Female sex in experimental traumatic brain injury research: forging a path forward.
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ABSTRACT:
SUBMITTER: Currier Thomas T
PROVIDER: S-EPMC8504385 | biostudies-literature | 2022 Mar
REPOSITORIES: biostudies-literature
Publications
Female sex in experimental traumatic brain injury research: forging a path forward.
Currier Thomas Theresa T Bromberg Caitlin E CE Krishna Gokul G
Neural regeneration research 20220301 3
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Project description:IntroductionTraumatic brain injury is a leading cause of injury-related death and morbidity. Multiple clinical and pre-clinical studies have reported various results regarding sex-based differences in TBI. Our accepted rodent model of traumatic brain injury was used to identify sex-based differences in the pathological features of TBI.MethodsMale and female Sprague-Dawley rats were subjected to either controlled-cortical impact (CCI) or sham injury; brain tissue was harvested at different time intervals depending on the specific study. Blood-brain barrier (BBB) analysis was performed using infrared imaging to measure fluorescence dye extravasation. Microglia and splenocytes were characterized with traditional flow cytometry; microglia markers such as CD45, P2Y12, CD32, and CD163 were analyzed with t-distributed stochastic neighbor embedding (t-SNE). Flow cytometry was used to study tissue cytokine levels, and supplemented with ELISAs of TNF-⍺, IL-17, and IL-1β of the ipsilateral hemisphere tissue.ResultsCCI groups of both sexes recorded a higher BBB permeability at 72 hours post-injury than their respective sham groups. There was significant difference in the integrated density value of BBB permeability between the male CCI group and the female CCI group (female CCI mean = 3.08 x 108 ± 2.83 x 107, male CCI mean = 2.20 x 108 ± 4.05 x 106, p = 0.0210), but otherwise no differences were observed. Traditional flow cytometry did not distinguish any sex-based difference in regards to splenocyte cell population after CCI. t-SNE did not reveal any significant difference between the male and female injury groups in the activation of microglia. Cytokine analysis after injury by flow cytometry and ELISA was limited in differences at the time point of 6 hours post-injury.ConclusionIn our rodent model of traumatic brain injury, sex-based differences in pathology and neuroinflammation at specified time points are limited, and only noted in one specific analysis of BBB permeability.
| S-EPMC8864286 | biostudies-literature
Project description:Under normal conditions, heat shock proteins work in unison through dynamic protein interactions collectively referred to as the "chaperome." Recent work revealed that during cellular stress, the functional interactions of the chaperome are modified to form the "epichaperome," which results in improper protein folding, degradation, aggregation, and transport. This study is the first to investigate this novel mechanism of protein dishomeostasis in traumatic brain injury (TBI). Male and female adult, Sprague-Dawley rats received a lateral controlled cortical impact (CCI) and the ipsilateral hippocampus was collected 24 h 1, 2, and 4 weeks after injury. The epichaperome complex was visualized by measuring HSP90, HSC70 and HOP expression in native-PAGE and normalized to monomeric protein expression. A two-way ANOVA examined the effect of injury and sex at each time-point. Native HSP90, HSC70 and HOP protein expression showed a significant effect of injury effect across all time-points. Additionally, HSC70 and HOP showed significant sex effects at 24 h and 4 weeks. Altogether, controlled cortical impact significantly increased formation of the epichaperome across all proteins measured. Further investigation of this pathological mechanism can lead to a greater understanding of the link between TBI and increased risk of neurodegenerative disease and targeting the epichaperome for therapeutics.
