Traumatic Brain Injury (TBI) is the most frequent cause of death and disability in young adults and children in the developed world, occurring in over 1.7 million persons and resulting in 50,000 ...deaths in the United States alone. The Centers for Disease Control and Prevention estimate that between 3.2 and 5.3 million persons in the United States live with a TBI‐related disability, including several neurocognitive disorders and functional limitations. Following the primary mechanical injury in TBI, literature suggests the presence of a delayed secondary injury involving a variety of neuroinflammatory changes. In the hours to days following a TBI, several signaling molecules and metabolic derangements result in disruption of the blood–brain barrier, leading to an extravasation of immune cells and cerebral edema. The primary, sudden injury in TBI occurs as a direct result of impact and therefore cannot be treated, but the timeline and pathophysiology of the delayed, secondary injury allows for a window of possible therapeutic options. The goal of this review is to discuss the pathophysiology of the primary and delayed injury in TBI as well as present several preclinical studies that identify molecular targets in the potential treatment of TBI. Additionally, certain recent clinical trials are briefly discussed to demonstrate the current state of TBI investigation.
Traumatic brain injury (TBI) afflicts people of all ages and genders, and the severity of injury ranges from concussion/mild TBI to severe TBI. Across all spectrums, TBI has wide-ranging, and ...variable symptomology and outcomes. Treatment options are lacking for the early neuropathology associated with TBIs and for the chronic neuropathological and neurobehavioral deficits. Inflammation and neuroinflammation appear to be major mediators of TBI outcomes. These systems are being intensively studies using animal models and human translational studies, in the hopes of understanding the mechanisms of TBI, and developing therapeutic strategies to improve the outcomes of the millions of people impacted by TBIs each year. This manuscript provides an overview of the epidemiology and outcomes of TBI, and presents data obtained from animal and human studies focusing on an inflammatory and immunological context. Such a context is timely, as recent studies blur the traditional understanding of an "immune-privileged" central nervous system. In presenting the evidence for specific, adaptive immune response after TBI, it is hoped that future studies will be interpreted using a broader perspective that includes the contributions of the peripheral immune system, to central nervous system disorders, notably TBI and post-traumatic syndromes.
Traumatic brain injury (TBI) is a devastating disorder causing negative outcomes in millions of people each year. Despite the alarming number of brain injuries and the long-term detrimental outcomes ...that can be associated with TBI, treatment options are lacking. Extensive investigation is underway, in hopes of identifying effective treatment strategies. Among the most state-of-the-art strategies is cell replacement therapy. TBI is a seemingly good candidate for cell replacement studies because there is often loss of neurons. However, translation of this therapy has not yet been successful. It is possible that a better understanding of endogenous neurogenic mechanisms after TBI could lead to more efficacious study designs using exogenous cell replacement strategies. Therefore, this study was designed to examine the number and migration of immature neurons at 1 and 7 d after a fluid percussion TBI. The results show that the number of immature neurons increases from 7 d after a fluid percussion injury (FPI), and there is ectopic migration of doublecortin (DCX+) immature neurons into the hilar region of the dentate gyrus. These results add important data to the current understanding of the endogenous neurogenic niche after TBI. Follow-up studies are needed to better understand the functional significance of elevated neurogenesis and aberrant migration into the hilus.
Gulf War illness (GWI) is a chronic, multi-symptom disorder that has impacted approximately one third of Gulf War veterans. GWI and its symptoms have been linked to the exposure to neurological ...chemicals, including the anti-nerve gas drug pyridostigmine bromide (PB) and the insecticide permethrin (PER), among others. Mouse models utilizing these chemicals have reported symptomology analogous to human GWI. These changes include behavioral and cognitive impairment, neuroinflammation and hippocampal pathogenesis. Disease modifying interventions that target these pathological components are desperately needed. Vagus nerve stimulation (VNS) is FDA approved for drug-resistant epilepsy and depression. VNS has also been used off-label to target a myriad of symptoms, some of which are encompassed within the Kansas and CDC definitions of clinical GWI symptomology. A GWI animal model in which mice are exposed to a daily injection of PB and PER for 10 consecutive days has been shown to exhibit cognitive impairment and hippocampal pathology. The purpose of this study was to determine if 2–4 weeks of continuous vagus nerve stimulation initiated at 32 weeks after exposure to PB and PER would improve cognitive performance and hippocampal pathology. The results of the study revealed that exposure to PB and PER produces long-term cognitive deficits and reduced hippocampal neurogenesis. The results also showed that the VNS treatment was anxiolytic, improved some aspects of pattern separation deficits, and mitigated the reduced hippocampal neurogenesis. Thus, VNS improves outcomes in a mouse model of GWI and should be examined as a potential therapeutic strategy for mitigating some symptomology associated with GWI.
