The Sub-ventricular Zone in Mild Traumatic Brain Injury at Single-cell Resolution
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE198074 | GEO | 2022/06/28
REPOSITORIES: GEO
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Project description:Primary blast-induced mild traumatic brain injury (mTBI) represents a common injury experienced during modern warfare. With virtually no apparent physical damage or symptoms presented, an effective source with minimum-invasion for mTBI biomarker discovery is required. In this study, we measure the transcriptomic sensitivity of the hair follicles in relation to the severity of primary blast-derived TBI.
2016-05-07 | GSE80371 | GEO
Project description:To elucidate molecular features of the cells of Sub-ventricular Zone (SVZ), their progeny at each differentiation stage, and surrounding cells in SVZ under blast wave-induced changes, cells were profiled from matched SVZ of 3 mice that had received blast injury and 3 controls（The controls sequencing profile can be assessed in GEO at GSM5938054）.Cell type specific gene expression responding to (blast-related traumatic brain injury, bTBI) were revealed, some of which were closely associated with pathogenesis post-injury. Furthermore, the diverse cell to cell interaction networks uncovered an array of cellular processes under bTBI. Our gene expression atlas provides extensive resources for future researches regarding bTBI induced pathogenesis, its therapeutic interventions or diagnostic tests.
2022-06-28 | GSE207078 | GEO
Project description:The etiology of mild traumatic brain injury (mTBI) remains elusive due to the tissue and cellular heterogeneity of the affected brain regions that underlie cognitive impairments and subsequent neurological disorders. This complexity is further exacerbated by disrupted circuits within and between cell populations across brain regions and the periphery, which occur at different timescales and in spatial domains. We profiled three tissues (hippocampus, frontal cortex, and blood leukocytes) at the acute (24hr) and chronic (7days) phases of mTBI at single cell resolution and demonstrated that the coordinated gene expression patterns across cell types were disrupted and re-organized by TBI at different timescales with distinct regional and cellular patterns. Gene expression-based network modeling identified astrocytes as a key regulator of the cell-cell coordination following mTBI in both hippocampus and frontal cortex across timepoints, and mt-Rnr2, which encodes the mitochondrial peptide humanin, as a potential target for intervention based on its broad regional and dynamic dysregulation following mTBI. Treatment of a murine mTBI model with humanin reversed cognitive impairment caused by mTBI through the restoration of metabolic pathways within astrocytes. Our results offer a systems-level understanding of the dynamic and spatial regulation of gene programs by mTBI and pinpoint key target genes, pathways, and cell circuits that are amenable to therapeutics.
2022-08-17 | GSE180862 | GEO
Project description:To elucidate molecular features of the cells of Hippocampus, their progeny at each differentiation stage, and surrounding cells in hippocampus under blast wave-induced changes, cells were profiled from matched hippocampus of 3 mice that had received blast injury and 3 controls.Cell type specific gene expression responding to (blast-related traumatic brain injury, bTBI) were revealed, some of which were closely associated with pathogenesis post-injury. Furthermore, the diverse cell to cell interaction networks uncovered an array of cellular processes under bTBI. Our gene expression atlas provides extensive resources for future researches regarding bTBI induced pathogenesis, its therapeutic interventions or diagnostic tests.