| S-EPMC10698712 | biostudies-literature
Project description:BackgroundAlcohol-related brain degeneration (ARBD) is associated with cognitive-motor impairments that can progress to disability and dementia. White matter (WM) is prominently targeted in ARBD due to chronic neurotoxic and degenerative effects on oligodendrocytes and myelin. Early detection and monitoring of WM pathology in ARBD could lead to therapeutic interventions.ObjectiveThis study examines the potential utility of a non-invasive strategy for detecting WM ARBD using exosomes isolated from serum. Comparative analyses were made with paired tissue (Tx) and membrane vesicles (MVs) from the temporal lobe (TL).MethodsLong Evans rats were fed for 8 weeks with isocaloric liquid diets containing 37% or 0% caloric ethanol (n = 8/group). TL-Tx, TL-MVs, and serum exosomes (S-EVs) were used to examine ethanol's effects on oligodendrocyte glycoprotein, astrocyte, and oxidative stress markers.ResultsEthanol significantly decreased the TL-Tx expression of platelet-derived growth factor receptor alpha (PDGFRA), 2',3'-cyclic nucleotide 3' phosphodiesterase (CNPase), proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG), glial fibrillary acidic protein (GFAP), and 8-OHdG, whereas in the TL-MVs, ethanol increased CNPase, PDGFRA, and 8-OHdG, but decreased MOG and GFAP concordantly with TL-Tx. Ethanol modulated the S-EV expression by reducing PLP, nestin, GFAP, and 4-hydroxynonenal (HNE).ConclusionChronic ethanol exposures differentially alter the expression of oligodendrocyte/myelin, astrocyte, and oxidative stress markers in the brain, brain MVs, and S-EVs. However, directionally concordant effects across all three compartments were limited. Future studies should advance these efforts by characterizing the relationship between ABRD and molecular pathological changes in brain WM-specific exosomes in serum.
| S-EPMC11810071 | biostudies-literature
Project description:PURPOSE OF REVIEW:The underlying mechanisms responsible for chronic and progressive neurological damage after traumatic brain injury (TBI) are poorly understood, and therefore, current treatment options are limited. Proteomics is an emerging methodology to study changes to the TBI proteome in both patients and experimental models. RECENT FINDINGS:Although experimentally complex, mass spectrometry-based proteomics approaches are converging on a set of common methods. However, these methods are being applied to an increasingly diverse range of experimental models and types of injury. SUMMARY:In this review, our aim is to briefly describe experimental TBI models and the underlying methods common to most proteomic approaches. We will then review a series of articles that have recently appeared in which these approaches have been applied to important TBI questions. We will summarize several recent experimental studies, and suggest how the results of these emerging studies might impact future research as well as patient treatment.
| S-EPMC6221404 | biostudies-other
Project description:ObjectiveTo investigate possible electroencephalography (EEG) correlates of epileptogenesis after traumatic brain injury (TBI) using the fluid percussion model.MethodsExperiments were conducted on adult 2- to 4-month-old male Sprague-Dawley rats. Two groups of animals were studied: (1) the TBI group with depth and screw electrodes implanted immediately after the fluid percussion injury (FPI) procedure, and (2) a naive age-matched control group with the same electrode implantation montage. Pairs of tungsten microelectrodes (50 μm outer diameter) and screw electrodes were implanted in neocortex inside the TBI core, areas adjacent to TBI, and remote areas. EEG activity, recorded on the day of FPI, and continuously for 2 weeks, was analyzed for possible electrographic biomarkers of epileptogenesis. Video-EEG monitoring was also performed continuously in the TBI group to capture electrographic and behavioral seizures until the caps came off (28-189 days), and for 1 week, at 2, 3, and 6 months of age, in the control group.ResultsPathologic high-frequency oscillations (pHFOs) with a central frequency between 100 and 600 Hz, were recorded from microelectrodes, beginning during the first two post-FPI weeks, in 7 of 12 animals in the TBI group (58%) and never in the controls. pHFOs only occurred in cortical areas within or adjacent to the TBI core. These were associated with synchronous multiunit discharges and popSpikes, duration 15-40 msec. Repetitive pHFOs and EEG spikes (rHFOSs) formed paroxysmal activity, with a unique arcuate pattern, in the frequency band 10-16 Hz in the same areas as isolated pHFOs, and these events were also recorded by screw electrodes. Although loss of caps prevented long-term recordings from all rats, pHFOs and rHFOSs occurred during the first 2 weeks in all four animals that later developed seizures, and none of the rats without these events developed late seizures.SignificancepHFOs, similar to those associated with epileptogenesis in the status rat model of epilepsy, may also reflect epileptogenesis after FPI. rHFOSs could be noninvasive biomarkers of epileptogenesis.
