Abstract
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.
Highlights
Traumatic brain injury (TBI), a worldwide health problem, contributes to about a third of all injury-related deaths in the United States, while most of the 1.7 million TBIs that occur each year belong to mild TBI or concussion [1]
A substantial amount of axonal varicosities formed in the corpus callosum (CC) and external capsule (EC) in Closed‐head impact model of engineered rotational acceleration (CHIMERA), whereas no significant increase in CC and a relatively small but significant increase in EC in terms of axonal varicosity formation were found in Repetitive closed‐skull TBI (rcTBI) (Fig. 1C,D,F–H and Additional file 2-5)
Since there are normally less than 2 min between impact and cardiac perfusion, our results show that mechanical impact can very rapidly, or immediately, induce axonal varicosity formation in vivo, representing the earliest subcellular event that is known in mild TBI (mTBI) primary injury
Summary
Traumatic brain injury (TBI), a worldwide health problem, contributes to about a third of all injury-related deaths in the United States, while most of the 1.7 million TBIs that occur each year belong to mild TBI (mTBI) or concussion [1]. Consistent with our findings, several groups independently reported that axonal varicosities were observed from 3 h to 3 days after one impact in the brain of Thy1-YFP transgenic mice in different closed-skull mTBI models [15,16,17], as well as in an open-skull TBI model combined with immunostaining for amyloid precursor protein [18] It remains unknown whether axonal varicosities can be induced in vivo immediately but not hours after one mechanical impact, just like rapid axonal varicosity formation in cultured neurons induced by fluid puffing shown in our recent study [12]
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