Traumatic Injury to the Immature Brain Results in Progressive Neuronal Loss, Hyperactivity and Delayed Cognitive Impairments

Abstract

The immature brain may be particularly vulnerable to injury during critical periods of development. To address the biologic basis for this vulnerability, mice were subjected to traumatic brain injury at postnatal day 21, a time point that approximates 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-injured mice exhibited hyperactivity and age-dependent anxiolysis. Cortical lesion volume and subcortical neuronal loss were greater in brain-injured adults than in juveniles. Importantly, cognitive decline was delayed in onset and coincided with loss of neurons in the hippocampus. Our findings demonstrate that trauma to the developing brain results in a prolonged period of pathogenesis in both cortical and subcortical structures. Behavioral changes are a likely consequence of regional-specific neuronal degeneration.

Mild traumatic brain injury to the infant mouse causes robust white matter axonal degeneration which precedes apoptotic death of cortical and thalamic neurons

“…Therefore it is possible that injury-induced disconnection between these neurons may contribute to the initiation of the apoptotic cell death process in both neuronal groups. In infant animals similar mechanisms of disconnectioninduced apoptotic neuronal cell death has been implicated after visual cortex ablation and after TBI (Conti et al, 1998;Natale et al, 2002;Tong et al, 2002;Repici et al, 2003;Pullela et al, 2006;Igarashi et al, 2007). …”

“…However after severe unilateral injury to P11 rats brain atrophy and behavioral deficits were detected at four weeks following TBI. In P21 mice subjected to unilateral cortical injury early behavioral changes were manifested as hyperactivity and anxiolysis followed by delayed learning deficits which became evident three months posttrauma (Pullela et al, 2006). Ongoing behavioral studies are aimed to assess the behavioral deficits following graded injury severities including mild impact.…”

“…However, post-traumatic apoptotic cell death declined significantly during the second postnatal week and was almost a non factor by P14 (Bittigau et al, 1999). Neuronal loss was also found in P11-P17 rodents following controlled cortical impact (Adelson et al, 1996;Tong et al, 2002;Pullela et al, 2006).…”

“…Based on these and other comparative data, immature rodents 7-14 days of age are considered to correspond to the infant age (up to 12 months) in humans, whereas rodents 17-21 days of age are equivalent to toddlers (2-3 years of age) (Yager and Thornhill, 1997;Rice and Barone, 2000;Kochanek, 2006). Accordingly, these two age groups have been widely used to model the neurodegenerative and neurophatological consequences of TBI in infants and toddlers (Adelson et al, 1996;Prins et al, 1996;Tong et al, 2002;Bittigau et al, 2003;Pullela et al, 2006;Huh et al, 2007). It has been shown that moderate to severe TBI in infant rats (P3-P14) resulted in initial excitotoxic/necrotic cell death at the impact site within 4-5 hours after impact, which was followed by disproportionally larger apoptotic cell death in the cortex and subcortical regions peaking at 24 hrs post-injury (Bittigau et al, 1999;Felderhoff-Mueser et al, 2002;Bittigau et al, 2003;Bayly et al, 2006b).…”

A New Rabbit Model of Pediatric Traumatic Brain Injury

“…These findings are consistent with other rodent models with parietal cortex injury. 67,68 It is also possible that the diffuse bilateral neuroinflammatory response seen in the immature rabbit following a focal contusion leads to a more diffuse injury, which could explain the robust cognitive deficits seen in the rabbit model. In our future studies, we will alter the injury site and monitor the change in motor function, social behavior and cognition.…”