Differential responses to increasing numbers of mild traumatic brain injury in a rodent closed‐head injury model

Fehily, Brooke; Bartlett, Carole A.; Lydiard, Stephen; Archer, Michael A.; Milbourn, Hannah; Majimbi, Maimuna; Hemmi, Jan M.; Dunlop, Sarah; Yates, Nathanael J.; Fitzgerald, Maria

doi:10.1111/jnc.14673

Cited by 23 publications

(34 citation statements)

References 76 publications

(93 reference statements)

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“…hour through 7 days [30], and 24 hours [31], although others have also found no detriment [32]. The data shown here suggests that even though mild impacts in our model were administered below the threshold seen previously in similar studies, there was still measurable neurological disturbance manifested in behavioural testing.…”

Section: Plos Onesupporting

confidence: 55%

“…Findings from the behavioural data include differences in NSS in the acute phase of recovery 24 hours after final injury, but no differences between groups in the NSS at three months. Previous studies using a similar acceleration mTBI mechanism have shown NSS detriment at 1 hour through 7 days [ 30 ], and 24 hours [ 31 ], although others have also found no detriment [ 32 ]. The data shown here suggests that even though mild impacts in our model were administered below the threshold seen previously in similar studies, there was still measurable neurological disturbance manifested in behavioural testing.…”

Section: Discussionmentioning

confidence: 99%

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Repetitive mild traumatic brain injury affects inflammation and excitotoxic mRNA expression at acute and chronic time-points

et al. 2021

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The cumulative effect of mild traumatic brain injuries (mTBI) can result in chronic neurological damage, however the molecular mechanisms underpinning this detriment require further investigation. A closed head weight drop model that replicates the biomechanics and head acceleration forces of human mTBI was used to provide an exploration of the acute and chronic outcomes following single and repeated impacts. Adult male C57BL/6J mice were randomly assigned into one of four impact groups (control; one, five and 15 impacts) which were delivered over 23 days. Outcomes were assessed 48 hours and 3 months following the final mTBI. Hippocampal spatial learning and memory assessment revealed impaired performance in the 15-impact group compared with control in the acute phase that persisted at chronic measurement. mRNA analyses were performed on brain tissue samples of the cortex and hippocampus using quantitative RT-PCR. Eight genes were assessed, namely MAPT, GFAP, AIF1, GRIA1, CCL11, TARDBP, TNF, and NEFL, with expression changes observed based on location and follow-up duration. The cortex and hippocampus showed vulnerability to insult, displaying upregulation of key excitotoxicity and inflammation genes. Serum samples showed no difference between groups for proteins phosphorylated tau and GFAP. These data suggest that the cumulative effect of the impacts was sufficient to induce mTBI pathophysiology and clinical features. The genes investigated in this study provide opportunity for further investigation of mTBI-related neuropathology and may provide targets in the development of therapies that help mitigate the effects of mTBI.

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Section: Plos Onesupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Repetitive mild traumatic brain injury affects inflammation and excitotoxic mRNA expression at acute and chronic time-points

et al. 2021

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“…As a measure of astroglial activation in human mTBI, GFAP has been shown to be a sensitive and specific marker of injury (Papa et al, ). GFAP was commonly assessed in the animal studies of this review, and demonstrated utility in detecting injury either via mRNA expression (Yu, Wergedal, Rundle, & Mohan, ), protein levels in the brain (Fehily et al, ; Viano et al, ), or in serum (Candy et al, ). Production of inflammatory cytokines is also linked with glial cell activation following injury, and was commonly assessed in these studies.…”

Section: Discussionmentioning

confidence: 99%

Modeling sports‐related mild traumatic brain injury in animals—A systematic review

Hiskens

Angoa‐Pérez

Schneiders

et al. 2019

J of Neuroscience Research

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Sports-related head trauma has emerged as an important public health issue, as mild traumatic brain injuries (mTBIs) may result in neurodegenerative disorders such as chronic traumatic encephalopathy (CTE). Research into mTBI and CTE pathophysiology are difficult to undertake in athletes, with observational trials and post-mortem analysis the current mainstays. Thus, animal models play an important role in the study of mTBI, however, traditional animal models have focused on acute, severe injuries rather than the more typical mTBI's seen in sport injuries. Recently, a number of animal models have been developed that are both appropriately scaled and biomechanically relevant to the forces sustained by athletes. This review aimed to examine the literature for variables included in these animal models, and the resulting neurotrauma as evidenced by pathology and behavioral deficits. A systematic search of the literature was performed in multiple electronic databases. The inclusion criteria required mimicry of athlete mTBI conditions: freedom of head movement, lack of surgical alteration of the skull, and application of direct contact force. Studies were analyzed for variables including apparatus design features (impact force, change in animal head velocity, and kinetic energy transfer to the head), demonstrated pathology (phosphorylated tau, TDP-43 aggregation, diffuse axonal injury, gliosis, cytokine inflammation response, and genetic integrity), and behavioral changes. These studies suggested that appropriate animal models can assist in understanding the pathological and functional outcomes of athlete mTBI, and could be used as a platform for future studies of diagnostic/prognostic markers and in the development of treatment interventions. K E Y W O R D S animal models, chronic traumatic encephalopathy, concussion, neurotrauma | INTRODUC TI ONAthlete head impacts continue to attract significant media and research attention with sports such as soccer, football, ice hockey, lacrosse, and rugby displaying significant rates of head injury in American high school and collegiate athletes O'Connor et al., 2017). These impacts occur across a continuum of severity; from injuries resulting in unconsciousness and requiring the athlete to be assisted on the field, to contact with no immediate observable consequences, such as heading a soccer ball. The nature of many of these sports predicates that head impacts are not sustained in isolation, but are often an intrinsic by-product of the rules of the sport, and as such are repetitively sustained across a match | 1195 HISKENS Et al.

