title: Electrophysiological white matter dysfunction and association with neurobehavioral deficits following low-level primary blast trauma.
abstract: There is strong evidence that primary blast injuries can cause neuropathological alterations in the brain. Clinical findings from war veterans indicating evidence of diffuse axonal injury have been corroborated by numerous primary blast models in animals. However, the effect of a subclinical blast (blast with no obvious sign of external trauma or lung injury) as a contributing factor to the neurological symptoms and neuropathology is less clear. Our group recently developed a model of low-level primary blast and characterized aberrant expression of white matter cytoskeletal proteins in the cortex and hippocampus following a subclinical wave shock exposure. Here we examined the susceptibility of the corpus callosum following subclinical blast. We also demonstrate that white matter dysfunction is associated with neurobehavioral deficits associated with anxiety and stress in rats. Anesthetized male Sprague-Dawley rats (~300 g) were exposed to a primary blast (approx. 28 kPa), below the threshold required to induce pulmonary trauma. Rats were evaluated on three behavioral outcome measures; the rotarod, the light/dark box and open field anxiety test. We used Western blotting to examine expression and degradation of axonally expressed αII-spectrin, NF200 and voltage-gated sodium channels (VGSC) in the corpus callosum. Acute slice preparations were used for electrophysiological analysis of evoked compound action potentials (CAPs) in the corpus callosum. There was evidence of αII-spectrin degradation in the corpus callosum at 48 h post-injury detectable up to 14 days post-injury, as well as increased heavy neurofilament expression. A reduction in VGSC expression was observed at 48 h post-blast as well as a reduction in the interaction between ankyrin G and intact αII-spectrin. Blast exposed rats had significantly lower rotarod latency times relative to sham rats (p=0.002). Increased anxiety-related and stress-related behavior were observed in blast rats relative to sham animals as indicated by the increased frequency of fecal droppings (p=0.029) and reduced exploratory activity (p=0.036) in the open-field test. Blast rats had fewer transitions and time spent in lit sections of the light/dark box. Electrophysiological recordings from the corpus callosum indicated greater deficits in unmyelinated fibers of the corpus callosum relative to myelinated fibers characterized by reduced CAP amplitude response at 14 days post-injury. Analysis of the relationship between stimulation distance to evoked response indicated an underlying abnormality in N1 myelinated fibers at close stimulation distances. Collectively, our results indicate that subclinical blast exposure can result in persistent neurological changes in cerebral white matter occurring in parallel with detectable neurobehavioral deficits.
authors.affiliation: Keenan Research Centre in the Li Ka Shing Knowledge Institute at St. Michael's Hospital, Toronto, ON, Canada. parke@smh.ca
authors.forename: Eugene
authors.initials: E
authors.lastname: Park
authors.forename: Rebecca
authors.initials: R
authors.lastname: Eisen
authors.forename: Anna
authors.initials: A
authors.lastname: Kinio
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Baker
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001753:Blast Injuries / Q000473:pathology / Q000503:physiopathology*; D001930:Brain Injuries / Q000473:pathology / Q000503:physiopathology*; D003337:Corpus Callosum / Q000293:injuries / Q000473:pathology / Q000503:physiopathology*; D004594:Electrophysiology; D005106:Exploratory Behavior / Q000502:physiology*; D008297:Male; D009048:Motor Skills / Q000502:physiology*; D009413:Nerve Fibers, Myelinated / Q000473:pathology / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D045442:Rotarod Performance Test