2023-09-04 | GSE230253 | GEO
Project description:Purpose: High throughput small RNA-Seq analysis from circulating biofluids is crucial in driving the discovery of non-invasive miRNA biomarkers for TBI. In this study, we focused our analysis on acute post-TBI alterations in plasma miRNA profiles in adult, male Sprague-Dawley rats. We compared the plasma miRNA profiles from naive, sham-operated controls and rats with mild and severe TBI. The aim was to identify a miRNA signature that would distinguish the rats with mTBI from the naive and sham-operated controls. Next, we compared the rats with mild and severe TBIs to investigate if a dose-dependent increase would occur in the plasma miRNA levels with corresponding increase in injury severities. Finally, we analysed if the sham surgery itself results in alterations in circulating miRNA profiles, by comparing the naive and sham-operated controls. Methods: TBI was induced with the lateral fluid percussion injury (FPI) model. Tail-vein plasma was collected at 2 days post-TBI from 31 adult male, Sprague-Dawley rats (5 naive, 8 sham-operated controls, 10 mTBI and 8 sTBI) under inhalation of isoflurane anesthesia. Small RNA-Seq was performed from plasma samples of a subset of 20 rats (5 cases each from naive, sham-operated controls, mTBI and sTBI groups). For each case, RNA was isolated from 200 µL plasma using the miRNeasy serum/plasma kit. The extracted RNA was subjected to qPCR-based quality control (QC). Small RNA library preparation was performed with the QIASeq miRNA library kit for Illumina NGS systems. Single-end sequencing of 75 bp reads was performed at a depth of 12M, with one sample/lane in the Illumina NextSeq 550. One naive plasma sample failed at the library preparation step. Hence, small RNA-Seq was succesful for 19/20 cases. The raw fastq files obtained from small RNA-Seq were first manually inspected with FastQC (v0.11.3) to check the overall quality of the sequencing data. For primary quantification of read counts, the fastq files were then uploaded to the Qiagen Geneglobe Data analysis center (DAC), a freely available web resource to analyze data from Qiagen’s QIASeq NGS library kits (https://geneglobe.qiagen.com/in/analyze/). Mapping was performed in the DAC portal with bowtie, using the rat reference genome RGSC Rnor_6.0. Annotation of miRNAs was performed with miRBase v21. Following primary quantification, differential expression analysis for miRNAs was performed with DESeq2 (v1.22.2) in R environment (v3.5.3). Logistic regression (LR) with feature selection utilizing nested leave-one-out cross-validation was also performed to identify miRNAs (“features”) contributing most to groupwise differences (differences between naïve, sham, mTBI, sTBI, sTBI + mTBI and naïve + sham). Results: A total of 748 miRNAs were detected across all samples, out of which 723 (97%) were expressed in all the four groups (naive, sham-operated, mTBI and sTBI). Based on the differential expression and logistic regression analyses, we identified five miRNA candidates that contributed most to the seperation between the mTBI and naive groups: rno-miR-9a-3p, rno-miR-153-3p, rno-miR-15a-3p, rno-miR-136-3p and rno-miR-434-3p. We validated the small RNA-Seq data for these miRNA candidates with miRCURY reverse transcriptase quantitative PCR (RT-qPCR). We could succesfully validate elevated levels of miR-9a-3p, miR-136-3p and miR-434-3p in the mTBI group in comparison to naive. When analysed from the whole cohort, the elevated levels of these miRNAs were consistently observed in the mTBI group compared to the naive, both with RT-qPCR and droplet digital PCR (ddPCR). Further, all the three miRNAs revealed elevated plasma levels in the sTBI group in comparison to the mTBI. Conclusions: Elevated plasma miRNA signature of miR-9a-3p, miR-136-3p and miR-434-3p distinguishes rats with mTBI from the naive, in the lateral FPI model of TBI. Further, all these miRNAs exhibit a dose-dependent increase in plasma levels with increase in injury severities.
2021-03-03 | GSE159011 | GEO
Project description:Repetitive mild traumatic brain injury (mTBI) in children and adolescents leads to acute and chronic neurological sequelae and is linked by epidemiological data to later life neurodegenerative disease. However, the biological mechanisms connecting early life mTBI to neurodegeneration remain unknown. Using an adolescent mouse repetitive closed head injury (CHI) model that induces progressive cognitive impairment in the absence of overt histopathology, we examined transcriptional and translational changes in neurons isolated from sham and injured brain in the chronic phase after injury. At 14 months, single nuclei RNA sequencing of cortical brain tissue identified disruption of genes associated with neuronal proteostasis in injured mice. Western blot analysis of neurons isolated by immunopanning showed evidence of inflammasome activation, accumulation of misfolded, hyperphosphorylated Tau, and changes in expression of proteins suggestive of impaired translation. Compared to injured wild type, injured interleukin-1 receptor 1 knockout mice, which are protected from post-injury cognitive deficits, had reduced microgliosis and decreased accumulation of pro-interleukin-1 beta and misfolded tau in cortex and cerebellum at six months. Taken together, our findings provide evidence for neuronal inflammasome activation and impaired proteostasis as key mechanisms linking repetitive mTBI in adolescence to later life neurological dysfunction and neurodegeneration.
