Diffuse traumatic axonal injury in the mouse induces atrophy, c-Jun activation, and axonal outgrowth in the axotomized neuronal population

• Published in: The Journal of neuroscience Vol. 31; no. 13; pp. 5089 - 5105
• Main Authors: Greer, John E, McGinn, Melissa J, Povlishock, John T
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 30-03-2011
• Subjects: Activating Transcription Factor 3 - genetics; Activating Transcription Factor 3 - metabolism; Activating Transcription Factor 3 - physiology; Animals; Atrophy; Axons - enzymology; Axons - metabolism; Axons - pathology; Axotomy - methods; Diffuse Axonal Injury - enzymology; Diffuse Axonal Injury - metabolism; Diffuse Axonal Injury - pathology; Enzyme Activation - genetics; JNK Mitogen-Activated Protein Kinases - genetics; JNK Mitogen-Activated Protein Kinases - metabolism; JNK Mitogen-Activated Protein Kinases - physiology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Regeneration - genetics; Neurogenesis - genetics; Neurons - enzymology; Neurons - metabolism; Neurons - pathology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.5103-10.2011

Traumatic axonal injury (TAI) is a consistent component of traumatic brain injury (TBI) and is associated with much of its morbidity. Little is known regarding the long-term retrograde neuronal consequences of TAI and/or the potential that TAI could lead to anterograde axonal reorganization and repair. To investigate the repertoire of anterograde and retrograde responses triggered by TIA, Thy1-YFP-H mice were subjected to mild central fluid percussion injury and killed at various times between 15 min and 28 d post-injury. Based upon confocal assessment of the endogenous neuronal fluorescence, such injury was found to result in diffuse TAI throughout layer V of the neocortex within yellow fluorescent protein (YFP)-positive axons. When these fluorescent approaches were coupled with various quantitative and immunohistochemical approaches, we found that this TAI did not result in neuronal death over the 28 d period assessed. Rather, it elicited neuronal atrophy. Within these same axotomized neuronal populations, TAI was also found to induce an early and sustained activation of the transcription factors c-Jun and ATF-3 (activating transcription factor 3), known regulators of axon regeneration. Parallel ultrastructural studies confirmed that these reactive changes are consistent with atrophy in the absence of neuronal death. Concurrent with those events ongoing in the neuronal cell bodies, their downstream axonal segments revealed, as early as 1 d post-injury, morphological changes consistent with reactive sprouting that was accompanied by significant axonal elongation over time. Collectively, these TAI-linked events are consistent with sustained neuronal recovery, an activation of a regenerative genetic program, and subsequent axonal reorganization suggestive of some form of regenerative response.