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Updated: Jun 1, 2026
A Mouse Model of Single and Repetitive Mild Traumatic Brain Injury
Published on: June 20, 2017
Repetitive closed-skull traumatic brain injury in mice causes persistent multifocal axonal injury and microglial
Yoshitsugu Shitaka1, Hien T Tran, Rachel E Bennett
1Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Abstract:
Repetitive mild or "concussive" traumatic brain injury (TBI) can cause substantial neurologic impairment, but the pathological features of this type of injury are not fully understood. We report an experimental model of TBI in which the closed skulls of anesthetized male C57BL/6J mice are struck with an electromagnetically controlled rubber impactor twice with an interval of 24 hours between impacts. The mice had deficits in Morris water maze performance in the first week after injury that only partially resolved 7 weeks later. By routine histology, there was no apparent bleeding, neuronal cell loss, or tissue disruption, and amyloid precursor protein immunohistochemistry demonstrated very few immunoreactive axonal varicosities. In contrast, silver staining revealed extensive abnormalities in the corpus callosum and bilateral external capsule, the ipsilateral cortex and thalamus, and the contralateral hippocampal CA1 stratum radiatum and stratum oriens. Electron microscopy of white matter regions demonstrated axonal cytoskeletal disruption, intra-axonal organelle compaction, and irregularities in axon caliber. Reactive microglia were observed in the same areas as the injured axons by both electron microscopy and Iba1 immunohistochemistry. Quantitative analyses of silver staining and Iba1 immunohistochemistry at multiple time points demonstrated transient cortical and thalamic abnormalities but persistent white matter pathology as late as 7 weeks after injury.Thus, prominent and long-lasting abnormalities in this TBI model were underestimated using conventional approaches. The model may be useful for mechanistic investigations and preclinical assessment of candidate therapeutics.
Insights
Repetitive mild traumatic brain injury (TBI) causes lasting white matter damage and cognitive deficits in mice. Conventional methods underestimate TBI pathology, highlighting the need for advanced analysis in TBI research.
Area of Science:
- Neuroscience
- Neuropathology
- Experimental Neurology
Background:
- Repetitive mild traumatic brain injury (TBI) can lead to significant neurological impairment.
- The precise pathological characteristics of concussive TBI remain incompletely understood.
- Conventional histological methods may underestimate the extent of TBI-induced damage.
Purpose of the Study:
- To establish and characterize an experimental model of repetitive mild TBI in mice.
- To investigate the neuropathological consequences of this TBI model using advanced techniques.
- To assess the long-term effects of TBI on cognitive function and white matter integrity.
Main Methods:
- Anesthetized male C57BL/6J mice were subjected to two closed-skull impacts 24 hours apart.
- Cognitive function was assessed using the Morris water maze.
- Pathological changes were evaluated using routine histology, silver staining, amyloid precursor protein immunohistochemistry, and electron microscopy.
- Iba1 immunohistochemistry was used to identify reactive microglia.
Main Results:
- Mice exhibited partial recovery of Morris water maze performance 7 weeks post-injury.
- Routine histology and APP immunohistochemistry showed minimal acute damage.
- Silver staining revealed widespread axonal abnormalities in white matter tracts (corpus callosum, external capsule) and gray matter regions (cortex, thalamus, hippocampus).
- Electron microscopy confirmed axonal cytoskeletal disruption and organelle compaction in white matter.
- Reactive microglia were present in injured areas, with persistent white matter pathology observed up to 7 weeks post-injury.
Conclusions:
- Repetitive mild TBI induces significant and persistent white matter pathology that is often underestimated by standard histological assessments.
- The developed TBI model demonstrates long-lasting neurological deficits and neuropathological changes.
- This model is suitable for investigating TBI mechanisms and evaluating potential therapeutic interventions.
