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