Diffuse brain injury in the immature rat: evidence for an age-at-injury effect on cognitive function and histopathologic damage

Abstract

Diffuse axonal injury is a significant component of the pathology of moderate-severe pediatric traumatic brain injury in children less than 4 years of age, and is associated with poor cognitive outcome. However, cognitive deficits or gross histopathologic abnormalities are typically not observed following moderate-severe diffuse brain injury in the immature (17-day-old) rat. In order to test whether the age of the immature animal may influence post-traumatic outcome, non-contusive brain trauma was induced in post-natal day (PND) 11 or 17 rats. Brain injury in the PND11 rat, but not in the PND17 rat, was associated with a significant acquisition deficit at 28 days post-injury (p<0.0005 compared with age-matched sham rats, and with brain-injured PND17 rats). All brain-injured animals exhibited a retention deficit in the probe trial (p<0.001), but also demonstrated a significant visual deficit in the visible platform trial (p<0.05 compared to sham animals). Although significantly longer times of apnea and loss of righting reflex were observed in brain-injured PND17 rats compared to PND11 rats (p<0.05), overt cytoarchitectural alterations and reactive gliosis were not observed in the older age group. No focal pathology was observed in the cortex below the impact site in the PND11 rat but by 28 days, the brain-injured PND11 rat exhibited atrophy in multiple brain regions and an enlarged lateral ventricle in the impact hemisphere. Quantitative analysis revealed a time-dependent increase in tissue loss in the injured hemisphere (7-10%) in the younger animals, and a modest extent of tissue loss in the older animals (3-4%). Traumatic axonal injury was observed to similar extents in the white matter and thalamus below the impact site in both brain-injured PND11 and 17 rats. These data demonstrate that non-contusive (diffuse) brain injury of moderate severity in the immature rat is associated with chronic cognitive deficits and long-term histopathologic alterations and suggest that the age-at-injury is an important parameter of behavioral and pathologic outcome following closed head injury in the immature age group.