Repeated Mild Traumatic Brain Injury Causes Chronic Neuroinflammation, Changes in Hippocampal Synaptic Plasticity, and Associated Cognitive Deficits

Aungst, Stephanie; Kabadi, Shruti V.; Thompson, Scott M.; Stoica, Bogdan A.; Faden, Alan I.

doi:10.1038/jcbfm.2014.75

Cited by 211 publications

(166 citation statements)

References 40 publications

Supporting

Mentioning

157

Contrasting

Order By: Relevance

“…17 CTE is unique among tauopathies in that its onset and progression are thought to be associated with repetitive head injury. 2,25 Currently, diagnostic and treatment options are unavailable for this disease, although they are improving with the use of the [ 18 F]FDDNP-PET imaging probe. 46 The growing number of athletes and soldiers experiencing CTE, characterized by symptoms of impulsivity, cognitive decline, and depression, urges renewed focus on understanding disease mechanism and disease progression.…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy

Lucke‐Wold

Turner

Logsdon

et al. 2016

JNS

View full text Add to dashboard Cite

abbreviatioNs ATF6 = activating transcription factor 6; BiP = binding immunoglobulin protein; CHOP = C/EBP homology protein; CTE = chronic traumatic encephalopathy; DAB = diaminobenzidine; DHA = docosahexaenoic acid; ER = endoplasmic reticulum; GADD34 = growth arrest and DNA damage-inducible protein 34; GSK3b = glycogen synthase kinase-3b; IHC = immunohistochemistry; IRE1a = inositol requiring enzyme 1a; JNK = c-Jun N-terminal kinase; NFL = National Football League; PBS = phosphate-buffered saline; PERK = protein kinase RNA-like ER kinase; PHF = paired helical filament; p-eIF2a = phosphorylated eukaryotic initiation factor 2a; TBI = traumatic brain injury; WWE = World Wrestling Entertainment; XBP1 = X-box binding protein 1. obJective Chronic traumatic encephalopathy is a progressive neurodegenerative disease characterized by neurofibrillary tau tangles following repetitive neurotrauma. The underlying mechanism linking traumatic brain injury to chronic traumatic encephalopathy has not been elucidated. The authors investigate the role of endoplasmic reticulum stress as a link between acute neurotrauma and chronic neurodegeneration. methods The authors used pharmacological, biochemical, and behavioral tools to assess the role of endoplasmic reticulum stress in linking acute repetitive traumatic brain injury to the development of chronic neurodegeneration. Data from the authors' clinically relevant and validated rodent blast model were compared with those obtained from postmortem human chronic traumatic encephalopathy specimens from a National Football League player and World Wrestling Entertainment wrestler. results The results demonstrated strong correlation of endoplasmic reticulum stress activation with subsequent tau hyperphosphorylation. Various endoplasmic reticulum stress markers were increased in human chronic traumatic encephalopathy specimens, and the endoplasmic reticulum stress response was associated with an increase in the tau kinase, glycogen synthase kinase-3b. Docosahexaenoic acid, an endoplasmic reticulum stress inhibitor, improved cognitive performance in the rat model 3 weeks after repetitive blast exposure. The data showed that docosahexaenoic acid administration substantially reduced tau hyperphosphorylation (t = 4.111, p < 0.05), improved cognition (t = 6.532, p < 0.001), and inhibited C/EBP homology protein activation (t = 5.631, p < 0.01). Additionally the data showed, for the first time, that endoplasmic reticulum stress is involved in the pathophysiology of chronic traumatic encephalopathy. coNclusioNs Docosahexaenoic acid therefore warrants further investigation as a potential therapeutic agent for the prevention of chronic traumatic encephalopathy.

show abstract

Section: Discussionmentioning

confidence: 99%

Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy

Lucke‐Wold

Turner

Logsdon

et al. 2016

JNS

View full text Add to dashboard Cite

show abstract

“…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

150

103

View full text Add to dashboard Cite

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.

show abstract

“…130 A series of contributions from Petraglia et al [131][132][133][134] have described the pathological and behavioral effects of repetitive TBI in a closed skull model of TBI in mice and demonstrated the clearly greater effects of multiple impacts on a variety of behavioral measures. While much attention has been focused on the cellular (both neural and glial) response to TBI, as well as its behavioral consequences, less attention has been directed toward understanding possible effects of TBI on cerebral vasculature.…”

Section: Comparison Of Single Vs Multiple Impactsmentioning

confidence: 99%

Effects of concussion on the blood–brain barrier in humans and rodents

Sahyouni

Gutierrez

Gold

et al. 2017

Journal of Concussion

View full text Add to dashboard Cite

Traumatic brain injury and the long-term consequences of repeated concussions constitute mounting concerns in the United States, with 5.3 million individuals living with a traumatic brain injury-related disability. Attempts to understand mechanisms and possible therapeutic approaches to alleviate the consequences of repeat mild concussions or traumatic brain injury on cerebral vasculature depend on several aspects of the trauma, including: (1) the physical characteristics of trauma or insult that result in damage; (2) the time ''window'' after trauma in which neuropathological features develop; (3) methods to detect possible breakdown of the blood-brain barrier; and (4) understanding different consequences of a single concussion as compared with multiple concussions. We review the literature to summarize the current understanding of blood-brain barrier and endothelial cell changes post-neurotrauma in concussions and mild traumatic brain injury. Attention is focused on concussion and traumatic brain injury in humans, with a goal of pointing out the gaps in our knowledge and how studies of rodent model systems of concussion may help in filling these gaps. Specifically, we focus on disruptions that concussion causes to the blood-brain barrier and its multifaceted consequences. Importantly, the magnitude of post-concussion blood-brain barrier dysfunction may influence the time course and extent of neuronal recovery; hence, we include in this review comparisons of more severe traumatic brain injury to concussion where appropriate. Finally, we address the important, and still unresolved, issue of how best to detect possible breakdown in the blood-brain barrier following neurotrauma by exploring intravascular tracer injection in animal models to examine leakage into the brain parenchyma.

show abstract

Repeated Mild Traumatic Brain Injury Causes Chronic Neuroinflammation, Changes in Hippocampal Synaptic Plasticity, and Associated Cognitive Deficits

Cited by 211 publications

References 40 publications

Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy

Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy

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

Effects of concussion on the blood–brain barrier in humans and rodents

Contact Info

Product

Resources

About