title: Blast exposure causes dynamic microglial/macrophage responses and microdomains of brain microvessel dysfunction.
abstract: Exposure to blast overpressure (BOP) is associated with behavioral, cognitive, and neuroimaging abnormalities. We investigated the dynamic responses of cortical vasculature and its relation to microglia/macrophage activation in mice using intravital two-photon microscopy following mild blast exposure. We found that blast caused vascular dysfunction evidenced by microdomains of aberrant vascular permeability. Microglial/macrophage activation was specifically associated with these restricted microdomains, as evidenced by rapid microglial process retraction, increased ameboid morphology, and escape of blood-borne Q-dot tracers that were internalized in microglial/macrophage cell bodies and phagosome-like compartments. Microdomains of cortical vascular disruption and microglial/macrophage activation were also associated with aberrant tight junction morphology that was more prominent after repetitive (3×) blast exposure. Repetitive, but not single, BOPs also caused TNFα elevation two weeks post-blast. In addition, following a single BOP we found that aberrantly phosphorylated tau rapidly accumulated in perivascular domains, but cleared within four hours, suggesting it was removed from the perivascular area, degraded, and/or dephosphorylated. Taken together these findings argue that mild blast exposure causes an evolving CNS insult that is initiated by discrete disturbances of vascular function, thereby setting the stage for more protracted and more widespread neuroinflammatory responses.
authors.affiliation: VA Jamaica Plain, Department of Neurology, Boston University School of Medicine, Jamaica Plain, MA, USA.
authors.forename: B R
authors.initials: BR
authors.lastname: Huber
authors.affiliation: Northwest Network Mental Illness, Research, Education, and Clinical Center (MIRECC), VA Puget Sound Healthcare Systems, Seattle, WA, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Meabon
authors.affiliation: United States Army, Madigan Army Medical Center, Joint Base Lewis-McChord, WA, USA.
authors.forename: Z S
authors.initials: ZS
authors.lastname: Hoffer
authors.affiliation: Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Hoekstra
authors.affiliation: Northwest Network Mental Illness, Research, Education, and Clinical Center (MIRECC), VA Puget Sound Healthcare Systems, Seattle, WA, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
authors.forename: K F
authors.initials: KF
authors.lastname: Pagulayan
authors.affiliation: Northwest Network Mental Illness, Research, Education, and Clinical Center (MIRECC), VA Puget Sound Healthcare Systems, Seattle, WA, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: McMillan
authors.affiliation: Northwest Network Mental Illness, Research, Education, and Clinical Center (MIRECC), VA Puget Sound Healthcare Systems, Seattle, WA, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Mayer
authors.affiliation: Geriatric Research, Education, and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: W A
authors.initials: WA
authors.lastname: Banks
authors.affiliation: Geriatric Research, Education, and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Kraemer
authors.affiliation: Northwest Network Mental Illness, Research, Education, and Clinical Center (MIRECC), VA Puget Sound Healthcare Systems, Seattle, WA, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Raskind
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: McGavern
authors.affiliation: Northwest Network Mental Illness, Research, Education, and Clinical Center (MIRECC), VA Puget Sound Healthcare Systems, Seattle, WA, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
authors.forename: E R
authors.initials: ER
authors.lastname: Peskind
authors.affiliation: Geriatric Research, Education, and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, USA; Department of Pharmacology, University of Washington School of Medicine, Seattle, WA, USA. Electronic address: dgcook@u.washington.edu.
authors.forename: D G
authors.initials: DG
authors.lastname: Cook
mesh_terms: D000818:Animals; D001753:Blast Injuries / Q000473:pathology*; D001812:Blood-Brain Barrier / Q000473:pathology; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply / Q000473:pathology; D001930:Brain Injuries / Q000473:pathology*; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D000069416:Intravital Microscopy; D008264:Macrophages / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000473:pathology*; D055806:Microvessels / Q000473:pathology
keywords: blood–brain barrier; macrophages; microglia; neuropathology; two-photon microscopy