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

Abstract

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.

Impact of gulf war toxic exposures after mild traumatic brain injury

“…In addition to studying oligodendrocyte involvement, we evaluated the effect of GW toxicant exposure and r-mTBI on the integrity and pathology of the CC through analyzing the thickness and extent of axonal injury. The CC is particularly sensitive to insult from mTBI in humans and our preclinical models, with thinning of the body of the CC occurring post injury [ 44 , 47 , 63 ]. This finding of decreased CC width post mTBI was reflected in our findings.…”

Potential Progression Mechanism and Key Genes in Early Stage of mTBI

“…In particular, its activation is required for both classical and alternative complement activation pathways. The complement system is a biochemical pathway involved in both innate and adaptive immune responses and has four main functions: lysis of microorganisms, promotion of phagocytosis, triggering inflammation, and immune clearance [ 25 , 26 ]. The activation of C3 can trigger a continuous degradation mechanism to activate microglia and astrocytes, reduce the density of dendritic cells and synapses, and inhibit the migration of neuroblast cells, which leads to neuron loss after several weeks of TBI [ 27 , 28 ].…”

N-Acetyl-Aspartyl-Glutamate in Brain Health and Disease

“…Common causes of TBI are violent hits to the head or objects penetrating through the skull and into the brain. The pathophysiology of TBI is complex [85], involving neuroinflammation [86,87], oxidative stress [88], mitochondrial dysfunction [89,90], demyelination, and other mechanisms [91]. Excitotoxicity is at the core of neural loss in response to TBI.…”