A Clinically Relevant Mouse Model of Concussion Incorporating High Rotational Forces.

Area of Science:

• Neuroscience
• Traumatic Brain Injury Research
• Animal Models

Background:

• Concussion research requires clinically relevant animal models that mimic human mild traumatic brain injuries (mTBIs).
• Existing models often lack the specific biomechanical properties of human concussions, limiting their translational value.
• Bridging the gap between preclinical and clinical studies necessitates models with high construct validity.

Purpose of the Study:

• To develop and validate a mouse model of concussion that accurately replicates the biomechanical and pathological features of human concussions.
• To assess the construct validity by comparing biomechanical parameters to human football impacts.
• To evaluate the face validity through histopathological analysis of injury-induced changes.

Main Methods:

• A closed-head mild traumatic brain injury (mTBI) model was created using a cortical impactor in mice.
• Mice were placed on a break-away platform allowing unrestrained head and body motion during impact.
• Over 100 mice, including those with humanized amyloid precursor protein and tau genes, were used; histopathology assessed injury outcomes.

Main Results:

• The model consistently produced peak angular velocities in mice that, when scaled, approximated those in human football impacts.
• Histopathology revealed diffuse axonal injury, astrogliosis, and microglial activation one week after three impacts.
• Persistent axonal degeneration was observed up to six months post-injury, particularly in white matter tracts.

Conclusions:

• This mouse model effectively captures key biomechanical and pathological features of human concussions.
• The model demonstrates high construct and face validity, making it suitable for studying concussion pathophysiology and long-term outcomes.
• This tool advances preclinical research by providing a more accurate representation of concussive injuries.