Primary traumatic axonopathy in mice subjected to impact acceleration: A reappraisal of pathology and mechanisms with high-resolution anatomical methods

Nikolaos K. Ziogas, Vassilis E. Koliatsos

Research output: Contribution to journalArticlepeer-review

Abstract

Traumatic axonal injury (TAI) is a common neuropathology in traumatic brain injury and is featured by primary injury to axons. Here, we generated TAI with impact acceleration of the head in male Thy1-eYFP-H transgenic mice in which specific populations of neurons and their axons are labeled with yellow fluorescent protein. This model results in axonal lesions in multiple axonal tracts along with blood– brain barrier disruption and neuroinflammation. The corticospinal tract, a prototypical long tract, is severely affected and is the focus of this study. Using optimized CLARITY at single-axon resolution, we visualized the entire corticospinal tract volume from the pons to the cervical spinal cord in 3D and counted the total number of axonal lesions and their progression over time. Our results divulged the presence of progressive traumatic axonopathy that was maximal at the pyramidal decussation. The perikarya of injured corticospinal neurons atrophied, but there was no evidence of neuronal cell death. We also used CLARITY at single-axon resolution to explore the role of the NMNAT2-SARM1 axonal self-destruction pathway in traumatic axonopathy. When we interfered with this pathway by genetically ablating SARM1 or by pharmacological strategies designed to increase levels of Nicotinamide (Nam), a feedback inhibitor of SARM1, we found a significant reduction in the number of axonal lesions early after injury. Our findings show that high-resolution neuroanatomical strategies reveal important features of TAI with biological implications, especially the progressive axonopathic nature of TAI and the role of the NMNAT2-SARM1 pathway in the early stages of axonopathy.

Original languageEnglish (US)
Pages (from-to)4031-4047
Number of pages17
JournalJournal of Neuroscience
Volume38
Issue number16
DOIs
StatePublished - Apr 18 2018

Keywords

  • 2-photon microscopy
  • Axonopathy
  • CLARITY
  • Corticospinal tract
  • NMNAT2-SARM1
  • Traumatic brain injury

ASJC Scopus subject areas

  • Neuroscience(all)

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