Single-cell sequencing of cortical cells following murine traumatic brain injury [scRNA-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE160763 | GEO | 2020/11/15
REPOSITORIES: GEO
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Project description:Traumatic brain injury (TBI) can lead to significant neuropsychiatric problems and neurodegenerative pathologies, which develop and persist years after injury. Neuroinflammatory processes evolve over this same period. Therefore, we aimed to determine the contribution of microglia to neuropathology at acute (1-day post-injury; dpi), subacute (7 dpi), and chronic (30 dpi) time-points. Microglia were depleted with PLX5622, a CSF1R antagonist, prior to midline fluid percussion injury in male mice and cortical neuropathology/inflammation was assessed using a neuropathology mRNA panel. NanoString Neuropathology gene expression panel was used to quantify expression from RNA microdissected from the mouse cortex.
2020-11-15 | GSE160651 | GEO
Project description:In this study, we performed bulk RNA sequencing of concurrently isolated microglia and astrocytes to evaluate their cell-specific transcriptional responses to TBI 7 days post-injury. Our findings revealed sustained, cell-specific transcriptional changes in both microglia and astrocytes, with microglia showing a greater transcriptional response than astrocytes at this subacute timepoint. The microglia and astrocyte transcriptional response to TBI was unique from other neurodegenerative and neuroinflammatory diseases that have been described. In addition, microglia and astrocytes showed overlapping enrichment for genes related to type I interferon signaling and MHC class I antigen presentation.
2021-06-01 | GSE167459 | GEO
Project description:Background: Severe Traumatic Brain Injury (TBI) has become a growing health problem, causing a vast society burden worldwide. However, characteristic mechanisms between acute and subacute stages have not been systemically revealed. Methods: Sixty rats were randomly divided into sham surgery and model groups. Severe TBI model was induced by controlled cortical impact (CCI). Neurological deficits were evaluated by modified neurological severity score (mNSS). H&E staining and immunofluorescence were performed to assess the injured brain tissues. The protein expressions of hippocampus were analyzed by the tandem mass tag-based (TMT) quantitative proteomics on the third and fourteenth days. The shared and stage-specific differentially expressed proteins (DEPs) were screened, and then analyzed by the gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG) and protein-protein interaction (PPI). Eventually, target proteins were further verified by Western blotting (WB). Results: The neurological deficits always exist from the acute stage to the subacute stage of severe TBI and showed a downward trend. The brain parenchyma of TBI models was dramatically impaired. A total of 375 and 139 DEPs were identified at day 3 and 14, respectively. Sixty-three DEPs were co-existed between the two stages. Both stages were mainly related to the complement and coagulation cascades pathway. Three pathways associated with gastric acid secretion, insulin secretion and thyroid hormone synthesis were only enriched in the acute phase. Comparatively, amyotrophic lateral sclerosis (ALS) was significantly enriched in the subacute stage. WB confirmed the reliability of the TMT quantitative proteomics results. Conclusion: Our findings highlight the same and different pathological processes in the acute and subacute phases of severe TBI and provide potential protein biomarkers.
2023-06-07 | PXD029312 | Pride
Project description:Using an experimental TBI rat model of mild/moderate Controlled Cortical Impact (CCI) injury, we combined large-scale proteomics identification and relative quantification using Spatially-Resolved Microproteomics with MALDI MS Imaging of Lipids. Spatially by studying different regions in the brain post injury in a coronal view, with main focus on the injury site itself. Temporally by studying the acute and subacute phase post injury, including injured rat brains at 1 day, 3 days, 7 days, and 10 days post injury. Direct on-tissue micro-digestion followed by micoextraction from 1 mm2 surface area within the injured cortical tissue were subjected to LC-MS & MS/MS analysis using HR MS. In addition, several identified potential biomarkers within our study were used to stimulate dorsal root ganglion (DRG), astrocyte, and macrophage cell lines to obtain a better understanding of their role and contribution in the injury.
2019-06-19 | PXD011262 | Pride
Project description:The temporal course of microglial inflammation-related gene expression was defined uding nanostring platform at acute, subacute, and chronic time points in a pre-clinical TBI model.
2019-06-18 | GSE132809 | GEO
Project description:Traumatic brain injury (TBI) is a leading cause of chronic brain impairment and results in a robust, but poorly understood, neuroinflammatory response that contributes to the long-term pathology. We used snRNA-seq to study transcriptomic changes in different cell populations in human brain tissue obtained acutely after severe, life-threatening TBI. This revealed a unique transcriptional response in oligodendrocyte precursors and mature oligodendrocytes, including the activation of a robust innate immune response, indicating an important role for oligodendroglia in the initiation of neuroinflammation. The activation of an innate immune response correlated with transcriptional upregulation of endogenous retroviruses in oligodendroglia. This observation was causally linked in vitro using human glial progenitors, implicating these ancient viral sequences in human neuroinflammation. In summary, this work provides a unique insight into the initiating events of the neuroinflammatory response in TBI, which has new therapeutic implications.