| S-EPMC5081251 | biostudies-literature
Project description:The inflammatory response to moderate-severe controlled cortical impact (CCI) in adult male mice has been shown to exhibit greater glial activation compared with age-matched female mice. However, the relative contributions of resident microglia and infiltrating peripheral myeloid cells to this sexually dimorphic neuroinflammatory responses remains unclear. Here, 12-week-old male and female C57Bl/6 mice were subjected to sham or CCI, and brain samples were collected at 1, 3, or 7 days post-injury for flow cytometry analysis of cytokines, reactive oxygen species (ROS), and phagocytosis in resident microglia (CD45intCD11b+) versus infiltrating myeloid cells (CD45hiCD11b+). Motor (rotarod, cylinder test), affect (open field), and cognitive (Y-maze) function tests also were performed. We demonstrate that male microglia had increased phagocytic activity and higher ROS levels in the non-injured brain, whereas female microglia had increased production of tumor necrosis factor (TNF) α and interleukin (IL)-1β. Following CCI, males showed a significant influx of peripheral myeloid cells by 1 day post-injury followed by proliferation of resident microglia at 3 days. In contrast, myeloid infiltration and microglial activation responses in female CCI mice were significantly reduced. No sex differences were observed for TNFα, IL-1β, transforming growth factor β, NOX2, ROS production, or phagocytic activity in resident microglia or infiltrating cells at any time. However, across these functions, infiltrating myeloid cells were significantly more reactive than resident microglia. Female CCI mice also had improved motor function at 1 day post-injury compared with male mice. Thus, we conclude that sexually dimorphic responses to moderate-severe CCI result from the rapid activation and infiltration of pro-inflammatory myeloid cells to brain in male, but not female, mice.
| S-EPMC6444913 | biostudies-literature
Project description:Although moderate to severe traumatic brain injury (TBI) leads to facial affect recognition impairments in up to 39% of individuals, protective and risk factors for these deficits are unknown. The aim of the current study was to examine the effect of sex on emotion recognition abilities following TBI. We administered two separate emotion recognition tests (one static and one dynamic) to 53 individuals with moderate to severe TBI (females = 28) and 49 demographically matched comparisons (females = 22). We then investigated the presence of a sex-by-group interaction in emotion recognition accuracy. In the comparison group, there were no sex differences. In the TBI group, however, females significantly outperformed males in the dynamic (but not the static) task. Moreover, males (but not females) with TBI performed significantly worse than comparison participants in the dynamic task. Further analysis revealed that sex differences in emotion recognition abilities within the TBI group could not be explained by lesion location, TBI severity, or other neuropsychological variables. These findings suggest that sex may serve as a protective factor for social impairment following TBI and inform clinicians working with TBI as well as research on the neurophysiological correlates of sex differences in social functioning.
