Microglial regional heterogeneity and its role in the brain

Molecular Psychiatry, Journal Year: 2019, Volume and Issue: 25(2), P. 351 - 367

Published: Nov. 26, 2019

Abstract Microglia have been recently shown to manifest a very interesting phenotypical heterogeneity across different regions in the mammalian central nervous system (CNS). However, underlying mechanism and functional meaning of this phenomenon are currently unclear. Baseline diversities adult microglia their cell number, cellular subcellular structures, molecular signature as well relevant functions discovered. But recent transcriptomic studies using bulk RNAseq single-cell produced conflicting results on region-specific signatures microglia. It is highly speculative whether such spatial contributes varying sensitivities individual same physiological pathological signals CNS regions, hence underlie relevance for disease development. This review aims thoroughly summarize up-to-date knowledge specific topic provide some insights potential mechanisms, starting from microgliogenesis. Understanding regional context diverse neighboring neurons other glia may an important clue future development innovative therapies neuropsychiatric disorders.

Language: Английский

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Tuning neural circuits and behaviors by microglia in the adult brain

Trends in Neurosciences, Journal Year: 2024, Volume and Issue: 47(3), P. 181 - 194

Published: Jan. 21, 2024

Language: Английский

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The emerging tale of microglia in psychiatric disorders

Neuroscience & Biobehavioral Reviews, Journal Year: 2021, Volume and Issue: 131, P. 1 - 29

Published: Sept. 15, 2021

Language: Английский

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Microglial Inflammatory-Metabolic Pathways and Their Potential Therapeutic Implication in Major Depressive Disorder

Frontiers in Psychiatry, Journal Year: 2022, Volume and Issue: 13

Published: June 16, 2022

Increasing evidence supports the notion that neuroinflammation plays a critical role in etiology of major depressive disorder (MDD), at least subset patients. By virtue their capacity to transform into reactive states response inflammatory insults, microglia, brain’s resident immune cells, play pivotal induction neuroinflammation. Experimental studies have demonstrated ability microglia recognize pathogens or damaged leading activation cytotoxic exacerbates damage brain cells. However, display wide range responses injury and may also promote resolution stages inflammation tissue regeneration. MDD has been associated with chronic priming microglia. Recent suggest altered microglial morphology function, caused either by intense senescence, contribute depression impairments neuroplasticity. In this context, modifying phenotype tuning pathways might important translational relevance harness MDD. Interestingly, it was recently shown different phenotypes are distinct metabolic analysis underlying molecular mechanisms points an instrumental for energy metabolism shaping functions. Here, we review various canonical pro-inflammatory, anti-inflammatory provide new therapeutic opportunities control disorders, strong focus on

Language: Английский

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Attenuation of neuroinflammation reverses Adriamycin-induced cognitive impairments

Acta Neuropathologica Communications, Journal Year: 2019, Volume and Issue: 7(1)

Published: Nov. 21, 2019

Numerous clinical studies have established the debilitating neurocognitive side effects of chemotherapy in treatment breast cancer, often referred as chemobrain. We hypothesize that cognitive impairments are associated with elevated microglial inflammation brain. Thus, either elimination microglia or restoration function could ameliorate dysfunction. Using a rodent model chronic Adriamycin (ADR) treatment, commonly used cancer chemotherapy, we evaluated two strategies to chemobrain: 1) depletion using colony stimulating factor-1 receptor (CSF1R) inhibitor PLX5622 and 2) human induced pluripotent stem cell-derived (iMG)-derived extracellular vesicle (EV) treatment. In strategy 1 mice received ADR once weekly for 4 weeks were then administered CSF1R (PLX5622) starting 72 h post-ADR ADR-treated animals given normal diet exhibited significant behavioral deficits increased activation 4-6 later. PLX5622-treated no ADR-related near complete IBA-1 CD68+ Cytokine RNA sequencing analysis pathways validated these findings. 2, week after last retro-orbital vein injections iMG-EV (once weeks) later, underwent behavior testing. receiving EV showed nearly reductions compared untreated mice. Our data demonstrate elevates CNS is linked dysfunction attenuation neuroinflammation reverses adverse chemotherapy.

