Abstract

Cerebral vascular injury as a consequence of blast-induced traumatic brain injury is primarily the result of blast wave-induced mechanical disruptions within the neurovascular unit. In rodent models of blast-induced traumatic brain injury, chronic vascular degenerative processes are associated with the development of an age-dependent post-traumatic stress disorder-like phenotype. To investigate the evolution of blast-induced chronic vascular degenerative changes, Long-Evans rats were blast-exposed (3 × 74.5 kPa) and their brains analyzed at different times post-exposure by X-ray microcomputed tomography, immunohistochemistry and electron microscopy. On microcomputed tomography scans, regional cerebral vascular attenuation or occlusion was observed as early as 48 h post-blast, and cerebral vascular disorganization was visible at 6 weeks and more accentuated at 13 months post-blast. Progression of the late-onset pathology was characterized by detachment of the endothelial and smooth muscle cellular elements from the neuropil due to degeneration and loss of arteriolar perivascular astrocytes. Development of this pathology was associated with vascular remodeling and neuroinflammation as increased levels of matrix metalloproteinases (MMP-2 and MMP-9), collagen type IV loss, and microglial activation were observed in the affected vasculature. Blast-induced chronic alterations within the neurovascular unit should affect cerebral blood circulation, glymphatic flow and intramural periarterial drainage, all of which may contribute to development of the blast-induced behavioral phenotype. Our results also identify astrocytic degeneration as a potential target for the development of therapies to treat blast-induced brain injury.

Highlights

  • Traumatic brain injury (TBI) has been linked to mental health disorders and is considered a risk factor for later development of neurodegenerative disorders [31]

  • Research in rat models of repetitive low level blast exposure has shown that animals exposed to repetitive low-level blast exhibit chronic cognitive impairment and post-traumatic stress disorder (PTSD)-related traits that develop over time [30, 33, 100, 101, 123]

  • Cerebral vascular disorganization revealed by micro‐CT scanning The evolution of the blast-induced chronic cerebral vascular pathology was investigated by X-ray high-resolution micro-CT scanning of brains of blast-exposed rats at 48 h, 6 weeks and 13 months post-blast exposure following perfusion with the Brite Vu contrast agent

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Summary

Introduction

Traumatic brain injury (TBI) has been linked to mental health disorders and is considered a risk factor for later development of neurodegenerative disorders [31]. Research in rat models of repetitive low level blast exposure has shown that animals exposed to repetitive low-level blast exhibit chronic cognitive impairment and PTSD-related traits that develop over time [30, 33, 100, 101, 123]. These traits include anxiety, enhanced acoustic startle, altered fear learning and impaired cognition in tests such as novel object recognition. A single predator scent challenge delivered 8 months after the last blast exposure induces additional anxietyrelated changes that are still present 45 days later [101] suggesting that besides inducing PTSD-related traits blast exposure sensitizes the brain to react abnormally to subsequent psychological stressors

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