A mouse Model of Focal Vascular Injury Induces Astrocyte Reactivity, Tau Oligomers, and Aberrant Behavior

Abstract

Neuropsychiatric symptom development has become more prevalent with 270,000 blast exposures occurring in the past 10 years in the United States. How blast injury leads to neuropsychiatric symptomology is currently unknown. Preclinical models of blast-induced traumatic brain injury have been used to demonstrate blood-brain barrier disruption, degenerative pathophysiology, and behavioral deficits. Vascular injury is a primary effect of neurotrauma that can trigger secondary injury cascades and neurodegeneration. Here we present data from a novel scaled and clinically relevant mouse blast model that was specifically developed to assess the outcome of vascular injury. We look at the biochemical effects and behavioral changes associated with blast injury in young-adult male BALB/c mice. We report that blast exposure causes focal vascular injury in the Somatosensory Barrel Field cortex, which leads to perivascular astrocyte reactivity, as well as acute aberrant behavior. Biochemical analysis revealed that mild blast exposure also invokes tauopathy, neuroinflammation, and oxidative stress. Overall, we propose our model to be used to evaluate focal blood-brain barrier disruption and to discover novel therapies for human neuropsychiatric symptoms.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.

Cognitive and emotional alterations in App knock-in mouse models of Aβ amyloidosis

“…These data from App -KI mice suggest that anxiolytic-like behaviors observed in mouse models of Aβ amyloidosis are associated with Aβ-mediated pathologies [ 24 , 53 ] rather than overexpression of APP. Interestingly, some mouse models with traumatic brain injury exhibit increases in open arm exploration in the EPM task, followed by elevated levels of reactive gliosis and cerebrovascular dysfunction [ 63 – 66 ]. Another study demonstrated that local neuroinflammation within the dorsal raphe nucleus, resulting in serotonergic hypofunction, caused the same behavioral consequences in the EPM task [ 67 ].…”

Neurotoxic tau oligomers after single versus repetitive mild traumatic brain injury

“…The mice, from which the brains were obtained, were 6-month-old wild-type C57BL/6 male mice that had undergone blast-induced traumatic brain injury (mTBI) as described in Fig. 1 (Logsdon et al , 2017). The mice were placed in a PVC pipe with the head extending from one side.…”

Brain and blood biomarkers of tauopathy and neuronal injury in humans and rats with neurobehavioral syndromes following blast exposure

“…In our well-established and characterized battlefieldrelevant rat model of blast-induced mTBI, we found that animals exhibited increased levels of immunoreactive p-tau following blast exposure in the anterior cingulate and anterior motor/sensory cortices. Prior studies have addressed tau processing in experimental animal models of blast TBI, with many reporting elevated levels of tau in brain or blood [21,[46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65]. Two studies reported the presence of tau oligomers following blast exposure [59,61] and others have suggested that p-tau metabolism following blast may be regulated by APOE genotype [62].…”