Long-term Behavioral Assessment in Two Mouse Models of Juvenile TBI.

Traumatic brain injury (TBI) in infants and children is a leading cause of long-term disability, but few animal models are available to study therapeutic approaches. In this study, we characterized the long-term behavioral effects of TBI in juvenile mice. At P7

or P10, mice were subjected to moderate (impact depth of 2 mm) or severe (impact depth of 2.5 mm) closed-skull controlled impact injury (or sham) surgery. Anothergroup was subjected to controlled cortical impact injury (or sham) at P21. Longitudinal behavioral tests were conducted shortly after injury and through adulthood. Tests included the water maze (general and spatial learning), rotarod (sensorimotor coor-dination and balance), open field (overall activity levels), and zero maze (anxiety).Testing shortly after injury revealed significant water maze performance deficits in allTBI mice, and trends toward sensorimotor deficits on the rotarod. Even with repeatedtesting throughout life, significant behavioral deficits were observed in injured mice asadults. In general, ‘‘severe’’ P7 male mice exhibited the worst behavioral deficits as adults.Water maze performance suggested that mice injured as juveniles exhibited cognitive deficits in adulthood, although the deficits were, in general, less severe than those observed shortly after injury. Rotarod performance, however, suggested that sensorimotor and coordination deficits were more significant as adults than juveniles. Additionally, ‘‘severe’’ P7 mice exhibited worse rotarod performance than other injured groups, and males were more affected by P7 TBI than females. Open field observation revealed significant hyperactivity in adulthood, with ‘‘severe’’ P7 mice exhibiting the most activity. Additionally, males seemed to be equally affected by moderate and severe injury, whereas females were less affected by moderate injury. Finally, performance on the zero maze revealed that injured mice (especially males) spent more time in the open areas, which is often interpreted as hypo-anxiety, but which could alsobe affected by hyperactivity, an abnormal exploratory response, or excessive risk-taking behavior.The observation of long-term behavioral deficits in these mouse models of juvenile.TBI suggests that cognitive and sensorimotor deficits can persist well into adulthood, and that these behavioral tests may present viable measures of the long-term therapeutic efficacy.