2021-05-01 | GSE167942 | GEO
Project description:Ischemic stroke is a serious medical condition that leads to the onset of neurological symptoms such as loss of motor and cognitive functions. Focal cerebral ischemia (FCI) occurs due to the interrupted blood supply to the site of injury, resulting in the demise of brain cells. The subventricular zone (SVZ) is a source of stem and progenitor cells (NS/PCs), which proliferate and differentiate in multiple cell types in order to substitute the injured tissue. We isolated cells from the SVZ and the adjacent striatum three days after middle cerebral artery occlusion (MCAO) in order to map cellular changes and NS/PCs plasticity in adult brain upon injury. Expression profiling of the isolated tissue at the single cell level enables the identification of cell population subtypes in the region and their characteristic gene expression.
2021-01-01 | E-MTAB-9935 | biostudies-arrayexpress
Project description:Isocitrate dehydrogenase 1 mutations drive human gliomagenesis, probably through neomorphic enzyme activity that produces D-2-hydroxyglutarate. To model this disease, we conditionally expressed Idh1R132H in the subventricular zone (SVZ) of the adult mouse brain. The mice developed hydrocephalus and grossly dilated lateral ventricles, with accumulation of 2-hydroxyglutarate and reduced -ketoglutarate. Stem and transit amplifying/progenitor cell populations were expanded, and proliferation increased.Cells expressing SVZ markers infiltrated surrounding brain regions. SVZ cells also gave rise to proliferative subventricular nodules. DNA methylation was globally increased, while hydroxymethylation was decreased. Mutant SVZ cells over-expressed Wnt, cell cycle and stem cell genes, and shared an expression signature with human gliomas. Idh1R132H mutation in the major adult neurogenic stem cell niche causes a phenotype resembling gliomagenesis. Isocitrate dehydrogenase 1 mutations drive human gliomagenesis, probably through neomorphic enzyme activity that produces D-2-hydroxyglutarate. To model this disease, we conditionally expressed Idh1R132H in the subventricular zone (SVZ) of the adult mouse brain. The mice developed hydrocephalus and grossly dilated lateral ventricles, with accumulation of 2-hydroxyglutarate and reduced -ketoglutarate. Stem and transit amplifying/progenitor cell populations were expanded, and proliferation increased. Cells expressing SVZ markers infiltrated surrounding brain regions. SVZ cells also gave rise to proliferative subventricular nodules. DNA methylation was globally increased, while hydroxymethylation was decreased. Mutant SVZ cells over-expressed Wnt, cell cycle and stem cell genes, and shared an expression signature with human gliomas. Idh1R132H mutation in the major adult neurogenic stem cell niche causes a phenotype resembling gliomagenesis.
2017-01-30 | GSE85080 | GEO
Project description:While traumatic brain injury (TBI) acutely disrupts the cortex, most TBI-related disabilities reflect secondary injuries that accrue over time. The thalamus is a likely site of secondary damage because of its reciprocal connections with the cortex. Using a mouse model of mild cortical injury that does not directly damage subcortical structures (mTBI), we found a chronic increase in C1q expression specifically in the corticothalamic circuit. Increased C1q expression co-localized with neuron loss and chronic inflammation, and correlated with disruption in sleep spindles and emergence of epileptic activities. Blocking C1q counteracted these outcomes, suggesting that C1q is a disease modifier in mTBI. Single-nucleus RNA sequencing demonstrated that microglia are the source of thalamic C1q. Since the corticothalamic circuit is important for cognition and sleep, which can be impaired by TBI, this circuit could thus be a new target for treating TBI-related disabilities.
