Repetitive Mild Non-Contusive Brain Trauma in Immature Rats Exacerbates Traumatic Axonal Injury and Axonal Calpain Activation: A Preliminary Report

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Abstract
Infants who experience inflicted brain injury (shaken-impact syndrome) present with subdural hematoma, brain atrophy, and ventriculomegaly, pathologic features that are suggestive of multiple incidences of brain trauma. To develop a clinically relevant model of inflicted brain injury in infants, the skulls of anesthetized 11-day-old rat pups were subjected to one, two, or three successive mild impacts. While skull fractures were not observed, a single impact to the intact skull resulted in petechial hemorrhages in the subcortical white matter, and double or triple impacts led to hemorrhagic tissue tears at 1 day postinjury. Whereas the singly impacted brain did not exhibit overt damage at 7 days, two impacts resulted in an enlarged ventricle and white matter atrophy; three impacts to the brain led to similar pathology albeit at 3 days postinjury. By 7 days, cortical atrophy was observed following three impacts. Reactive astrocytes were visible in the deep cortical layers below the impact site after two impacts, and through all cortical layers after three impacts. Swellings were observed in intact axons in multiple white matter tracts at 1 day following single impact and progressed to axonal disconnections by 3 days. In contrast, double or triple impacts resulted in axonal disconnections by 1 day postinjury; in addition, three impacts led to extensive axonal injury in the dorsolateral thalamus by 3 days. Calpain activation was observed in axons in subcortical white matter tracts in all brain-injured animals at 1 day and increased with the number of impacts. Despite these pathologic alterations, neither one nor two impacts led to acquisition deficits on the Morris water maze. While indicative of the graded nature of the pathologic response, these data suggest that repetitive mild brain injury in the immature rat results in pathologic features similar to those following inflicted brain injuries in infants.