A single-cell atlas deconstructs heterogeneity across multiple models in murine traumatic brain injury and identifies novel cell-specific targets

Neuron, Год журнала: 2024, Номер 112(18), С. 3069 - 3088.e4

Опубликована: Июль 16, 2024

Traumatic brain injury (TBI) heterogeneity remains a critical barrier to translating therapies. Identifying final common pathways/molecular signatures that integrate this informs biomarker and therapeutic-target development. We present the first large-scale murine single-cell atlas of transcriptomic response TBI (334,376 cells) across clinically relevant models, sex, region, time as foundational step in molecularly deconstructing heterogeneity. Results were unique cell populations, regions, time, highlighting importance cell-level resolution. identify cell-specific targets previously unrecognized roles for microglial ependymal subtypes. Ependymal-4 was hub neuroinflammatory signaling. A distinct lineage shared features with disease-associated microglia at 24 h, persistent gene-expression changes microglia-4 even 6 months after contusional TBI, contrasting all other types mostly returned naive levels. Regional sexual dimorphism noted. CEREBRI, our searchable (https://shiny.crc.pitt.edu/cerebri/), identifies subtypes/molecular is leverageable platform future efforts diseases overlapping pathophysiology.

Язык: Английский

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cGAS-STING targeting offers novel therapeutic opportunities in neurological diseases

Ageing Research Reviews, Год журнала: 2025, Номер 105, С. 102691 - 102691

Опубликована: Фев. 13, 2025

Язык: Английский

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Cognitive impairment in Chinese traumatic brain injury patients: from challenge to future perspectives

Frontiers in Neuroscience, Год журнала: 2024, Номер 18

Опубликована: Март 11, 2024

Traumatic Brain Injury (TBI) is a prevalent form of neurological damage that may induce varying degrees cognitive dysfunction in patients, consequently impacting their quality life and social functioning. This article provides mini review the epidemiology Chinese TBI patients etiology impairment. It analyzes risk factors impairment, discusses current management strategies for summarizes strengths limitations primary testing tools TBI-related functions. Furthermore, offers prospective analysis future challenges opportunities. Its objective to contribute as reference prevention patients.

Язык: Английский

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Deplete and repeat: microglial CSF1R inhibition and traumatic brain injury

Frontiers in Cellular Neuroscience, Год журнала: 2024, Номер 18

Опубликована: Фев. 21, 2024

Traumatic brain injury (TBI) is a public health burden affecting millions of people. Sustained neuroinflammation after TBI often associated with poor outcome. As result, increased attention has been placed on the role immune cells in post-injury recovery. Microglia are highly dynamic and play key neuroinflammatory response. Therefore, microglia represent malleable target that could substantially influence long-term outcome TBI. This review highlights cell specific pathophysiology. have manipulated via genetic deletion, drug inhibition, pharmacological depletion various pre-clinical models. Notably, colony stimulating factor 1 (CSF1) its receptor (CSF1R) gained much traction recent years as microglia. CSF1R transmembrane tyrosine kinase essential for proliferation, differentiation, survival. Small molecule inhibitors targeting result swift effective rodents. Moreover, discontinuation sufficient repopulation. Attention summarizing studies incorporate inhibition Indeed, affects multiple aspects pathophysiology, including neuroinflammation, oxidative stress, functional recovery measurable astrocytes, peripheral cells, neurons. Taken together, data highlight an important sustaining increasing risk which lends to neuronal damage behavioral deficits chronically Ultimately, insights from critical understanding temporospatial develop mediating pathophysiology

Язык: Английский

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Application and research progress of different frequency tACS in stroke rehabilitation: A systematic review

Brain Research, Год журнала: 2025, Номер 1852, С. 149521 - 149521

Опубликована: Фев. 19, 2025

Язык: Английский

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Novel Insights into Neuroinflammatory Mechanisms in Traumatic Brain Injury: Focus on Pattern Recognition Receptors as Therapeutic Targets

Cytokine & Growth Factor Reviews, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Язык: Английский

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Prophylactic Effects of Betaine on Depression and Anxiety Behaviors in Mice with Dextran Sulfate Sodium-Induced Colitis

Journal of Agricultural and Food Chemistry, Год журнала: 2024, Номер unknown

Опубликована: Сен. 14, 2024

Ulcerative colitis (UC) is a typical type of inflammatory bowl disease, which accompanied by an increased risk depression and anxiety-related psychological symptoms. Betaine naturally derived compound that can function as anti-inflammatory drug neuromodulator. In-depth exploration the potential role betaine in treating UC-related anxiety crucial. This study aimed to elucidate effects on clarify underlying mechanisms. A dextran sulfate sodium (DSS)-induced mice model was established 4% DSS drinking ad libitum for 7 days. The colonic injury measured using hematoxylin-eosin (HE) staining Alcian blue-periodic acid Schiff (AB-PAS) staining. Depression anxiety-like behaviors were separately evaluated forced swimming test (FST), tail suspension (TST), light-dark box (LDBT), open field (OFT). Immunohistochemistry used detect DNA damage neurogenesis hippocampus. Western blotting applied protein levels macrophage polarization colons alteration mitochondrial dysfunction cGAS-STING pathway strongly alleviated mucosal structural disorder mucin secretion reduction promoted M2-macrophage colon DSS-treated mice. In addition, could mitigate depression- mice, reduce dysfunction, inhibit signaling pathway. Our reveals antidepression/anxiety further demonstrates mechanism inhibits block pathway, thereby repairing

