Injury timing alters metabolic, inflammatory and functional outcomes following repeated mild traumatic brain injury

Weil, Zachary M.; Gaier, Kristopher R.; Karelina, Kate

doi:10.1016/j.nbd.2014.06.016

Cited by 90 publications

(98 citation statements)

References 59 publications

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“…Chronic neuroinflammation has been found to persist years after neurotrauma in both experimental animal models of TBI [55][56][57][58] and in human studies [59][60][61] . Relative to healthy controls, chronically elevated levels of neuroinflammation, as detected via PET scan, can persists both years after a single remote TBI as well as years after exposure to repetitive neurotrauama, even in the absence of a clinically evident TBI [61][62][63][64] .…”

Section: Immunological Perspectives Of Tbi Sequelaementioning

confidence: 99%

The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease

Sundman

Chen

Subbian

et al. 2017

Brain, Behavior, and Immunity

155

103

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The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease. AbstractAs head injuries and their sequelae have become an increasingly salient matter of public health, experts in the field have made great progress elucidating the biological processes occurring within the brain at the moment of injury and throughout the recovery thereafter. Given the extraordinary rate at which our collective knowledge of neurotrauma has grown, new insights may be revealed by examining the existing literature across disciplines with a new perspective. This article will aim to expand the scope of this rapidly evolving field of research beyond the confines of the central nervous system (CNS). Specifically, we will examine the extent to which the bidirectional influence of the gut-brain axis modulates the complex biological processes occurring at the time of traumatic brain injury (TBI) and over the days, months, and years that follow. In addition to local enteric signals originating in the gut, it is well accepted that gastrointestinal (GI) physiology is highly regulated by innervation from the CNS. Conversely, emerging data suggests that the function and health of the CNS is modulated by the interaction between 1) neurotransmitters, immune signaling, hormones, and neuropeptides produced in the gut, 2) the composition of the gut microbiota, and 3) integrity of the intestinal wall serving as a barrier to the external environment. Specific to TBI, existing pre-clinical data indicates that head injuries can cause structural and functional damage to the GI tract, but research directly investigating the neuronal consequences of this intestinal damage is lacking. Despite this void, the proposed mechanisms emanating from a damaged gut are closely implicated in the inflammatory processes known to promote neuropathology in the brain following TBI, which suggests the gut-brain axis may be a therapeutic target to reduce the risk of Chronic Traumatic Encephalopathy and other neurodegenerative diseases following TBI. To better appreciate how various peripheral influences are implicated in the health of the CNS following TBI, this paper will also review the secondary biological injury mechanisms and the dynamic pathophysiological response to neurotrauma. Together, this review article will attempt to connect the dots to reveal novel insights into the bidirectional influence of the gut-brain axis and propose a conceptual model relevant to the recovery from TBI and subsequent risk for future neurological conditions.

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Section: Immunological Perspectives Of Tbi Sequelaementioning

confidence: 99%

The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease

Sundman

Chen

Subbian

et al. 2017

Brain, Behavior, and Immunity

155

103

View full text Add to dashboard Cite

show abstract

“…The degree of staining was then scored on a 4-point scale (0 = few axonal profiles, 3 = dense axonal degeneration throughout white matter tracts and the corpus callosum bilaterally). 17 C-Fos immunoreactive cells were counted bilaterally following acquisition of z stacks consisting of 10 sets of 4 lm slices per region. Stacks from the accumbens core and shell, central nucleus of the amygdala, and periaqueductal gray were flattened and cells counted using the Image J cell counter.…”

Section: Microscopymentioning

confidence: 99%

Juvenile Traumatic Brain Injury Increases Alcohol Consumption and Reward in Female Mice

Weil

Karelina

Gaier

et al. 2016

Journal of Neurotrauma

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Traumatic brain injury (TBI) is closely and bi-directionally linked with alcohol use, as by some estimates intoxication is the direct or indirect cause of one-third to one-half of all TBI cases. Alcohol use following injury can reduce the efficacy of rehabilitation and increase the chances for additional injury. Finally, TBI itself may be a risk factor for the development of alcohol use disorders. Children who suffer TBIs have poorer life outcomes and more risk of substance abuse. We used a standardized closed-head injury to model mild traumatic brain injuries. We found that mice injured as juveniles but not during adulthood exhibited much greater alcohol self-administration in adulthood. Further, this phenomenon was limited to female mice. Using behavioral testing, including conditioned place preference assays, we showed that early injuries increase the rewarding properties of alcohol. Environmental enrichment administered after injury reduced axonal degeneration and prevented the increase in drinking behavior. Additionally, brain-derived neurotrophic factor gene expression, which was reduced by TBI, was normalized by environmental enrichment. Together, these results suggest a novel model of alterations in reward circuitry following trauma during development.

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“…[65][66][67][68][69] Increasing amounts of head movement have also been incorporated, [70][71][72] to more closely approximate human head kinematics following mTBI. 73 As such, WD models are increasingly utilized to model repeated mTBI.…”

Section: Closed-head Models Of Tbimentioning

confidence: 99%

“…54,69,71 Indeed, while acute cerebral hypometabolism, mitochondrial dysregulation, and cognitive deficits resolve within 1 wk following a single WD mTBI, a second injury delivered after a 3 but not 20 d interval, resulted in exacerbated metabolic dysregulation concomitant with cumulative cognitive deficits. 68 While the implications of these findings on long-term outcome remain unexplored, it is possible that these earlier chemical vulnerabilities may be the impetus for longer-lasting metabolic cascades.…”

Section: Cbf-metabolism Uncoupling Following Repeated Mtbimentioning

confidence: 99%

“…57,71,151 As such, when repeated mTBIs are delivered within the "window of vulnerability" (described in Mechanisms of Pathology section), cumulative cognitive deficits persist and may be permanent. 54,65,71 Interestingly, longer inter-injury intervals up to 1 mo produce no deficits, 68,71 suggesting that longer time intervals may confer protection against subacute 212 and long-term functional sequelae. 70 Additionally, studies titrating mechanical input have revealed a threshold of injury severity required to elicit deficits.…”

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confidence: 99%

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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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Injury timing alters metabolic, inflammatory and functional outcomes following repeated mild traumatic brain injury

Cited by 90 publications

References 59 publications

The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease

The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease

Juvenile Traumatic Brain Injury Increases Alcohol Consumption and Reward in Female Mice

Repeated mild traumatic brain injury: potential mechanisms of damage

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