title: Rate of neurodegeneration in the mouse controlled cortical impact model is influenced by impactor tip shape: implications for mechanistic and therapeutic studies.
abstract: Controlled cortical impact (CCI), one of the most common models of traumatic brain injury, is being increasingly used with mice for exploration of cell injury mechanisms and pre-clinical evaluation of therapeutic strategies. Although CCI brain injury was originally effected using an impactor with a rounded tip, the majority of studies with mouse CCI use a flat or beveled tip. Recent finite element modeling analyses demonstrate that tip geometry is a significant determinant of predicted cortical tissue strains in rat CCI, and that cell death is proportional to predicted tissue strains. In the current study, a three-dimensional finite element model of a C57BL/6J mouse brain predicted higher maximum principal strains during a simulated 1.0-mm, 3.5-m/s CCI injury with a flat tip when compared to a rounded tip. Consistent with this prediction, experimental CCI with a flat-tip impactor resulted in greater acute cortical hemorrhage and neuron loss in adult male C57BL/6J mice. The amount of neocortical tissue damage was equivalent for the two tip geometries at 9 days following injury, but the rate of neocortical neurodegeneration was markedly slower following CCI with a rounded-tip impactor, with damage reaching a plateau after 24?h as opposed to after 4?h for the flat tip. The flat-tip impactor was associated in general with more regional hippocampal neurodegeneration, especially at early time points such as 4?h. Impactor tip geometry did not have a notable effect on blood?brain barrier breakdown, traumatic axonal injury, or motor and cognitive dysfunction. Execution of CCI injury with a rounded-tip impactor is posited to provide a substantially enhanced temporal window for the study of cellular injury mechanisms and therapeutic intervention while maintaining critical aspects of the pathophysiological response to contusion brain injury.
authors.affiliation: Spinal Cord and Brain Injury Research Center, Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0509, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Pleasant
authors.forename: Shaun W
authors.initials: SW
authors.lastname: Carlson
authors.forename: Haojie
authors.initials: H
authors.lastname: Mao
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scheff
authors.forename: King H
authors.initials: KH
authors.lastname: Yang
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Saatman
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000293:injuries / Q000473:pathology; D001930:Brain Injuries / Q000150:complications / Q000473:pathology*; D002540:Cerebral Cortex / Q000293:injuries / Q000473:pathology*; D004195:Disease Models, Animal; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000209:etiology / Q000473:pathology*; D013997:Time Factors