Язык: Английский

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The cGAS-STING pathway drives neuroinflammation and neurodegeneration via cellular and molecular mechanisms in neurodegenerative diseases

Neurobiology of Disease, Год журнала: 2024, Номер 202, С. 106710 - 106710

Опубликована: Окт. 28, 2024

Neurodegenerative diseases (NDs) are a type of common chronic progressive disorders characterized by damage to specific cell populations in the nervous system, ultimately leading disability or death. Effective treatments for these still lacking, due limited understanding their pathogeneses, which involve multiple cellular and molecular pathways. The triggering an immune response is feature neurodegenerative disorders. A critical challenge intricate interplay between neuroinflammation, neurodegeneration, responses, not yet fully characterized. In recent years, cyclic GMP-AMP synthase (cGAS)-stimulator interferon gene (STING) pathway, crucial intracellular DNA sensing, has gradually gained attention. However, roles this pathway within types such as cells, glial neuronal its contribution ND pathogenesis, remain elucidated. review, we systematically explore how cGAS-STING signaling links various with related effector pathways under context NDs multifaceted therapeutic directions. We emphasize discovery condition-dependent heterogeneity integral diverse responses potential targets. Additionally, review pathogenic role activation Parkinson's disease, ataxia-telangiectasia, amyotrophic lateral sclerosis. focus on complex bidirectional Alzheimer's Huntington's sclerosis, revealing double-edged nature disease progression. objective elucidate pivotal pathogenesis catalyze new insights facilitating development novel strategies.

Язык: Английский

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Single-cell RNA sequencing in stroke and traumatic brain injury: Current achievements, challenges, and future perspectives on transcriptomic profiling

Journal of Cerebral Blood Flow & Metabolism, Год журнала: 2024, Номер unknown

Опубликована: Дек. 9, 2024

Single-cell RNA sequencing (scRNA-seq) is a high-throughput transcriptomic approach with the power to identify rare cells, discover new cellular subclusters, and describe novel genes. scRNA-seq can simultaneously reveal dynamic shifts in phenotypes heterogeneities subtypes. Since publication of first protocol on 2009, this evolving technology has continued improve, through use cell-specific barcodes, adoption droplet-based systems, development advanced computational methods. Despite induction stress response during tissue dissociation process, remains popular technology, commercially available methods have been applied brain. Recent advances spatial transcriptomics now allow researcher capture positional context transcriptional activity, strengthening our knowledge organization cell-cell interactions spatially intact tissues. A combination data proteomic, metabolomic, or chromatin accessibility promising direction for future research. Herein, we provide an overview workflow, analyses methods, pros cons technology. We also summarize latest achievements stroke acute traumatic brain injury, applications transcriptomics.

Язык: Английский

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Diffuse Traumatic Brain Injury Induced Stimulator of Interferons (STING) Signaling in Microglia Drives Cortical Neuroinflammation, Neuronal Dysfunction, and Impaired Cognition

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Фев. 17, 2025

Neuropsychiatric complications including depression and cognitive impairment develop, persist, worsen in the years after traumatic brain injury (TBI), negatively affecting life lifespan. Inflammatory responses mediated by microglia are associated with transition from acute to chronic neuroinflammation TBI. Moreover, type I interferon (IFN-I) signaling is a key mediator of inflammation during this transition. Thus, purpose study was determine degree which microglia-specific knockout stimulator interferons (STING) influenced TBI-induced neuroinflammation, neuronal dysfunction, impairment. Here, microglial inducible STING (CX₃CR1Cre/ERT2 x STING^fl/fl) mice were created validated (mSTING^-/-). Diffuse (midline fluid percussion) male female increased expression microglia, promoted morphological restructuring, induced robust cortical pathology 7 days post (dpi). These TBI-associated attenuated mSTING^-/- mice. Increased astrogliosis rod-shaped TBI independent mSTING^-/-. dpi, 237 differentially expressed genes (DEG) cortex functionally wildtype (STING^+/+) associated STING, NF- κB, Interferon Alpha 85% Components reduced NeuN expression, lipofuscin, neurofilament light chain plasma dependent on mSTING. tasks (novel object recognition/location, NOR/NOL) at dpi Notably, deficits NOR/NOL unaffected global interferon-α/β receptor 1 (IFNAR1) In final study, RNA profile neurons STING^+/+ assessed single nucleus RNA-sequencing. There TBI-dependent suppression homeostasis reductions CREB signaling, synaptogenesis, oxytocin increases cilium assembly PTEN signaling. Overall, prevented 50% DEGs neurons. Collectively, ablation attenuates IFN-dependent responses, inflammation, pathology,

Язык: Английский

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