2023-03-03 | GSE209552 | GEO
Project description:Genetic factors are believed to be of importance for outcome of traumatic brain injury (TBI). However, so far mainly allelic variation in apolipoprotein E4 has been studied in human TBI. In order to study the role of genetic factors in experimental TBI, we examined parental DA and PVG strains before and after TBI. A standardized weight drop injury was used and the pericontusional area was dissected 1 day after TBI and transcriptional profiling was performed.
2012-09-06 | E-MTAB-795 | biostudies-arrayexpress
Project description:Background: Traumatic brain injury (TBI) often results in diverse molecular responses, challenging traditional proteomic studies that measure average changes at tissue levels and fail to capture the complexity and heterogeneity of the affected tissues. Spatial proteomics offers a solution by providing insights into sub-region-specific alterations within tissues. This study focuses on the hippocampal sub-regions, analyzing proteomic expression profiles in mice at the acute (1 day) and subacute (7 days) phases of post-TBI to understand subregion-specific vulnerabilities and long-term consequences. Methods: Three mice brains were collected from each group including Sham, 1-day post-TBI and 7-day post-TBI. Hippocampal subregions were extracted using Laser Microdissection (LMD); and subsequently analyzed by label-free quantitative proteomics. Results: The spatial analysis reveals region-specific protein abundance changes, highlighting the elevation of FN1, LGALS3BP, HP, and MUG-1 in the stratum moleculare (SM), suggesting potential immune cell enrichment post-TBI. Notably, established markers of chronic traumatic encephalopathy, IGHM and B2M, exhibit specific upregulation in the dentate gyrus bottom (DG2) independent of direct mechanical injury. Metabolic pathway analysis identifies disturbances in glucose and lipid metabolism, coupled with activated cholesterol synthesis pathways enriched in SM at 7-Day post-TBI and subsequently in deeper DG1 and DG2 suggesting a role in neurogenesis and onset of recovery. Coordinated activation of neuroglia and microtubule dynamics in DG2 suggest recovery mechanisms in less affected regions. Cluster analysis revealed spatial variations post-TBI, indicative of dysregulated neuronal plasticity and neurogenesis and further predisposition to neurological disorders. TBI-induced protein upregulation (MUG-1, PZP, GFAP, TJP, STAT-1 and CD44) across hippocampal sub-regions indicates shared molecular responses and links to neurological disorders. Spatial variations were demonstrated by proteins dysregulated in both or either of the time-points exclusively in each subregion (ELAVL2, CLIC1 in PL, CD44 and MUG-1 in SM, and SHOC2, LGALS3 in DG). Conclusions: Utilizing advanced spatial proteomics techniques, the study unveils the dynamic molecular responses in distinct hippocampal subregions post-TBI. It uncovers region-specific vulnerabilities and dysregulated neuronal processes, and potential recovery-related pathways that contribute to our understanding of TBI’s neurological consequences and provides valuable insights for biomarker discovery and therapeutic targets.
2024-06-23 | PXD051093 | Pride
Project description:The problem of traumatic brain injury (TBI) heterogeneity has been a critical barrier to successful translation of therapies in the field. TBI heterogeneity exists in the patient substrate pre-injury (genetics, sex, comorbidities), external injury characteristics (severity, mechanism), and resultant post-injury host response that is responsible for deleterious secondary injury processes (seizures, neuroinflammation, neurodegeneration) and repair/regeneration. Identification of final common molecular pathways and signatures that integrate this vast heterogeneity could be valuable for guiding biomarkers, therapeutic targets, and predictive enrichment. In this study, we present the first large-scale searchable murine single-cell atlas of the transcriptomic response to TBI in 339,357 cells as a foundational step in molecularly deconstructing TBI heterogeneity. We identify 23 cell types with massive heterogeneity in the single-cell response across extrinsicand intrinsic factors, that has been underestimated. Majority of response to TBI was unique to individual cell populations with minimal overlap even within a single injury-model thus highlighting the importance of cell-level resolution. Through this effort, we report novel cell-specific targets and a previously unrecognized role for specific microglial and ependymal subtypes in post-TBI pathophysiology that is highly variable depending on the extrinsic and intrinsic factors studied. One ependymal subtype was a hub of neuroinflammatory signaling after contusional-TBI, particularly related to Il-1b. A single microglial-lineage along pseudotime (comprising 3 microglial subtypes) was a key mediator of host-response after TBI, and shared features with disease associated microglia noted in Alzheimer’s disease and other neurodegenerative disorders, potentially providing a link between TBI and accelerated neurodegeneration. One microglial subtype within this lineage emerged as a key target – it was the only cell type of all 23 that retained persistent and marked gene expression changes 6 months post contusional-TBI. We identify sexually dimorphic gene expression and pathway vulnerabilities with cell-specific differences in both immune and non-immune biological processes. These likely contribute to sex-based outcome and warrant further study to facilitate discovery of cell- and sex-specific druggable targets. Active changes in brain regions distal from the site of primary TBI impact included infiltration of specific microglial populations as well as cell-specific transcriptomic changes in several genes and inflammatory processes distinct from both the peri-contusional and naïve signatures. This atlas validates several known contributors in TBI pathophysiology, and also identifies previously unrecognized targets and avenues for further research. Beyond our presented exemplar analyses (including pathways of clinical interest like sulfonylurea-receptor-1), the companion searchable atlas serves as a foundation for countless future efforts to understand cell-specific heterogeneity after TBI (https://shiny.crc.pitt.edu/cerebri/) as well as numerous other neurological diseases with overlapping pathophysiology.
