Timing matters: Sex differences in inflammatory and behavioral outcomes following repetitive blast mild traumatic brain injury

Baskin, Britahny M.; Logsdon, Aric F.; Lee, Suhjung Janet; Foresi, Brian; Peskind, Elaine R.; Banks, William A.; Cook, David G.; Schindler, Abigail G.

doi:10.1016/j.bbi.2023.03.003

Cited by 8 publications

(6 citation statements)

References 81 publications

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“…Our results are supported by a previous study evaluating serum and brain cytokine concentrations in mice 4 hours after the last injury in a repetitive blast-related mTBI model 28 . Baskin et al reported that female mice experience greater anti-inflammatory signaling acutely after mTBI, with significantly higher concentrations of IL-10 and G-CSF and significantly lower concentrations of IL-9, IL-12, and IP-10 in brain tissue homogenates, compared to male mice 28 .…”

Section: Discussionsupporting

confidence: 90%

“…A bead-based multiplex cytokine kit (LXSARM-17, R&D Systems, Minneapolis, MN, USA) was used to measure CSF levels of CXCL2, CXCL3, ICAM-1, IFN-γ, IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-13, IL-18, L-Selectin, TIMP1, TNF-α, and VEGF. This kit was chosen due to its published use in rat TBI studies 28,29 . All samples were run in duplicate.…”

Section: Luminex Xmap Multiplex Immunoassaymentioning

confidence: 99%

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Minimally invasive serial collection of cerebrospinal fluid reveals sex-dependent differences in neuroinflammation in a rat model of mild traumatic brain injury

Karam,

Ashfaq,

Benitez

et al. 2024

Preprint

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Traumatic brain injuries (TBI) are the seventh leading cause of disability globally with 48.99 million prevalent cases and 7.08 million years lived with diability. Approximately 80% of TBI patients are diagnosed with mild TBI (mTBI), or concussion, caused by nonpenetrating mechanical trauma to the head or body along with sudden rotational motion of the head. Major distinctions between mTBI and more severe TBI include the absence of intracranial lesions, hemorrhages, and skull fractures in mTBI. Further, there are differences in the inflammatory response based on injury severity. While some overlap of the neuroinflammatory response across TBI severities is expected, studies investigating the temporal dynamics of neuroinflammation after mTBI and the sex-dependent differences are still needed as there have been many reported sex-dependent differences in mTBI. To fully understand the inflammatory response to TBI, it is vital to assay cerebrospinal fluid (CSF), as it has been shown that CSF biomarkers such as MAP-2 enhance prognosis capabilities. The literature analyzing the CSF proteome over time after TBI is very limited, primarily due to the lack of a CSF collection method that is minimally invasive and enables serial collections. This study had three primary goals. First, we wanted to describe a method of minimally invasive serial CSF collection. The method described in this study can easily be adapted by any laboratory prepared for animal studies. Second, we wanted to confirm that serial collection of the CSF does not alter CSF protein levels. Of the 17 analytes we tested, 16 showed no difference between serial collection and single collection. Third, we wanted to establish a framework for assessing sex differences in neuroinflammation after a concussion. We showed that results vary based on the framing of the statistical test. However, it is evident that males experience a more robust inflammatory response to a single concussion than females.

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Section: Discussionsupporting

confidence: 90%

Section: Luminex Xmap Multiplex Immunoassaymentioning

confidence: 99%

Minimally invasive serial collection of cerebrospinal fluid reveals sex-dependent differences in neuroinflammation in a rat model of mild traumatic brain injury

Karam,

Ashfaq,

Benitez

et al. 2024

Preprint

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“…Regarding experimental design, only male mice were utilized in these studies. Very few TBI studies assessing changes to the GI tract or microbiome have included female mice 100 , 101 which may limit translatability of findings. Additionally, not all experimental procedures were carried out in all mice which limits the ability to directly correlate outcomes.…”

Section: Discussionmentioning

confidence: 99%

Acute gastrointestinal permeability after traumatic brain injury in mice precedes a bloom in Akkermansia muciniphila supported by intestinal hypoxia