Language: Английский

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Glia-Selective Deletion of Complement C1q Prevents Radiation-Induced Cognitive Deficits and Neuroinflammation

Cancer Research, Journal Year: 2020, Volume and Issue: 81(7), P. 1732 - 1744

Published: Dec. 15, 2020

Abstract The adverse neurocognitive sequelae following clinical radiotherapy (RT) for central nervous system (CNS) malignancies are often long-lasting without any recourse. Despite recent progress, the cellular mechanisms mediating RT-induced cognitive deficits (RICD) poorly understood. complement is an immediate sensor of a disturbed inflammatory environment and potent mediator gliosis with range nonimmune functions in CNS, including synaptic pruning, which detrimental if dysregulated. We hypothesize that complement-mediated changes glial cell function significantly contribute to RICD. underlying alterations CNS cascade proteins (C1q, C3), TLR4, colabeling glia (IBA1, GFAP) were examined using gene expression, immunofluorescence, silico modeling approaches adult mouse brain 9 Gy cranial RT. Three-dimensional volumetric quantification showed elevated molecular signatures at short- long-term post-RT times. found significant elevations C1q, C3, TLR4 accompanied by increased astrocytes microglia. To address mechanism activation, neuroinflammation, dysfunction, we used genetic approach—conditional, microglia-selective C1q (Flox) knockdown mice—to determine whether glia-specific, upstream contributes C1q-Flox mice exposed RT no compared irradiated WT mice. Further, protected from microglial activation loss, elevation anaphylatoxin C5a receptor, astrocytic-C3, microglial-TLR4 expression brain. Our findings demonstrate first time microglia-specific RICD involving component, C1q. Significance: Clinically-relevant induces aberrant leading injury. Microglia-selective deletion ameliorates radiation-induced impairments, highlighting potential as novel therapeutic target. See related commentary Korimerla Wahl, p. 1635

Language: Английский

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An emerging role for microglia in stress‐effects on memory

European Journal of Neuroscience, Journal Year: 2021, Volume and Issue: 55(9-10), P. 2491 - 2518

Published: March 16, 2021

Stressful experiences evoke, among others, a rapid increase in brain (nor)epinephrine (NE) levels and slower glucocorticoid hormones (GCs) the brain. Microglia are key regulators of neuronal function contain receptors for NE GCs. These cells may therefore potentially be involved modulating stress effects on learning memory. In this review, we discuss that induces (1) an microglial numbers as well (2) shift toward pro-inflammatory profile. microglia have (3) impaired crosstalk with neurons (4) disrupted glutamate signaling. Moreover, immune responses after (5) alter kynurenine pathway through metabolites impair glutamatergic transmission. All these could impairments memory synaptic plasticity caused by (prolonged) stress, implicating potential novel target stress-related impairments.

Language: Английский

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Microglia contribute to social behavioral adaptation to chronic stress

Glia, Journal Year: 2021, Volume and Issue: 69(10), P. 2459 - 2473

Published: June 19, 2021

Microglial activation has been regarded mainly as an exacerbator of stress response, a common symptom in psychiatric disorders. This study aimed to determine whether microglia contribute adaptive response the brain and behavior toward using mild model - chronic restraint (CRS) with wild type (WT) CX3CR1-GFP (CX3CR1[G]) mice human schizophrenia patients' data. Our results revealed that CRS did not exacerbate anxiety depressive-like behaviors, but instead strengthened social dominance short-term spatial learning WT mice. Compared CX3CR1(+/G) heterozygous mice, CX3CR1(G/G) homozygotes were subordinate interaction before after CRS. Microglia underwent series region-specific changes involving their phagocytosis presynaptic vesicular glutamate transporter 2 protein, contacts synaptic elements, CD206+ microglial proportion, gene expressions such Cx3cr1. By contrast, CX3CR1-deficient showed decreased while increased MHCII+ subpopulations hypo-ramification hippocampus, well sensitized polarization morphological change Furthermore, abundancy was positively correlated dominancy ramification Moreover, CX3CR1 mRNA level reduced CRS-treated mouse brains smaller interactome other genes dorsal-lateral prefrontal cortices patients schizophrenia. findings overall highlight its receptor key contributors regulation behavioral adaptation stress.

Language: Английский

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Microglial activation in the medial prefrontal cortex after remote fear recall participates in the regulation of auditory fear extinction

European Journal of Pharmacology, Journal Year: 2024, Volume and Issue: 978, P. 176759 - 176759

Published: June 18, 2024

Language: Английский

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Chemogenetic activation of microglial Gi signaling decreases microglial surveillance and impairs neuronal synchronization

Science Advances, Journal Year: 2025, Volume and Issue: 11(9)

Published: Feb. 28, 2025

Microglia actively survey the brain and dynamically interact with neurons to maintain homeostasis. Microglial Gi protein–coupled receptors (Gi-GPCRs) play a critical role in microglia-neuron communications. However, impact of temporally activating microglial signaling on dynamics neuronal activity homeostatic remains largely unknown. In this study, we used Gi-based designer exclusively activated by drugs (Gi-DREADD) selectively modulate pathway. By integrating chemogenetic approach vivo two-photon imaging, observed that exogenous activation transiently inhibited process dynamics, reduced activity, impaired synchronization. These altered functions were associated decrease interactions between microglia neuron somata. Together, study demonstrates acute, regulates circuit function, offering potential pharmacological target for neuromodulation through microglia.

Language: Английский

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