Juvenile mild traumatic brain injury elicits distinct spatiotemporal astrocyte responses

Abstract

Mild‐traumatic brain injury (mTBI) represents ~80% of all emergency room visits and increases the probability of developing long‐term cognitive disorders in children. To date, molecular and cellular mechanisms underlying post‐mTBI cognitive dysfunction are unknown. Astrogliosis has been shown to significantly alter astrocytes' properties following brain injury, potentially leading to significant brain dysfunction. However, such alterations have never been investigated in the context of juvenile mTBI (jmTBI). A closed‐head injury model was used to study jmTBI on postnatal‐day 17 mice. Astrogliosis was evaluated using glial fibrillary acidic protein (GFAP), vimentin, and nestin immunolabeling in somatosensory cortex (SSC), dentate gyrus (DG), amygdala (AMY), and infralimbic area (ILA) of prefrontal cortex in both hemispheres from 1 to 30 days postinjury (dpi). In vivo T2‐weighted‐imaging (T2WI) and diffusion tensor imaging (DTI) were performed at 7 and 30 dpi to examine tissue level structural alterations. Increased GFAP‐labeling was observed up to 30 dpi in the ipsilateral SSC, the initial site of the impact. However, vimentin and nestin expression was not perturbed by jmTBI. The morphology of GFAP positive cells was significantly altered in the SSC, DG, AMY, and ILA up to 7 dpi that some correlated with magnetic resonance imaging changes. T2WI and DTI values were significantly altered at 30 dpi within these brain regions most prominently in regions distant from the impact site. Our data show that jmTBI triggers changes in astrocytic phenotype with a distinct spatiotemporal pattern. We speculate that the presence and time course of astrogliosis may contribute to pathophysiological processes and long‐term structural alterations following jmTBI.

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.…”

Age-at-Injury Determines the Extent of Long-Term Neuropathology and Microgliosis After a Diffuse Brain Injury in Male Rats

“…Astrogliosis is typically reported to increase after a TBI in post-mortem tissue and experimental models ( 78 ), whilst in this study there were no significant differences in the extent of astrogliosis post-injury in any of the ROIs, quantified by the percentage of GFAP per mm 2 , compared to naïve or between the different ages at which the injury occurred. Studies in juvenile and young adult mice reported changes in astrocyte processes up to 30-days after a juvenile-closed head injury and moderate lateral FPI, respectively ( 79 , 80 ). Specifically, after a TBI in juvenile mice, astrocyte processes became longer and thicker which initiated at the injury site and became evident in connecting brain regions with time post-injury ( 80 ).…”

Blood–Brain Barrier Dysfunction in Mild Traumatic Brain Injury: Evidence From Preclinical Murine Models

“…Functional assessments revealed that repeated impacts cause sustained decreases of CBF and cerebrovascular reactivity, along with neuronal function deficits and astrogliosis in peri-contusion areas (Adams et al, 2018). In addition, mTBI can elicit an early and long-lasting cerebrovascular dysfunction in juvenile mice (Wendel et al, 2018;Ichkova et al, 2020), accompanied by astrocyte response and gliovascular changes (Rodriguez-Grande et al, 2018;Clément et al, 2020). Furthermore, pediatric mTBI can morphologically alter the vasculature of the ipsilateral corpus callosum differentially between the acute/subacute stage and the chronic stage (Wendel et al, 2018).…”