2021-09-14 | GSE179541 | GEO
Project description:The relationship between repetitive mild traumatic brain injury (r-mTBI) and Alzheimer’s disease (AD) is well-recognized. However, the precise nature of how r-mTBI leads to or precipitates AD pathogenesis is currently not understood. Part A: Plasma biomarkers potentially provide non-invasive tools for detecting neurological changes in the brain, and can reveal overlaps between long-term consequences of r-mTBI and AD. In this study we address this by generating time-dependent molecular profiles of response to r-mTBI and AD pathogenesis in mouse models using unbiased proteomic analyses. To model AD, we used the well-validated hTau and PSAPP(APP/PS1) mouse models that develop age-related tau and amyloid pathological features respectively, and our well-established model of r-mTBI in C57BL/6 mice. Plasma were collected at different ages (3, 9, and 15 months-old for hTau and PSAPP mice), encompassing pre-, peri- and post-“onset” of the cognitive and neuropathological phenotypes, or at different timepoints after r-mTBI (24hrs, 3, 6, 9 and 12 months post-injury). Liquid chromatography/mass spectrometry (LC-MS) approaches coupled with Tandem Mass Tag labeling technology were applied to develop molecular profiles of protein species that were significantly differentially expressed as a consequence of mTBI or AD. Mixed model ANOVA after Benjamini-Hochberg correction, and a stringent cut-off identified 31 proteins significantly changing in r-mTBI groups over time and, when compared with changes over time in sham mice, 13 of these were unique to the injured mice. The canonical pathways predicted to be modulated by these changes were LXR/RXR activation, production of nitric oxide and reactive oxygen species and complement systems. We identified 18 proteins significantly changing in PSAPP mice and 19 proteins in hTau mice compared to their wildtype littermates with ageing. Six proteins were found to be significantly regulated in all three models i.e. r-mTBI, hTau and PSAPP mice compared to their controls. The top canonical pathways coincidently changing in all three models were LXR/RXR activation, and production of nitric oxide and reactive oxygen species. This work suggests potential biomarkers for TBI and AD pathogenesis and for the overlap between these two, and warrant targeted investigation in human populations. Part B: In this study we also address the aformention gap in the field by utilizing our unbiased proteomic approach to generate detailed time-dependent brain molecular profiles of response to repetitive mTBI and AD pathogenesis in established mouse models. Methods: We used the well-validated hTau and PSAPP(APP/PS1) mouse models that develops age-related tau and amyloid pathological features respectively, and our well-established model of repetitive-mTBI in C57BL/6 mice. Brain tissue from these animals were collected at different time points after repetitive mTBI (24hrs -12 months post-injury) and at different ages (3-15 months-old for hTau and PSAPP mice), encompassing pre-, peri- and post-“onset” of the cognitive and neuropathological phenotypes previously described in all models. Liquid chromatography/mass spectrometry (LC-MS) approach coupled with Tandem Mass Tag labeling technology were applied to reveal molecular profiles of proteins and pathways that are significantly altered as a consequence of AD or repetitive mTBI. Results: Mixed model ANOVA after Benjamin Hochberg correction identified 30 and 47 proteins that were specifically unique and changing in the hippocampus and cortex, respectively, within the r-mTBI group alone when compared with changes overtime in sham mice. PI3K/AKT signaling, Protein Kinase A signaling and PPAR/RXR activation in the hippocampus, and Protein Kinase A signaling, GNRH signaling and B cell receptor signaling in the cortex were the top canonical systems significantly altered in injury groups compared to sham mice. Mixed model AONVA identified 19 proteins significantly changing in the cortex of PSAPP mice and 7 proteins in hTau mice compared to their relative wildtype littermates respectively. In addition to the heterogeneous changes observed in the TBI and AD mouse models, there was a notable convergence and coincidental change in 6 unique proteins identified in the repetitive mTBI model and the hTau and PSAPP model. These proteins ostensibly indicate significant common pathobiological responses involving alterations in mitochondrial bioenergetics and energy metabolism, aberrant cytoskeletal reorganization and alterations in intracellular signaling transduction cascades. Conclusion: We believe that this work could help identify the common molecular substrates responsible for the precipitation of AD pathogenesis following repetitive mTBI, and also help to identify novel biological targets for therapeutic modulation in mTBI and AD.
2022-02-22 | PXD010602 | Pride