Diffuse Traumatic Axonal Injury in the Mouse Induces Atrophy, c-Jun Activation, and Axonal Outgrowth in the Axotomized Neuronal Population

Abstract

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 sacrificed at various times between 15 minutes and 28 days 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 YFP+ 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 day 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, known regulators of axon regeneration. Parallel ultrastructural studies confirmed these reactive changes 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 day 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.

Corneal Neurotoxicity Due to Topical Benzalkonium Chloride

“…Thy1-YFP mice have been used previously to demonstrate that the disappearance of YFP fluorescence in axotomized neurons signifies atrophy, whereas the reappearance of YFP fluorescence fibers signifies nerve regeneration. 29 We, as well as others, have reported that regenerating nerves in the cornea do not follow pre-existing tracks; therefore, the appearance of new fluorescent nerve fibers in a new pattern signifies nerve regeneration. [14][15][16] We visualized two forms of stromal nerve neurotoxicity.…”

Therapy Development for Diffuse Axonal Injury

“…Showing signs of success, some models produce selective axonal pathology of similar appearance to that found after TBI in humans. 74,76,77 Progress toward identifying optimal small animal models of TAI will clearly be important for the development of therapies for DAI.…”

Critical role of trkB receptors in reactive axonal sprouting and hyperexcitability after axonal injury

“…Pyramidal cells can generate new local axon collaterals after injury in vivo (Greer et al 2011;Nadler 2003;Perez et al 1996). Irreparable damage to axons is a common feature of TBI and can result directly from the trauma of a penetrating injury or indirectly from the shearing and stretching of axons that occur with rapid acceleration and deceleration of the brain (Povlishock and Katz 2005).…”

“…Irreparable damage to axons is a common feature of TBI and can result directly from the trauma of a penetrating injury or indirectly from the shearing and stretching of axons that occur with rapid acceleration and deceleration of the brain (Povlishock and Katz 2005). The cells whose axons are injured usually survive (Singleton et al 2002), but the axons themselves may be damaged irreversibly and ultimately degenerate (Greer et al 2011). In hippocampal slice cultures, axonal injury causes upregulation of BDNF and trkB, the growth of new axon collaterals by CA3 cells, and hyperexcitability.…”