Immediate induction of varicosities by transverse compression but not uniaxial stretch in axon mechanosensation

Uniaxial stretch is believed to drive diffuse axonal injury (DAI) in mild traumatic brain injury (mTBI). Axonal varicosities are enlarged structures along axonal shafts and represent a hallmark feature of DAI. Here we report that axonal varicosities initiate in vivo immediately after head impact and are mainly induced by transverse compression but not uniaxial stretch. Vertical and lateral impacts to the mouse head induced axonal varicosities in distinct brain regions before any changes of microglial markers. Varicosities preferentially formed along axons perpendicular to impact direction. In cultured neurons, whereas 50% uniaxial strain was needed to rapidly induce axonal varicosities in a nanowrinkled stretch assay, physiologically-relevant transverse compression effectively induced axonal varicosities in a fluid puffing assay and can generate large but nonuniform deformation simulated by finite element analysis. Therefore, impact strength and direction may determine the threshold and spatial pattern of axonal varicosity initiation, respectively, partially resulting from intrinsic properties of axon mechanosensation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-022-01309-8.