antineuronal nuclear protein (NeuN), and Hoechst 33258 of parallel sections showed frequent apoptotic neurons. These findings demonstrate 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 strategies for evaluating novel pharmacological treatment strategies may be identified using this model.
authors.affiliation: Georgetown Institute for Cognitive and Computational Sciences and Department of Neurology, Georgetown University Medical Center, Washington, DC 20007-2197, USA.
authors.forename: G B
authors.initials: GB
authors.lastname: Fox
authors.forename: L
authors.initials: L
authors.lastname: Fan
authors.forename: R A
authors.initials: RA
authors.lastname: Levasseur
authors.forename: A I
authors.initials: AI
authors.lastname: Faden
mesh_terms: D000208:Acute Disease; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D001925:Brain Damage, Chronic / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D001930:Brain Injuries / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D003072:Cognition Disorders / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009048:Motor Skills / Q000502:physiology; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology; D011596:Psychomotor Disorders / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D012075:Remission, Spontaneous; D018709:Statistics, Nonparametric; D013997:Time Factors; D015599:Trauma Severity Indices