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•GWI mouse model was induced via 10-day i.p. exposure to PB and PER.•GWI induction increased anxiety and altered pattern separation ability.•Vagus nerve stimulation was anxiolytic.•Vagus nerve stimulation improved age and GWI-induced reductions in neurogenesis.
Traumatic brain injury (TBI) occurs in as many as 64-74 million people worldwide each year and often results in one or more post-traumatic syndromes, including depression, cognitive, emotional, and ...behavioral deficits. TBI can also increase seizure susceptibility, as well as increase the incidence of epilepsy, a phenomenon known as post-traumatic epilepsy (PTE). Injury type and severity appear to partially predict PTE susceptibility. However, a complete mechanistic understanding of risk factors for PTE is incomplete.
From the earliest days of modern neuroscience, to the present day, accumulating evidence supports a significant role for neuroinflammation in the post-traumatic epileptogenic progression. Notably, substantial evidence indicates a role for astrocytes, microglia, chemokines, and cytokines in PTE progression. Although each of these mechanistic components is discussed in separate sections, it is highly likely that it is the totality of cellular and neuroinflammatory interactions that ultimately contribute to the epileptogenic progression following TBI.
This comprehensive review focuses on the neuroinflammatory milieu and explores putative mechanisms involved in the epileptogenic progression from TBI to increased seizure-susceptibility and the development of PTE.
Traumatic brain injury (TBI) is a major health concern. Each year, over 50 million individuals worldwide suffer from TBI, and this leads to a number of acute and chronic health issues. These include ...affective and cognitive impairment, as well as an increased risk of alcohol and drug use. The dopaminergic system, a key component of reward circuitry, has been linked to alcohol and other substance use disorders, and previous research indicates that TBI can induce plasticity within this system. Understanding how TBI modifies the dopaminergic system may offer insights into the heightened substance use and reward-seeking behavior following TBI. The hippocampus, a critical component of the reward circuit, is responsible for encoding and integrating the spatial and salient aspects of rewarding stimuli. This study explored TBI-related changes in neuronal D2 receptor expression within the hippocampus, examining the hypothesis that sex differences exist in both baseline hippocampal D2 receptor expression and its response to TBI. Utilizing D2-expressing tdTomato transgenic male and female mice, we implemented either a sham injury or the lateral fluid percussion injury (FPI) model of TBI and subsequently performed a region-specific quantification of D2 expression in the hippocampus. The results show that male mice exhibit higher baseline hippocampal D2 expression compared to female mice. Additionally, there was a significant interaction effect between sex and injury on the expression of D2 in the hippocampus, particularly in regions of the dentate gyrus. Furthermore, TBI led to significant reductions in hippocampal D2 expression in male mice, while female mice remained mostly unaffected. These results suggest that hippocampal D2 expression varies between male and female mice, with the female dopaminergic system demonstrating less susceptibility to TBI-induced plasticity.
Summary
Astrocyte and microglial activation occurs following seizures and plays a role in epileptogenesis. However, the precise temporal and spatial response to seizures has not been fully examined. ...The pilocarpine model of temporal lobe epilepsy was selected to examine glial changes following seizures because morphological changes in the hippocampus closely mimic the human condition. Astrocytic and microglial changes in the hippocampus were examined during the first 5 days after pilocarpine‐induced seizures in rats by analyzing GFAP, Iba1 and S100B‐immunolabeling in CA1, CA3, and the hilus. Also, 3‐dimensional reconstructions of microglial cells from the hilus and granule cell layer were analyzed. Lastly, astrocyte hypertrophy was examined in the hilus using electron microscopy. At 1 day after seizures and continuing throughout the 5 days examined, hypertrophied Iba1‐labeled microglial cells and glial fibrillary acidic protein (GFAP)‐labeled astrocytes were observed. At 1 and 2 days after seizures, significantly greater Iba1 immunolabeling was observed in CA1, CA3, and the hilus. In addition, both the area of Iba1 labeled processes and the number of their endings were increased in the hilus beginning at 1 day after seizures. S100B‐immunolabeling was significantly elevated in CA3 at 1 day, in CA3 and CA1 at 2 days, and in all three hippocampal regions at 3 days after seizures. Electron microscopy confirmed astrocytic hypertrophy and demonstrated astrocytic cell bodies in the location where glial endfeet normally appear on capillaries. The differential response patterns of astrocytes and microglial cells following pilocarpine‐induced seizures may signify their detrimental role in neuroinflammation after seizures.
