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.

Experimental Mild Traumatic Brain Injury Induces Functional Alteration of the Developing Hippocampus

“…The "optimal" age window appears to vary in different species. A critical developmental period with optimal postinsult recovery at around P30 has been observed in cats (Villablanca et al 1998) and at around P17 day in rats (Fineman et al 2000;Raghupathi and Huh 2007). Similarly in our study, a critical time window of in vitro development was found at around 8 DIV, during which hippocampal slice cultures were less vulnerable to injury responding with reduced deficits in the maximal evoked response and excitability.…”

“…On one hand, as reviewed by Prins and Hovda (2003), a critical developmental window may exist during the period of greatest neuronal plasticity and therefore potential recovery, which could alleviate posttraumatic degeneration of neural circuits and restore hippocampal organization and development. Consistent with the in vivo findings identifying a critical developmental period with maximal neuronal plasticity and optimal postinsult recovery at P17 (Fineman et al 2000;Raghupathi and Huh 2007), the window of greatest intrinsic neuronal plasticity is expected during the period of postnatal 15-24 days; thus 8 DIV for the cultures which were harvested from P9-to 10-day rat pups might be expected to be within the period of greatest intrinsic neuronal plasticity as well. On the other hand, taking into account the external effect of dissection and in vitro culture, the degeneration due to dissection may be complete by 8 DIV, as dissectioninduced, degenerated neuronal cells were rarely seen after 6 DIV in other studies (Kiernan and Pettit 1971).…”

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

“…Moderate and severe TBI in P11-P21 rodents has been shown to cause axonal degeneration detectable up to two weeks post-injury (Adelson et al, 2001;Raghupathi et al, 2002;Tong et al, 2002;Huh et al, 2007;Raghupathi and Huh, 2007). However, the onset and early progression of axonal injury in white matter tracts in response to brain injury has not been investigated.…”

“…Axonal injury has been described in the subcortical white matter following brain trauma in P11-21 rodents (Adelson et al, 2001;Tong et al, 2002;Huh et al, 2007;Raghupathi and Huh, 2007). However, no systematic data are available characterizing axonal degeneration in infant mice following TBI and its relationship to neuronal cell death.…”

Influences of Developmental Age on the Resolution of Diffuse Traumatic Intracranial Hemorrhage and Axonal Injury

“…9,17,40,41 In particular, Ibrahim and colleagues used the same RNR injury model but with rotations in the axial plane, and found that when five-day-old and four-week-old piglets experienced comparable mass-scaled angular accelerations the five-day-olds sustained significantly more TAI than the four-week-old piglets at the 6 h post-injury time point. 17 Although our dataset exhibited significantly higher TAI in five-day-olds overall ( p = 0.016), this did not reach significance at the 3-8 h time point and is somewhat confounded by the overall lower scaled angular velocities in the four-week-old age group.…”