Midline brain injury in the immature rat induces sustained cognitive deficits, bihemispheric axonal injury and neurodegeneration

Abstract

Infants and children less than 4 years old suffer chronic cognitive deficits following mild, moderate or severe diffuse traumatic brain injury (TBI). It has been suggested that the underlying neuropathologic basis for behavioral deficits following severe TBI is acute brain swelling, subarachnoid hemorrhage and axonal injury. To better understand mechanisms of cognitive dysfunction in mild-moderate TBI, a closed head injury model of midline TBI in the immature rat was developed. Following an impact over the midline suture of the intact skull, 17-day-old rats exhibited short apnea times (3-15 s), did not require ventilatory support and suffered no mortality, suggestive of mild TBI. Compared to un-injured rats, brain-injured rats exhibited significant learning deficits over the first week post-injury (p<0.0005), and, significant learning (p<0.005) and memory deficits (p<0.05) in the third post-injury week. Between 6 and 72 h, blood-brain barrier breakdown, extensive traumatic axonal injury in the subcortical white matter and thalamus, and focal areas of neurodegeneration in the cortex and hippocampus were observed in both hemispheres of the injured brain. At 8 to 18 days post-injury, reactive astrocytosis in the cortex, axonal degeneration in the subcortical white matter tracts, and degeneration of neuronal cell bodies and processes in the thalamus of both hemispheres were observed; however, cortical volumes were not different between un-injured and injured rat brains. These data suggest that diffuse TBI in the immature rat can lead to ongoing degeneration of both cell soma and axonal compartments of neurons, which may contribute, in part, to the observed sustained cognitive deficits.

An fMRI Study of Auditory Orienting and Inhibition of Return in Pediatric Mild Traumatic Brain Injury

“…It is critical to specifically examine pediatric patients, as the semi-acute injury response and recovery trajectories following mTBI are likely to be different for the immature and mature brain (Suskauer and Huisman, 2009). For example, both animal (Bayly et al, 2006;Huh et al, 2008) and human (Hessen et al, 2007) studies have shown that the developing brain may be more susceptible than the developed brain to mild diffuse brain injury (Adelson and Kochanek, 1998;Levin, 2003). Finally, our current results also demonstrate that fMRI is more sensitive to the effects of mTBI than behavioral, neuropsychological, and traditional MRI measures, and they underscore the promise of fMRI for elucidating the potential neural substrates of subtle cognitive deficits associated with this condition.…”

Repetitive Mild Traumatic Brain Injury in a Mouse Model Produces Learning and Memory Deficits Accompanied by Histological Changes

“…When tested for cognitive performance in the BM, both injury groups showed cognitive impairment consistent with findings in previous brain injury studies. 25,30,31,42,44,45 There was a worsening trend for r-mTBI compared with s-mTBI during the acquisition trials as well as on time to zone in the probe trial, and on the final day of acquisition training the r-mTBI group performed significantly worse than the other three groups.…”

“…By 10 days postinjury (s-mTBI-10D) there was no evidence for APP immunoreactivity, consistent with the current literature for animal models in that strong APP staining is present at 24 h post-injury, 22,30,47 which diminishes by 14 days post-injury. 42,46 In the r-mTBI group, more widespread damage was observed, with immunoreactive axons also evident in the spinal trigeminal tracts of the BS and beneath the impact site in the form of APP immunoreactive neuronal perikaryas. However, in the r-mTBI group, the APP immunoreactive axonal swellings were less frequent and less robustly stained in the CC than those observed at 24 h after s-mTBI.…”

“…For example, the pathological consequences of axonal injury (axonal varicosities, axonal bulbs) have been observed in humans, pigs, rats, and mice. 17,22,31,42 The other advantages of mouse models (genetic manipulability, ease of protocol implementation, and cost) make this an appropriate platform in which to identify molecular consequences of repetitive versus single injury for exploration in higher mammals. -D), s-mTBI10D (I-L), and r-sham animals (M-P) was negative for APP immunostaining.…”

A New Rabbit Model of Pediatric Traumatic Brain Injury

“…65 Midline brain injury in immature rats led to diffuse neurodegeneration in both hemispheres that was felt to be responsible for the sustained cognitive deficits observed in these animals. 66 In our model, we used unilateral injury to the parietal cortex, which led to significant cognitive deficits and delay in developmental maturation. These findings are consistent with other rodent models with parietal cortex injury.…”