Defense Date

2006

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Anatomy & Neurobiology

First Advisor

Dr. John T. Povlishock

Abstract

A significant component of diffuse brain injury (DBI) is diffuse axonal injury (DAI) which is responsible for the morbidity and mortality associated with this condition. DAI and its experimental counterpart traumatic axonal injury (TAI) result in scattered microscopic pathology characterized by focal impairment of axonal transport leading to progressive swelling and delayed axotomy. DBI-mediated perisomatic axotomy does not result in acute neuronal death suggesting that delayed axotomy was responsible for this unanticipated response. To evaluate this hypothesis, we examined the spatiotemporal progression of DBI-mediated perisomatic TAI. LM / TEM identified impaired axonal transport within 15 - 30 min post-injury. Perisomatic TAI revealed somata and related proximal / distal axonal segments with normal ultrastructural detail continuous with axonal swellings. In other cases, axotomy was confirmed by loss of axonal continuity distal to the swelling. By 60 - 180 min post-injury, somatic, proximal segment, and swelling ultrastructure were comparable to earlier time points although swelling diameter increased. Distal segment ultrastructure revealed the initial stages of Wallerian degeneration. Axotomy sites did not internalize pre-injury administered dextran suggesting pathogenesis independent of altered axolemmal permeability. Given the rapidity of perisomatic axotomy, absence of axolemmal permeability may constitute the more significant finding in terms of somatic protection.DBI-mediated neuroinflammatory reactions were then examined to see if this non-lethal neuronal pathology evoked responses comparable to those following focal injury. Microglia / macrophage responses within diffusely injured loci uncomplicated by focal pathology were explored using LM, TEM, and confocal evaluations as was albumin immunoreactivity to assess injury-induced blood-brain barrier (BBB) alterations. Initially, microglial activation was observed within injured loci while microglia within adjoining regions maintained resting phenotypes. Scattered activated microglia were observed among injured axons though no clear associations were seen. Later, activated microglia contained myelin debris while only limited microglial aggregations were recognized. Macrophages also localized to injured loci with select cells approximating somata of axotomized neurons. Immune cell observations correlated with altered BBB permeability. These data indicated rapid, yet initially uncoordinated, and persistent immune cell reactivity to DBI pathology. Taken together, these responses suggest that histopathological evaluation following DBI may include non-lethal neuronal injury with unique neuroinflammatory findings.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

June 2008

Share

COinS