DeSana,

Estus,

Barrett

et al. 2024

Sci Rep

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Traumatic brain injury (TBI) increases gastrointestinal morbidity and associated mortality. Clinical and preclinical studies implicate gut dysbiosis as a consequence of TBI and an amplifier of brain damage. However, little is known about the association of gut dysbiosis with structural and functional changes of the gastrointestinal tract after an isolated TBI. To assess gastrointestinal dysfunction, mice received a controlled cortical impact or sham brain injury and intestinal permeability was assessed at 4 h, 8 h, 1 d, and 3 d after injury by oral administration of 4 kDa FITC Dextran prior to euthanasia. Quantification of serum fluorescence revealed an acute, short-lived increase in permeability 4 h after TBI. Despite transient intestinal dysfunction, no overt morphological changes were evident in the ileum or colon across timepoints from 4 h to 4 wks post-injury. To elucidate the timeline of microbiome changes after TBI, 16 s gene sequencing was performed on DNA extracted from fecal samples collected prior to and over the first month after TBI. Differential abundance analysis revealed that the phylum Verrucomicrobiota was increased at 1, 2, and 3 d after TBI. The Verrucomicrobiota species was identified by qPCR as Akkermansia muciniphila, an obligate anaerobe that resides in the intestinal mucus bilayer and produces short chain fatty acids (e.g. butyrate) utilized by intestinal epithelial cells. We postulated that TBI promotes intestinal changes favorable for the bloom of A. muciniphila. Consistent with this premise, the relative area of mucus-producing goblet cells in the medial colon was significantly increased at 1 d after injury, while colon hypoxia was significantly increased at 3 d. Our findings reveal acute gastrointestinal functional changes coupled with an increase of beneficial bacteria suggesting a potential compensatory response to systemic stress after TBI.

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“…Several studies have been conducted to determine blast parameters that represent military-relevant LLB blast exposure. Rodents exposed to static peak overpressures ranging from 74 kPa (~11 psi) [ 37 , 38 , 39 , 40 , 41 ] to 124 kPa (~18 psi) [ 42 ] exhibit symptomology in line with characteristics of mTBI, including no loss of consciousness or observable gross pathology in the brain, lungs, and other organs. The range of blast overpressures for mild blast severity depends on a number of variables, including animal species, positive overpressure duration, and animal orientation to the blast.…”

Section: Neurovascular Dysfunction Following Low-level Blast Exposurementioning

confidence: 99%

Effects of Low-Level Blast on Neurovascular Health and Cerebral Blood Flow: Current Findings and Future Opportunities in Neuroimaging

Kilgore,

Hubbard

2024

IJMS

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Low-level blast (LLB) exposure can lead to alterations in neurological health, cerebral vasculature, and cerebral blood flow (CBF). The development of cognitive issues and behavioral abnormalities after LLB, or subconcussive blast exposure, is insidious due to the lack of acute symptoms. One major hallmark of LLB exposure is the initiation of neurovascular damage followed by the development of neurovascular dysfunction. Preclinical studies of LLB exposure demonstrate impairment to cerebral vasculature and the blood–brain barrier (BBB) at both early and long-term stages following LLB. Neuroimaging techniques, such as arterial spin labeling (ASL) using magnetic resonance imaging (MRI), have been utilized in clinical investigations to understand brain perfusion and CBF changes in response to cumulative LLB exposure. In this review, we summarize neuroimaging techniques that can further our understanding of the underlying mechanisms of blast-related neurotrauma, specifically after LLB. Neuroimaging related to cerebrovascular function can contribute to improved diagnostic and therapeutic strategies for LLB. As these same imaging modalities can capture the effects of LLB exposure in animal models, neuroimaging can serve as a gap-bridging diagnostic tool that permits a more extensive exploration of potential relationships between blast-induced changes in CBF and neurovascular health. Future research directions are suggested, including investigating chronic LLB effects on cerebral perfusion, exploring mechanisms of dysautoregulation after LLB, and measuring cerebrovascular reactivity (CVR) in preclinical LLB models.

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Timing matters: Sex differences in inflammatory and behavioral outcomes following repetitive blast mild traumatic brain injury

Cited by 8 publications

References 81 publications

Minimally invasive serial collection of cerebrospinal fluid reveals sex-dependent differences in neuroinflammation in a rat model of mild traumatic brain injury

Minimally invasive serial collection of cerebrospinal fluid reveals sex-dependent differences in neuroinflammation in a rat model of mild traumatic brain injury

Acute gastrointestinal permeability after traumatic brain injury in mice precedes a bloom in Akkermansia muciniphila supported by intestinal hypoxia

Effects of Low-Level Blast on Neurovascular Health and Cerebral Blood Flow: Current Findings and Future Opportunities in Neuroimaging

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