Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Basic Science Research Dev Neurosci 2006;28:396–409 DOI: 10.1159/000094166 Traumatic Injury to the Immature Brain Results in Progressive Neuronal Loss, Hyperactivity and Delayed Cognitive Impairments Ramadevi Pullela a Jacob Raber d–f Timothy Pfankuch d Donna M. Ferriero a, b Catherine P. Claus c Seong-Eun Koh c Toshihiro Yamauchi c Radoslaw Rola c John R. Fike c Linda J. Noble-Haeusslein c Departments of a Pediatrics, b Neurology and c Neurosurgery, University of California, San Francisco, Calif., d Behavioral Neuroscience, e Neurology, and f Division of Neuroscience, ONPRC, Oregon Health and Science University, Portland, Oreg., USA Introduction Cognitive dysfunction and disruption of attention and information processing ability are common sequelae of traumatic brain injury in children [Levin et al., 1982; Murray et al., 1992]. Neurobehavioral sequelae in brain- injured children include attention deficit and hyperactiv- ity disorder [Konrad et al., 2003], as well as impairments in learning, memory and executive functions [Anderson et al., 1996; Ewing-Cobbs et al., 1989; Levin et al., 1998; Yeates et al., 1995]. The immature brain may be vulnerable to injury dur- ing critical periods of development. Children less than 4 years of age exhibit poorer motor and cognitive function than older children after traumatic brain injury [Ewing- Cobbs et al., 1989; Koskiniemi et al., 1995; Luerssen et al., 1988]. Approximately 20% of these young children attain a favorable outcome after traumatic brain injury, as de- fined by good recovery and moderate disability, by 1 year after injury [Ewing-Cobbs et al., 1989]. This is in sharp contrast to older children where approximately 75% attain a favorable outcome in a similar time frame. Poor outcomes may be attributed to a failure to meet new developmental demands [Radcliffe et al., 1994]. Brain injury at a young age interferes with acquisition of cogni- tive skills, and hence, the young child may initially appear to have few observable deficits. However, impairments Key Words Traumatic brain injury  Immature brain  Cognitive function  Delayed cell loss Abstract The immature brain may be particularly vulnerable to injury during critical periods of development. To address the bio- logic basis for this vulnerability, mice were subjected to trau- matic brain injury at postnatal day 21, a time point that ap- proximates that of the toddler-aged child. After motor and cognitive testing at either 2 weeks (juveniles) or 3 months (adults) after injury, animals were euthanized and the brains prepared for quantitative histologic assessment. Brain-in- jured mice exhibited hyperactivity and age-dependent an- xiolysis. Cortical lesion volume and subcortical neuronal loss were greater in brain-injured adults than in juveniles. Impor- tantly, cognitive decline was delayed in onset and coincided with loss of neurons in the hippocampus. Our findings dem- onstrate that trauma to the developing brain results in a pro- longed period of pathogenesis in both cortical and subcorti- cal structures. Behavioral changes are a likely consequence of regional-specific neuronal degeneration. Copyright © 2006 S. Karger AG, Basel Received: May 9, 2005 Accepted: August 10, 2005 Linda J. Noble-Haeusslein 521 Parnassus Ave, Room C-224 San Francisco, CA 94143-0520 (USA) Tel. +1 415 476 4850, Fax +1 415 476 5634 E-Mail noblelj@itsa.ucsf.edu © 2006 S. Karger AG, Basel Accessible online at: www.karger.com/dne R.P. and J.R. contributed equally to this paper.