Elsevier

Experimental Neurology

Volume 213, Issue 1, September 2008, Pages 84-92
Experimental Neurology

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

https://doi.org/10.1016/j.expneurol.2008.05.009Get rights and content

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.

Section snippets

Brain injury

The numbers of animals used in the present study are described in Table 1. Brain injuries were induced using the electronically driven controlled cortical impact (eCCI) device (Custom Design International, Richmond, VA), a modification of the pneumatic CCI previously described (Dixon et al., 1991) and used in previous studies in immature rats (Huh and Raghupathi, 2007, Raghupathi and Huh, 2007). The metal indentor was convex, measured 5 mm in diameter and was driven with a velocity of 5 m/s

Midline impact results in skull fractures and brief apnea

Closed head injury with the metal-tipped indenter over the midline suture in the PND17 rat did not result in acute or delayed mortality. Impact resulted in linear skull fractures along the suture line in all injured animals (Table 2). In 5 injured animals (1 each at 6 h and 8 day survival times and 3 at the 18 day survival time), a slight herniation of the brain through the midline fracture was observed. In all remaining injured animals, severe discoloration was observed under the site of

Discussion

The present study demonstrates that impact over the midline suture of the intact skull of the 17-day-old rat resulted in cognitive deficits within the first week post-injury, which was sustained until the third week post-injury. These behavioral deficits were accompanied, in the acute post-traumatic period (6 h–3 days) by blood–brain barrier breakdown, neurodegeneration in the cortex and hippocampus, and traumatic axonal injury (TAI) in the subcortical white matter and thalamus in both

Conclusion

We have developed a clinically-relevant model of closed head injury in the immature rat that exhibits diffuse histopathologic alterations in both hemispheres of the injured brain, and, acute and sustained cognitive deficits. Furthermore, the ongoing pathogenesis following diffuse injury in the immature brain suggest an extended critical window of opportunity for therapy, once a better understanding of the underlying cellular mechanisms associated with progressive pathogenesis is elucidated.

Acknowledgment

The authors acknowledge expert technical assistance from Michael Franklin. These studies were supported, in part, by The Endowed Chair of Critical Care Medicine, the Florence RC Murray grant from the Children's Hospital of Philadelphia (JWH, RR), a Research Foundation grant from the University of Pennsylvania (JWH, RR), and NINDS grants K08-NS053651 (JWH) and R01-NS41561 (RR).

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