Gliovascular changes precede white matter damage and long‐term disorders in juvenile mild closed head injury

Abstract

Traumatic brain injury (TBI) is a leading cause of hospital visits in pediatric patients and often leads to long-term disorders even in cases of mild severity. White matter (WM) alterations are commonly observed in patients months or years after the injury assessed by magnetic resonance imaging (MRI), but little is known about WM pathophysiology early after mild pediatric TBI. To evaluate the status of the gliovascular unit in this context, mild TBI was induced in postnatal-day 17 mice using a closed head injury model with two grades of severity (G1, G2). G2 resulted in significant WM edema (increased T2-signal) and BBB damage (IgG-extravasation immunostaining) whereas decreased T2 and the increased levels of astrocytic water-channel AQP4 were observed in G1 mice 1 day post-injury. Both severities induced astrogliosis (GFAP immunolabeling). No changes in myelin and neurofilament were detected at this acute time point. One month after injury G2 mice exhibited diffusion tensor imaging MRI alterations (decreased fractional anisotropy) accompanied by decreased neurofilament staining in the WM. Both severities induced behavioral impairments at this time point. In conclusion, long-term deficits and WM changes similar to those found after clinical TBI are preceded by distinct early gliovascular phenotype alterations after juvenile mild TBI, revealing AQP4 as a potential candidate for severity-based treatments.

Diffusion Tensor Imaging-Based Studies at the Group-Level Applied to Animal Models of Neurodegenerative Diseases

“…In a similar repeated-hit model, DTI has revealed disruption of axonal integrity in multiple white matter structures, irrespective of microhemorrhage detection (Robinson et al, 2017 ); substantial white matter damage was detected by DTI, together with histological approaches, in juvenile mice subject to repeated mild TBI (Yu et al, 2017 ; Lee et al, 2018 ). Similar alterations have been detected in rat models of repeated TBI (Calabrese et al, 2014 ; Singh et al, 2016 ; Wright et al, 2016 ; Qin et al, 2018 ; Kao et al, 2019 ) as well as in juvenile rat (Fidan et al, 2018 ; Wortman et al, 2018 ; Wright et al, 2018 ) or mouse (Rodriguez-Grande et al, 2018 ; Clément et al, 2020 ) cohorts subject to TBI. A few studies have applied ex-vivo DTI to obtain high-resolution maps of axonal disruption upon TBI, both in mouse (Weiss et al, 2020 ) and in rat (Donovan et al, 2014 ; Laitinen et al, 2015 ) models of brain trauma.…”

Noninvasive magnetic resonance imaging stratifies injury severity in a rodent model of male juvenile traumatic brain injury

“…T2WI is well known to assess edema and provides clear measures of edema (Obenaus & Badaut, ). While clinically, edema volumes are not utilized routinely, in animal models of TBI the extent of edema is useful to monitor the progression of intervention (Rodriguez‐Grande et al, ). SWI (and its variants) are now also used clinically and it have been shown to be very sensitive to extravascular blood following TBI in both adult and juvenile populations (Haacke et al, ; Tong et al, ).…”

“…The juvenile brain is still undergoing significant development and structurally may be more vulnerable to traumatic injury, as we observed here (Giza, Mink, & Madikians, ). While the CCI model is relatively invasive, even emerging models of mild pediatric TBI with a closed head injury approach have reported the appearance of cortical hemorrhage using SWI (Rodriguez‐Grande et al, ). Use of SWI is relatively atypical in preclinical model characterization and our findings along with others would suggest that this imaging modality would be useful for monitoring the appearance of hemorrhage after jTBI, particularly in the context of severity.…”

“…Explicit power analysis was not undertaken but previous published studies in similar groups of animals and in adult studies using MRI have found that n = 6 is typically sufficient for statistical reporting (Donovan et al, ; Fukuda et al, ; Igarashi et al, ; Jullienne et al, ; Obenaus et al, ; Rodriguez‐Grande et al, ). All juvenile animals and groups were randomized.…”

“…However, multimodal magnetic resonance imaging (MRI) can provide additional diagnostic information, including edema, hemorrhage, and assessment of white matter integrity. More importantly, the progression of the injury can be readily monitored temporally using MRI in animal models of TBI (Rodriguez‐Grande et al, ; Wendel et al, ), albeit less frequently in young patients (Levin et al, ). In preclinical TBI models, positive correlations between T2 relaxation values, poor histological and behavioral outcomes have been reported (Kharatishvili, Sierra, Immonen, Grohn, & Pitkanen, ).…”