| S-EPMC5823256 | biostudies-literature
Project description:Over 2.8 million traumatic brain injuries (TBIs) are reported in the United States annually, of which, over 75% are mild TBIs with diffuse axonal injury (DAI) as the primary pathology. TBI instigates a stress response that stimulates the hypothalamic-pituitary-adrenal (HPA) axis concurrently with DAI in brain regions responsible for feedback regulation. While the incidence of affective symptoms is high in both men and women, presentation is more prevalent and severe in women. Few studies have longitudinally evaluated the etiology underlying late-onset affective symptoms after mild TBI and even fewer have included females in the experimental design. In the experimental TBI model employed in this study, evidence of chronic HPA dysregulation has been reported at 2 months post-injury in male rats, with peak neuropathology in other regions of the brain at 7 days post-injury (DPI). We predicted that mechanisms leading to dysregulation of the HPA axis in male and female rats would be most evident at 7 DPI, the sub-acute time point. Young adult age-matched male and naturally cycling female Sprague Dawley rats were subjected to midline fluid percussion injury (mFPI) or sham surgery. Corticotropin releasing hormone, gliosis, and glucocorticoid receptor (GR) levels were evaluated in the hypothalamus and hippocampus, along with baseline plasma adrenocorticotropic hormone (ACTH) and adrenal gland weights. Microglial response in the paraventricular nucleus of the hypothalamus indicated mild neuroinflammation in males compared to sex-matched shams, but not females. Evidence of microglia activation in the dentate gyrus of the hippocampus was robust in both sexes compared with uninjured shams and there was evidence of a significant interaction between sex and injury regarding microglial cell count. GFAP intensity and astrocyte numbers increased as a function of injury, indicative of astrocytosis. GR protein levels were elevated 30% in the hippocampus of females in comparison to sex-matched shams. These data indicate sex-differences in sub-acute pathophysiology following DAI that precede late-onset HPA axis dysregulation. Further understanding of the etiology leading up to late-onset HPA axis dysregulation following DAI could identify targets to stabilize feedback, attenuate symptoms, and improve efficacy of rehabilitation and overall recovery.
| S-EPMC7554641 | biostudies-literature
Project description:Endorepellin plays a key role in the regulation of angiogenesis, but its effects on angiogenesis after traumatic brain injury are unclear. This study explored the effects of endorepellin on angiogenesis and neurobehavioral outcomes after traumatic brain injury in mice. Mice were randomly divided into four groups: sham, controlled cortical impact only, adeno-associated virus (AAV)-green fluorescent protein, and AAV-shEndorepellin-green fluorescent protein groups. In the controlled cortical impact model, the transduction of AAV-shEndorepellin-green fluorescent protein downregulated endorepellin while increasing the number of CD31+/Ki-67+ proliferating endothelial cells and the functional microvessel density in mouse brain. These changes resulted in improved neurological function compared with controlled cortical impact mice. Western blotting revealed increased expression of vascular endothelial growth factor and angiopoietin-1 in mice treated with AAV-shEndorepellin-green fluorescent protein. Synchrotron radiation angiography showed that endorepellin downregulation promoted angiogenesis and increased cortical neovascularization, which may further improve neurobehavioral outcomes. Furthermore, an in vitro study showed that downregulation of endorepellin increased tube formation by human umbilical vein endothelial cells compared with a control. Mechanistic analysis found that endorepellin downregulation may mediate angiogenesis by activating vascular endothelial growth factor- and angiopoietin-1-related signaling pathways.
| S-EPMC10749628 | biostudies-literature
Project description:Worldwide elderly traumatic brain injury (TBI) patients tend to become an increasing burden to the society. Thus, a faster and less expensive way of evaluating TBI victims is needed. In the present study we investigated if optical coherence tomography (OCT) could be used as such a method. By using an animal model, we established if OCT can detect cortical changes in the acute phase of a penetrating TBI, in young (5-7 months) and old (20-22 months) rats. Due to the long-term evolution of TBI's, we wanted to investigate to what extent OCT could detect changes within the cortex in the chronic phase. Adult (7-12 months) male rats were used. Surprisingly, OCT imaging of the normal hemisphere was able to discriminate age-related differences in the mean gray values (MGV) of recorded pixels (p = .032). Furthermore, in the acute phase of TBI, OCT images recorded at 24 hr after the injury showed differences between the apparent damaged area of young and aged animals. Changes of MGV and skewness were only recorded 48 hr after injury. Monitoring the chronical evolution of the TBI with OCT revealed changes over time exceeding the normal range recorded for MGV, skewness and kurtosis, 14 and 21 days after TBI. Although in the present study we still used an extremely invasive approach, as technology improves, less invasive and non-harmful ways of recording OCT may allow for an objective way to detect changes within the brain structure after brain injuries.
| S-EPMC7891427 | biostudies-literature