Sex matters: repetitive mild traumatic brain injury in adolescent rats

Wright, David K.; O’Brien, Terence J.; Shultz, Sandy R.; Mychasiuk, Richelle

doi:10.1002/acn3.441

Cited by 95 publications

(106 citation statements)

References 73 publications

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“…Using only male animals disregards the diverse response in outcome of mTBI in males and females (Gallagher et al, ). In the reviewed studies comparing sex differences in mTBI, differences were seen in male and female prefrontal cortex atrophy; white matter integrity in the corpus callosum; microglial activation; brain mRNA expression of GFAP, MBP, and tau; short‐term working memory; depressive‐like behavior; and social interaction (Hehar, Yu, Ma, & Mychasiuk, ; Mychasiuk, Hehar, et al, ; Wright, O'Brien, Shultz, & Mychasiuk, ; Yamakawa, Lengkeek, et al, ). While the majority of human CTE cases in the literature are male (McKee et al, ), it is unlikely that this represents the true proportion of CTE cases, but instead indicates that current research has been undertaken in traditionally male domains in sports, such as football and boxing, and occupations such as military service.…”

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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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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“…TWI measures have previously been shown to be altered in preclinical mTBI23, 24 and repeated mTBI25 models that involved the use of anesthetic and/or craniotomy. Compared to the sham group, repeated ACHI resulted in a significant increase in track density (i.e., TDI) in both the ipsilateral and contralateral fimbria, as well as the contralateral external capsule at Day 1.…”

Section: Discussionmentioning

confidence: 99%

“…Diffusion tensor imaging (DTI) is the most commonly applied DWI method, and initial studies have reported changes on DTI measures (e.g., fractional anisotropy, FA) in the clinical mTBI setting. [19][20][21][22] Furthermore, new DWI acquisition and analysis methods (e.g., track-weighted imaging, TWI) are being developed that may also be sensitive to mTBIs, [23][24][25] but remain to be comprehensively studied in this context.…”

Section: Introductionmentioning

confidence: 99%

Diffusion MRI abnormalities in adolescent rats given repeated mild traumatic brain injury

Wortman

Meconi

Neale

et al. 2018

Ann Clin Transl Neurol

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ObjectiveMild traumatic brain injury (mTBI) is a serious health concern in the adolescent population. Repeated mTBI may result in more pronounced deficits, and has been associated with long‐term neurological consequences including neurodegeneration. As such, there is a critical need for the development of objective mTBI biomarkers to help guide medical management. Diffusion‐weighted imaging (DWI) is an advanced magnetic resonance imaging (MRI) technique that may detect brain abnormalities after mTBI. Diffusion tensor imaging (DTI) is the most commonly applied DWI method, and initial studies have reported DTI changes in mTBI patients. Furthermore, new DWI methods (e.g., track‐weighted imaging; TWI) are being developed that may also be sensitive to mTBIs, but remain to be comprehensively studied.MethodsThis study utilized the Awake Closed Head Injury (ACHI) model of mTBI to investigate changes in DTI and TWI following repeated mTBI in adolescent male and female rats. A total of four ACHI impacts, two/day over two consecutive days, were delivered beginning on postnatal day 25. At 1 day and 7 days postinjury, rats were euthanized and brains were collected for DWI analyses.ResultsRats given repeated mTBI displayed changes in fractional anisotropy and radial diffusivity (i.e., DTI measures), as well as track density (i.e., TWI).InterpretationThese findings are consistent with initial DTI findings in mTBI patients, suggest that TWI may complement DTI, support the utility of DWI measures as biomarkers in mTBI, and further validate the ACHI rat model of mTBI.

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“…The pattern of increased FA and decreased RD in our study is in agreement with many of the reported clinical outcomes of pediatric mTBI, albeit many of the existing studies examined various WM structures in much shorter time frame [65-68]. Interestingly, a recent study examining rmTBI in adolescent rats showed reductions in ADC and AD but no significant alterations in FA or RD 2 weeks after the final injury in the CC, although these differences could be attributed to a different injury model (3 repeated injuries 4 days apart) or the age at injury (P30) [21]. …”

Section: Discussionmentioning

confidence: 99%

“…Another preclinical pediatric rmTBI study reported early evidence of axonal injury and microglial activation, as well as long-term associative learning deficits after 3 weeks and 3 months, respectively [20]. Furthermore, motor deficits, anxiety-like behaviors, and WM deficits have been reported in adolescent rmTBI using a rodent model [21]. However, the long-term pathophysiology and associated injury mechanisms, especially in the WM, have not been well characterized in the developing brain.…”

Section: Introductionmentioning

confidence: 99%

Repeated Pediatric Concussions Evoke Long-Term Oligodendrocyte and White Matter Microstructural Dysregulation Distant from the Injury

et al. 2018

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Concussion or mild traumatic brain injury (mTBI) is often accompanied by long-term behavioral and neuropsychological deficits. Emerging data suggest that these deficits can be exacerbated following repeated injuries. However, despite the overwhelming prevalence of mTBI in children due to falls and sports-related activities, the effects of mTBI on white matter (WM) structure and its development in children have not been extensively examined. Moreover, the effect of repeated mTBI (rmTBI) on developing WM has not yet been studied, despite the possibility of exacerbated outcomes with repeat injuries. To address this knowledge gap, we investigated the long-term effects of single (s)mTBI and rmTBI on the WM in the pediatric brain, focusing on the anterior commissure (AC), a WM structure distant to the injury site, using diffusion tensor imaging (DTI) and immunohistochemistry (IHC). We hypothesized that smTBI and rmTBI to the developing mouse brain would lead to abnormalities in microstructural integrity and impaired oligodendrocyte (OL) development. We used a postnatal day 14 Ascl1-CreER: ccGFP mouse closed head injury (CHI) model with a bilateral repeated injury. We demonstrate that smTBI and rmTBI differentially lead to myelin-related diffusion changes in the WM and to abnormal OL development in the AC, which are accompanied by behavioral deficits 2 months after the initial injury. Our results suggest that mTBIs elicit long-term behavioral alterations and OL-associated WM dysregulation in the developing brain. These findings warrant additional research into the development of WM and OL as key components of pediatric TBI pathology and potential therapeutic targets.

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Sex matters: repetitive mild traumatic brain injury in adolescent rats

Cited by 95 publications

References 73 publications

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

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

Diffusion MRI abnormalities in adolescent rats given repeated mild traumatic brain injury

Repeated Pediatric Concussions Evoke Long-Term Oligodendrocyte and White Matter Microstructural Dysregulation Distant from the Injury

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