2024-07-02 | GSE269748 | GEO
Project description:Warfare has long been associated with traumatic brain injury (TBI) in militarized zones. Common forms of TBI can be caused by a physical insult to the head-brain or by the effects of a high velocity blast shock wave generated by the detonation of an explosive device. While both forms of trauma are distinctly different regarding the mechanism of trauma induction, there are striking similarities in the cognitive and emotional status of survivors. Presently, proven effective therapeutics for the treatment of either form of TBI are unavailable. To be able to develop efficacious therapies, studies involving animal models of physical- and blast-TBI are required to identify possible novel or existing medicines that may be of value in the management of clinical events. We examined indices of cognition and anxiety-like behavior and the hippocampal gene transcriptome of mice subjected to both forms of TBI. We identified common behavioral deficits and gene expression regulations, in addition to unique injury-specific forms of gene regulation. Molecular pathways presented a pattern similar to that seen in gene expression. Interestingly, pathways connected to AlzheimerM-bM-^@M-^Ys disease displayed a markedly different form of regulation depending on the type of TBI. While these data highlight similarities in behavioral outcomes after trauma, the divergence in hippocampal transcriptome observed between models suggests that, at the molecular level, the TBIs are quite different. These models may provide tools to help define therapeutic approaches for the treatment of physical- and blast-TBIs. Based upon observations of increasing numbers of personnel displaying TBI related emotional and behavioral changes in militarized zones, the development of efficacious therapies will become a national if not a global priority. Keywords: Physical-traumatic brain injury; Blast-traumatic brain injury; Cognitive dysfunction; Gene expression; Molecular pathway(s); Neurodegeneration; Stem cells; AlzheimerM-bM-^@M-^Ys disease A mild physical-TBI was induced using a concussive head trauma device described previously (Milman et al., 2005; Zohar et al., 2003). Briefly, mice were lightly anesthetized (Isoflurane) and placed under the weight-drop concussive head trauma instrument. The device consisted of a metal tube (inner diameter 13 mm), placed vertically over the mouse head. A metal weight (30 g) was dropped from the top of the tube (80 cm) and struck the skull at the right side temporal area between the corner of the eye and the ear. A sponge supported the head, allowing some antero-posterior motion without any rotational head movement at the moment of the impact. Experimental conditions used to create a mild low-level blast-TBI and the subsequent model characterization, have been described in detail elsewhere (Rubovitch et al., 2011). In brief, mice were anaesthetized with a combination of ketamine (100 mg/kg) and xylazine (10 mg/kg). Once the animals were fully anaesthetized they were placed at a defined distance from a detonation source, in this case 7 meters. Pressure sensors were used to measure the explosion shock wave pressure (PSI) generated by the detonation (Free-Field ICPM-BM-. Blast Pressure Sensor; PCB Piezoelectronics, Depew, NY, USA, Model 137). At 7 meters from the source of the detonation, the animals were exposed to a maximum of a 2.5 PSI (17.2 kPa) pressure shock wave. Immediately after the induction of the injury, mice were placed back in their cages. Once the animals had recovered from the anesthesia, basic neurological assessments were undertaken to identify any acute neurological dysfunction. Only animals exhibiting no evidence of acute neurological damage post injury were subsequently used in further experiments. Sham treated mouse groups were treated identically; however, they were not exposed to physical- or blast-TBI. Mouse hippocampus tissues were randomly selected from the larger library of samples generated from the behavioral experiments and the numbers utilized in the gene expression study were as follows: sham, n = 5: physical-TBI, n = 4; blast-TBI, n = 7.
2013-03-18 | E-GEOD-44625 | biostudies-arrayexpress