Low-level blast exposure disrupts gliovascular and neurovascular connections and induces a chronic vascular pathology in rat brain

Abstract

Much concern exists over the role of blast-induced traumatic brain injury (TBI) in the chronic cognitive and mental health problems that develop in veterans and active duty military personnel. The brain vasculature is particularly sensitive to blast injury. The aim of this study was to characterize the evolving molecular and histologic alterations in the neurovascular unit induced by three repetitive low-energy blast exposures (3 × 74.5 kPa) in a rat model mimicking human mild TBI or subclinical blast exposure. High-resolution two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry of purified brain vascular fractions from blast-exposed animals 6 weeks post-exposure showed decreased levels of vascular-associated glial fibrillary acidic protein (GFAP) and several neuronal intermediate filament proteins (α-internexin and the low, middle, and high molecular weight neurofilament subunits). Loss of these proteins suggested that blast exposure disrupts gliovascular and neurovascular interactions. Electron microscopy confirmed blast-induced effects on perivascular astrocytes including swelling and degeneration of astrocytic endfeet in the brain cortical vasculature. Because the astrocyte is a major sensor of neuronal activity and regulator of cerebral blood flow, structural disruption of gliovascular integrity within the neurovascular unit should impair cerebral autoregulation. Disrupted neurovascular connections to pial and parenchymal blood vessels might also affect brain circulation. Blast exposures also induced structural and functional alterations in the arterial smooth muscle layer. Interestingly, by 8 months after blast exposure, GFAP and neuronal intermediate filament expression had recovered to control levels in isolated brain vascular fractions. However, despite this recovery, a widespread vascular pathology was still apparent at 10 months after blast exposure histologically and on micro-computed tomography scanning. Thus, low-level blast exposure disrupts gliovascular and neurovascular connections while inducing a chronic vascular pathology.

Blast-Related Mild TBI Alters Anxiety-Like Behavior and Transcriptional Signatures in the Rat Amygdala

“…While an anxiety phenotype was not detected at the chronic time-point in our model, previous rodent studies from our lab (Perez-Garcia et al, 2016;Gama Sosa et al, 2019) and human studies (Glenn et al, 2017) suggest that long-term pathology exists following blast exposure that may contribute to the lasting deleterious effects of blast in the Veteran population. We chose to measure gene expression in the amygdala of rats that were exposed to rBOP because of the importance of this brain region in mTBI-related psychopathology, including anxiety and PTSD.…”

“…Various animal models have been established to study TBI-related pathology, including direct exposure to live explosives and controlled blast waves from compressed air generators, with the use of these models increasing in recent years. In particular, our group has developed a model of blast overpressure in rats (Ahlers et al, 2012) to explore the pathology and molecular outcomes resulting from mild blast injury (Elder et al, 2012;Haghighi et al, 2015;Gama Sosa et al, 2019). High-level blast exposure is associated with hemorrhagic lesions as well as histological effects including axonal, glial, microglial, and myelin changes (Elder et al, 2010).…”

“…The majority of work investigating rodent models of TBI has focused on more sub-acute changes to behavior or structural/functional changes in the brain (days to weeks following blast), but more recent studies from our group suggest that deleterious effects of mTBI are long-lasting or may emerge 8-10 months following the blast exposure (Perez-Garcia et al, 2016;Gama Sosa et al, 2019). The long-term outcomes of mTBI are of particular interest due to the high levels of neurodegenerative disorders in aging, mTBI-exposed Veterans (Elder, 2015).…”

Nitric oxide synthase mediates cerebellar dysfunction in mice exposed to repetitive blast-induced mild traumatic brain injury

“…The risk of dementia more than doubles among military Veterans with TBI, but the mechanisms mediating this increased risk remain poorly understood 2 . Neurovascular dysfunction, including blood-brain barrier (BBB) disruption, may be an important initiating mechanism by which mTBI sets in motion pathogenic cascades leading to chronic neurodegenerative pathophysiology [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] . BBB disruption has been examined in a number of pre-clinical models of blast mTBI 10,11,[20][21][22][23][24][25] .…”

A comprehensive, FAIR file format for neuroanatomical structure modeling

“…Due to the data structure that stores each unique vessel point and its diameter, detailed analysis of length, surface area, volume, average thickness, and even tortuosity can be obtained through the vascular models. A recent study performed vascular reconstructions were generated of micro-CT rat brains on control and blast-exposed rats to examine the effects of traumatic brain injury on vascular networks (Gama Sosa et al 2019). Though the micro-CT images showed a clear decrease in vasculature structures, the reconstruction of both control and blast-induced rat brains provided meaningful quantitative results to back this observation.…”