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A New Rabbit Model of Pediatric Traumatic Brain Injury
Zhi Zhang1, Manda Saraswati1, Raymond C Koehler1
1Department of Anesthesiology and Critical Care, Johns Hopkins School of Medicine , Baltimore, Maryland.
Insights
A new rabbit model of pediatric traumatic brain injury (TBI) shows developmental delays and cognitive deficits, mimicking human pediatric TBI. This model is crucial for testing new neuroprotective therapies for children with TBI.
Area of Science:
- Neuroscience
- Developmental Biology
- Pediatric Medicine
Background:
- Traumatic brain injury (TBI) is a leading cause of childhood disability, leading to long-term physical, behavioral, and cognitive issues.
- The precise mechanisms by which pediatric TBI affects development are not well understood.
- Existing rodent models often fail to replicate the full spectrum of neurological deficits observed in human pediatric TBI cases.
Purpose of the Study:
- To develop and validate a New Zealand white rabbit model that accurately mimics pediatric traumatic brain injury (TBI) in humans.
- To characterize the functional and histological outcomes in this novel pediatric TBI model.
- To establish a platform for testing neuroprotective therapies for pediatric TBI.
Main Methods:
- Controlled cortical impact was applied to New Zealand white rabbits on postnatal days 5-7.
- Naïve and sham-operated littermates served as controls.
- Functional abilities, cognitive performance (T-maze, object discrimination), lesion volume, and microglial activation were assessed at various time points post-injury.
Main Results:
- Rabbits with TBI exhibited delayed developmental milestones and significant cognitive impairments, including reduced T-maze alternation and object discrimination.
- Lesion volume progressively increased from 16% at 3 days to 30% at 7 days post-injury, indicating ongoing secondary injury.
- Activated microglia were observed at the injury site and in both ipsilateral and contralateral white matter regions.
Conclusions:
- The developed rabbit model effectively replicates the neurological and histological characteristics of pediatric TBI seen in human patients.
- This model demonstrates significant cognitive deficits and ongoing secondary injury processes.
- The validated rabbit model offers a promising new platform for the preclinical evaluation of neuroprotective treatments for pediatric traumatic brain injury.
Abstract:
Traumatic brain injury (TBI) is a common cause of disability in childhood, resulting in numerous physical, behavioral, and cognitive sequelae, which can influence development through the lifespan. The mechanisms by which TBI influences normal development and maturation remain largely unknown. Pediatric rodent models of TBI often do not demonstrate the spectrum of motor and cognitive deficits seen in patients. To address this problem, we developed a New Zealand white rabbit model of pediatric TBI that better mimics the neurological injury seen after TBI in children. On postnatal Day 5-7 (P5-7), rabbits were injured by a controlled cortical impact (6-mm impactor tip; 5.5 m/sec, 2-mm depth, 50-msec duration). Rabbits from the same litter served as naïve (no injury) and sham (craniotomy alone) controls. Functional abilities and activity levels were measured 1 and 5 d after injury. Maturation level was monitored daily. We performed cognitive tests during P14-24 and sacrificed the animals at 1, 3, 7, and 21 d after injury to evaluate lesion volume and microglia. TBI kits exhibited delayed achievement of normal developmental milestones. They also demonstrated significant cognitive deficits, with lower percentage of correct alternation rate in the T-maze (n=9-15/group; p<0.001) and less discrimination between novel and old objects (p<0.001). Lesion volume increased from 16% at Day 3 to 30% at Day 7 after injury, indicating ongoing secondary injury. Activated microglia were noted at the injury site and also in white matter regions of the ipsilateral and contralateral hemispheres. The neurologic and histologic changes in this model are comparable to those reported clinically. Thus, this rabbit model provides a novel platform for evaluating neuroprotective therapies in pediatric TBI.