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“…: None 14b: Namjoshi [ 63 ] M: C57BL/6 m CH [C] 2 Int. : Anabolic steroids 15a: Semple [ 58 ] M: C57BL/6 m CI [C] 1 15b: Semple [ 58 ] M: C57BL/6 m CI [C] 2 16a: Shitaka [ 39 ] M: C57BL/6 J m CI [C] 2 17a: Fehily [ 43 ] R: PVG f WD [C] 1 17b: Fehily [ 43 ] R: PVG f WD [C] 2 17c: Fehily [ 43 ] R: PVG f WD [C] 3 18a: Maynard [ 49 ] M: C57BL/6 m WD [C] 3 19a: Brooks [ 47 ] R: Wistar m FPI [O] 4 20a: Maynard [ 50 ] M: C57BL/6 J ...…”

Section: Resultsmentioning

confidence: 99%

“…The possibility of a microglial response occurring very shortly after injury is supported by the detection of microglial activation as early as 2 h post-final injury in groups 06a [ 40 ] and 27a [ 41 ], the former of which involved a single mTBI to mice. Other timecourses that show no microglial activation at any timepoint (groups 21a [ 35 ], 12b and 5c [ 36 ], 22a-c [ 42 ], 17a and 17c [ 43 ], 13b and 9b [ 44 ], and 01a [ 45 ]) are similarly ambiguous, as they may reflect injuries which do not induce microglial activation in the white matter, injuries with delays to microglial activation in the white matter longer than the latest sampled timepoint, or injuries where microglial activation in the white matter resolved prior to the first assessment timepoint. It is important to consider that activation timecourses for experimental groups receiving multiple injuries may be misleading to directly compare with activation reported in single mTBI studies, as it is unclear if the observed activation was initiated by the final mTBI or by any of the preceding mTBIs.…”

Section: Resultsmentioning

confidence: 99%

Temporal patterns of microglial activation in white matter following experimental mild traumatic brain injury: a systematic literature review

Velayudhan

Schwab

Hazrati

et al. 2021

acta neuropathol commun

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Mild traumatic brain injuries (mTBIs) are a prevalent form of injury that can result in persistent neurological impairments. Microglial activation has become increasingly recognized as a key process regulating the pathology of white matter in a wide range of brain injury and disease contexts. As white matter damage is known to be a major contributor to the impairments that follow mTBI, microglia have rightfully become a common target of investigation for the development of mTBI therapies and biomarkers. Recent work has demonstrated that the efficacy of microglial manipulation as a therapeutic intervention following injury or disease is highly time-sensitive, emphasizing the importance of advancing our understanding of the dynamics of post-mTBI microglial activation from onset to resolution. Current reporting of microglial activation in experimental studies of mTBI is non-standardized, which has limited our ability to identify concrete patterns of post-mTBI microglial activation over time. In this review, we examine preclinical studies of mTBI that report on microglial activation in white matter regions to summarize our current understanding of these patterns. Specifically, we summarize timecourses of post-mTBI microglial activation in white matter regions of the brain, identify factors that influence this activation, examine the temporal relationship between microglial activation and other post-mTBI assessments, and compare the relative sensitivities of various methods for detecting microglial activation. While the lack of replicated experimental conditions has limited the extent of conclusions that can confidently be drawn, we find that microglia are activated over a wide range of timecourses following mTBI and that microglial activation is a long-lasting outcome of mTBI that may resolve after most typical post-mTBI assessments, with the exception of those measuring oligodendrocyte lineage cell integrity. We identify several understudied parameters of post-mTBI microglial activation in white matter, such as the inclusion of female subjects. This review summarizes our current understanding of the progression of microglial activation in white matter structures following experimental mTBI and offers suggestions for important future research directions.

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Differential responses to increasing numbers of mild traumatic brain injury in a rodent closed‐head injury model

Cited by 23 publications

References 76 publications

Repetitive mild traumatic brain injury affects inflammation and excitotoxic mRNA expression at acute and chronic time-points

Repetitive mild traumatic brain injury affects inflammation and excitotoxic mRNA expression at acute and chronic time-points

Modeling sports‐related mild traumatic brain injury in animals—A systematic review

Temporal patterns of microglial activation in white matter following experimental mild traumatic brain injury: a systematic literature review

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