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Neurobehavioral Assessments in a Mouse Model of Neonatal Hypoxic-ischemic Brain Injury
Published on: November 24, 2017
Newborn and juveniles exhibit distinct transcriptional and pathological profiles after brain injury
Oluwagbemisola Aderibigbe1, Akshara D Thakore1, Martin N Griffin2
1Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
Insights
Developmental stage, not injury force, significantly impacts brain molecular changes after traumatic brain injury (TBI). Newborn piglets show distinct responses from juveniles, highlighting age-related differences in TBI recovery.
Area of Science:
- Neuroscience
- Developmental Biology
- Traumatic Brain Injury Research
Background:
- Patient outcomes after traumatic brain injury (TBI) are influenced by age and injury severity.
- Limited understanding exists regarding the effects of age and biomechanical load on molecular brain changes post-pediatric TBI.
Purpose of the Study:
- To investigate transcriptional and axonal injury differences in newborn versus juvenile piglets after controlled rotational TBI.
- To determine the relative contributions of biomechanical load and developmental stage to TBI-induced molecular alterations.
Main Methods:
- Sagittal rapid non-impact head rotation (RNR) model in newborn (3-5 days) and juvenile (4 weeks) piglets.
- Exposure to varying rotational loads (Low and High) and age-matched sham controls.
- Analysis of frontal lobe transcriptional changes (differentially expressed genes) and axonal injury volume.
Main Results:
- Newborn piglets exhibited distinct gene expression profiles compared to juveniles, with newborns showing endothelial cell-related gene upregulation and juveniles showing neuron-related gene upregulation.
- Overlapping differentially expressed genes (DEGs) in newborns indicated stress, inflammation, and extracellular matrix remodeling, while high-load specific DEGs suggested exacerbated immune response.
- Axonal injury volume was significantly greater in high-load newborns, correlating with increased rotational loads, but TBI-specific molecular changes were primarily observed in juvenile piglets.
Conclusions:
- Developmental stage profoundly influences the brain's molecular and pathological response to TBI, often overriding the impact of biomechanical load.
- Distinct cellular responses (endothelial vs. neuronal) and microglia morphologies between age groups underscore critical differences in TBI susceptibility and recovery.
- Findings emphasize the need for age-specific TBI research and therapeutic strategies to address developmental variations in brain injury.
Abstract:
Age and injury severity influence patient outcomes and recovery trajectories after traumatic brain injury (TBI). However, there is a paucity of understanding the effects of age and biomechanical load on molecular changes to the brain after pediatric TBI. We examined frontal lobe transcriptional changes and axonal injury 1 day after sagittal rapid non-impact head rotation (RNR) in newborn 3-5 day old piglets (N = 26) exposed to either Low (43.9 ± 6.3 rad/s) or High (150 ± 2.6 rad/s) loads compared to juvenile 4 week old piglets (N = 40) exposed to scaled High loads (124.3 ± 1.7 rad/s) and to age-matched Shams. In newborns, we identified 780 differentially expressed genes (DEGs) and 333 DEGs in the Low and High groups, respectively, with 91 of these overlapping. While overlapping DEGs and gene sets were consistent with stress, inflammation, BBB disruption, mitochondrial maintenance, extracellular matrix (ECM) and collagen degradation and formation, DEGs specific to the High group signaled damage and exacerbated immune response. Axonal injury volume was significantly larger in the High group than the Low and Sham newborn groups, and increased axon growth and neuronal dysfunction DEGs were also correlated with increased rotational loads. Importantly, age had a profound influence, despite mechanically equivalent rotational loads. Upregulated DEGs from newborn piglets were associated with endothelial cells, while juvenile piglet DEGs were associated with neurons. Additionally, sham newborns and juveniles displayed distinct microglia morphologies, and TBI-induced changes were observed only in the juveniles. In summary, we conclude that biological differences associated with developmental stage, rather than biomechanical load, dominate the tissues level response. In total, our data reveal the influence of rotational magnitude and emphasize distinct changes in gene expression, cell response, and tissue pathology in newborn versus juvenile brains after TBI.
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