Neuroinflammation is implicated in a host of neurological insults, such as traumatic brain injury (TBI), ischemic stroke, Alzheimer's disease, Parkinson's disease, and epilepsy. The immune response ...to central nervous system (CNS) injury involves sequelae including the release of numerous cytokines and chemokines. Macrophage migration inhibitory factor (MIF), is one such cytokine that is elevated following CNS injury, and is associated with the prognosis of TBI, and ischemic stroke. MIF has been identified in astrocytes and neurons, and some of the trophic actions of MIF have been related to its direct and indirect actions on astrocytes. However, the potential modulation of CNS neuronal function by MIF has not yet been explored. This study tests the hypothesis that MIF can directly influence hippocampal neuronal function. MIF was microinjected into the hippocampus and the genetically encoded calcium indicator, GCaMP6f, was used to measure Ca
events in acute adult mouse brain hippocampal slices. Results demonstrated that a single injection of 200 ng MIF into the hippocampus significantly increased baseline calcium signals in CA1 pyramidal neuron somata, and altered calcium responses to
-methyl-d-aspartate (NMDA) + D-serine in pyramidal cell apical dendrites located in the stratum radiatum. These data are the first to show direct effects of MIF on hippocampal neurons and on NMDA receptor function. Considering that MIF is elevated after brain insults such as TBI, the data suggest that, in addition to the previously described role of MIF in astrocyte reactivity, elevated MIF can have significant effects on neuronal function in the hippocampus.
Despite extensive research on astrocytic Ca
in synaptic transmission, its contribution to the modulation of sensory transmission during different brain states remains largely unknown. Here, by using ...two-photon microscopy and whole-cell recordings, we show two distinct astrocytic Ca
signals in the murine barrel cortex: a small, long-lasting Ca
increase during sleep and a large, widespread but short-lasting Ca
spike when aroused. The large Ca
wave in aroused mice was inositol trisphosphate (IP3)-dependent, evoked by the locus coeruleus-norepinephrine system, and enhanced sensory input, contributing to reliable sensory transmission. However, the small Ca
transient was IP3-independent and contributed to decreased extracellular K
, hyperpolarization of the neurons, and suppression of sensory transmission. These events respond to different pharmacological inputs and contribute to distinct sleep and arousal functions by modulating the efficacy of sensory transmission. Together, our data demonstrate an important function for astrocytes in sleep and arousal states via astrocytic Ca
waves.
Traumatic brain injury (TBI) is a widespread epidemic with severe cognitive, affective, and behavioral consequences. TBIs typically result in a relatively rapid inflammatory and neuroinflammatory ...response. A major component of the neuroinflammatory response is astrocytes, a type of glial cell in the brain. Astrocytes are important in maintaining the integrity of neuronal functioning, and it is possible that astrocyte hypertrophy after TBIs might contribute to pathogenesis. The hippocampus is a unique brain region, because neurogenesis persists in adults. Accumulating evidence supports the functional importance of these newborn neurons and their associated astrocytes. Alterations to either of these cell types can influence neuronal functioning. To determine if hypertrophied astrocytes might negatively influence immature neurons in the dentate gyrus, astrocyte and newborn neurons were analyzed at 30 days following a TBI in mice. The results demonstrate a loss of radial glial-like processes extending through the granule cell layer after TBI, as well as ectopic growth and migration of immature dentate neurons. The results further show newborn neurons in close association with hypertrophied astrocytes, suggesting a role for the astrocytes in aberrant neurogenesis. Future studies are needed to determine the functional significance of these alterations to the astrocyte/immature neurons after TBI.
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