Repetitive mild traumatic brain injury induces ventriculomegaly and cortical thinning in juvenile rats

Goddeyne, Corey; Nichols, Joshua; Wu, Chen; Anderson, Trent

doi:10.1152/jn.00970.2014

Cited by 54 publications

(51 citation statements)

References 108 publications

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“…By contrast to reports in adult mice (Cantu et al ., ), recordings from pyramidal neurons in juvenile mice revealed a lack of generalized hyperexcitability (Goddeyne et al . ; Nichols et al . ) and the presence of unique excitatory and inhibitory synaptic bursts following CCI (Nichols et al .…”

Section: Discussionmentioning

confidence: 99%

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Parvalbumin fast‐spiking interneurons are selectively altered by paediatric traumatic brain injury

Nichols

Bjorklund

Newbern

et al. 2018

The Journal of Physiology

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Paediatric traumatic brain injury (TBI) is a leading cause of death and disability in children. Traditionally, ongoing neurodevelopment and neuroplasticity have been considered to confer children with an advantage following TBI. However, recent findings indicate that the paediatric brain may be more sensitive to brain injury. Inhibitory interneurons are essential for proper cortical function and are implicated in the pathophysiology of TBI, yet few studies have directly investigated TBI-induced changes to interneurons themselves. Accordingly, in the present study, we examine how inhibitory neurons are altered following controlled cortical impact (CCI) in juvenile mice with targeted Cre-dependent fluorescence labelling of interneurons (Vgat:Cre/Ai9 and PV:Cre/Ai6). Although CCI failed to alter the number of excitatory neurons or somatostatin-expressing interneurons in the peri-injury zone, it significantly decreased the density of parvalbumin (PV) immunoreactive cells by 71%. However, PV:Cre/Ai6 mice subjected to CCI showed a lower extent of fluorescence labelled cell loss. PV interneurons are predominantly of a fast-spiking (FS) phenotype and, when recorded electrophysiologically from the peri-injury zone, exhibited intrinsic properties similar to those of control neurons. Synaptically, CCI induced a decrease in inhibitory drive onto FS interneurons combined with an increase in the strength of excitatory events. The results of the present study indicate that CCI induced both a loss of PV interneurons and an even greater loss of PV expression. This suggests caution is required when interpreting changes in PV immunoreactivity alone as direct evidence of interneuronal loss. Furthermore, in contrast to reports in adults, TBI in the paediatric brain selectively alters PV-FS interneurons, primarily resulting in a loss of interneuronal inhibition.

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Section: Discussionmentioning

confidence: 99%

“…However, we have previously found that juvenile mice respond uniquely after TBI with a lack of generalized hyperexcitability (Goddeyne et al . ; Nichols et al . ) and the presence of unique synaptic bursts following more severe TBI (Nichols et al .…”

Section: Introductionmentioning

confidence: 99%

Parvalbumin fast‐spiking interneurons are selectively altered by paediatric traumatic brain injury

Nichols

Bjorklund

Newbern

et al. 2018

The Journal of Physiology

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“…254 Finally, pediatric populations exhibit different responses to adults experiencing a similar head trauma, 255 and limited studies have been conducted assessing younger populations. 235,236,256,257 Conclusions Long-term cognitive impairments following CNS injury and in neurodegenerative diseases have been associated with prolonged oxidative stress conditions 131,258 and impaired signal conduction along dysmyelinated axons. 259 Further, persisting behavioral deficits after TBI have been associated with progressive activation of astrocytes 260 and microglia.…”

Section: Barriers To Clinical Translationmentioning

confidence: 99%

Repeated mild traumatic brain injury: potential mechanisms of damage

2016

Cell Transplant

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Mild traumatic brain injury (mTBI) represents a significant public healthcare concern, accounting for the majority of all head injuries. While symptoms are generally transient, some patients go on to experience long-term cognitive impairments and additional mild impacts can result in exacerbated and persisting negative outcomes. To date, studies using a range of experimental models have reported chronic behavioral deficits in the presence of axonal injury and inflammation following repeated mTBI; assessments of oxidative stress and myelin pathology have thus far been limited. However, some models employed induced acute focal damage more suggestive of moderate-severe brain injury and are therefore not relevant to repeated mTBI. Given that the nature of mechanical loading in TBI is implicated in downstream pathophysiological changes, the mechanisms of damage and chronic consequences of single and repeated closed-head mTBI remain to be fully elucidated. This review covers literature on potential mechanisms of damage following repeated mTBI, integrating known mechanisms of pathology underlying moderate-severe TBIs, with recent studies on adult rodent models relevant to direct impact injuries rather than blast-induced damage. Pathology associated with excitotoxicity and cerebral blood flow-metabolism uncoupling, oxidative stress, cell death, blood-brain barrier dysfunction, astrocyte reactivity, microglial activation, diffuse axonal injury, and dysmyelination is discussed, followed by a summary of functional deficits and preclinical assessments of therapeutic strategies. Comprehensive characterization of the pathology underlying delayed and persisting deficits following repeated mTBI is likely to facilitate further development of therapeutic strategies to limit long-term sequelae.

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“…However, there is a disproportionate paucity of pediatric mTBI research in preclinical models for translation to the human condition. A handful of preclinical studies report acute cortical atrophy, axonal swelling, axonal disconnections [17], cortical thinning, and ventricular enlargement [18], in addition to edema and gliosis following pediatric and juvenile rmTBI [19]. 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].…”

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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Repetitive mild traumatic brain injury induces ventriculomegaly and cortical thinning in juvenile rats

Cited by 54 publications

References 108 publications

Parvalbumin fast‐spiking interneurons are selectively altered by paediatric traumatic brain injury

Parvalbumin fast‐spiking interneurons are selectively altered by paediatric traumatic brain injury

Repeated mild traumatic brain injury: potential mechanisms of damage

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

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