Sex-Specific Microglial Activation and SARS-CoV-2 Receptor Expression Induced by Chronic Unpredictable Stress

Liu, Yan; Mohan, J.; Chithanathan, Keerthana; Zharkovsky, Alexander; Tian, Li

doi:10.3389/fncel.2021.750373

Cited by 13 publications

(9 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is noteworthy that MCHII + -microglia were decreased in mAb102 group, indicating a neuroprotective role of this subgroup of microglia. Aligned with this, our recent study found that CUS increased hippocampal MCHII + -microglia in female mice that were more resilient to stress-induced anxiety as compared to male mice ( 32 ). Additionally, PLXNB2 is a functional receptor for ANG that promotes angiogenesis and neurite outgrowth ( 49 ), sequelae that microglia closely monitor as well ( 50 ).…”

Section: Discussionsupporting

confidence: 61%

See 1 more Smart Citation

Glial receptor PLXNB2 regulates schizophrenia-related stress perception via the amygdala

Xuan

Liu

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

Stress is a trigger for the development of psychiatric disorders. However, how stress trait differs in schizophrenia patients is still unclear. Stress also induces and exacerbates immune activation in psychiatric disorders. Plexins (Plxn) and its ligands semaphorins (Sema) are important cellular receptors with plural functions in both the brain and the immune system. Recently, the role of Plxn/Sema in regulation of neuroinflammation was also noticed. Here, when investigating immune mechanisms underlying stress susceptibility in schizophrenia, we discovered the role of Plxnb2 in stress response. Patients of first-episode schizophrenia (FES) with high stress (FES-hs, n=51) and low stress (FES-ls, n=50) perception and healthy controls (HCs) (n=49) were first recruited for neuroimaging and blood bulk RNA sequencing (RNA-seq). A mouse model of chronic unpredictable stress (CUS) and intra-amygdaloid functional blocking of Plxnb2 were further explored to depict target gene functions. Compared to HCs, FES-hs patients had bigger caudate and thalamus (FDR=0.02&0.001, respectively) whereas FES-ls patients had smaller amygdala (FDR=0.002). Blood RNA-seq showed differentially expressed PLXNB2 and its ligands among patient groups and HCs (FDR<0.05~0.01). Amygdaloid size and PLXNB2 level were both negatively correlated with stress perception (p<0.01&0.05, respectively), which fully mediated the amygdaloid positive association with PLXNB2 expression (β=0.9318, 95% CI: 0.058~1.886) in FES-hs patients. In mice, Plxnb2 was enriched in astrocytes and microglia and CUS reduced its expression in astrocytes (p<0.05). Inhibition of amygdaloid Plxnb2 by its functional blocking monoclonal antibody (mAb)-102 induced mice anxiety (p<0.05), amygdaloid enlargement (p<0.05), and microglial ramification (p<0.001) compared to saline. These data suggest that PLXNB2 regulates amygdala-dependent stress responses.

show abstract

Section: Discussionsupporting

confidence: 61%

“…Mice ( n =7+7 in both CUS and microinjection) were sacrificed with CO 2 . Tissues were gently homogenized through 70µm cell strainers (#352350, BD Biosciences) on ice as we described previously ( 24 , 32 ). Homogenates were blocked in PBS+10% rat serum for 1h with gentle rotation at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Glial receptor PLXNB2 regulates schizophrenia-related stress perception via the amygdala

Xuan

Liu

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…OFT was used to assess anxiety and locomotion was performed according to [34]. Mice were placed in an experimental room for about 1 h before starting the experiment for their habituation.…”

Section: Open Field Test (Oft)mentioning

confidence: 99%

Enhanced Cognition and Neurogenesis in miR-146b Deficient Mice

Chithanathan

Somelar

Jürgenson

et al. 2022

Cells

Self Cite

View full text Add to dashboard Cite

The miR-146 family consists of two microRNAs (miRNAs), miR-146a and miR-146b, which are both known to suppress a variety of immune responses. Here in this study, we show that miR-146b is abundantly expressed in neuronal cells, while miR-146a is mainly expressed in microglia and astroglia of adult mice. Accordingly, miR-146b deficient (Mir146b-/-) mice exhibited anxiety-like behaviors and enhanced cognition. Characterization of cellular composition of Mir146b-/- mice using flow cytometry revealed an increased number of neurons and a decreased abundancy of astroglia in the hippocampus and frontal cortex, whereas microglia abundancy remained unchanged. Immunohistochemistry showed a higher density of neurons in the frontal cortex of Mir146b-/- mice, enhanced hippocampal neurogenesis as evidenced by an increased proliferation, and survival of newly generated cells with enhanced maturation into neuronal phenotype. No microglial activation or signs of neuroinflammation were observed in Mir146b-/- mice. Further analysis demonstrated that miR-146b deficiency is associated with elevated expression of glial cell line-derived neurotrophic factor (Gdnf) mRNA in the hippocampus, which might be at least in part responsible for the observed neuronal expansion and the behavioral phenotype. This hypothesis is partially supported by the positive correlation between performance of mice in the object recognition test and Gdnf mRNA expression in Mir146b-/- mice. Together, these results show the distinct function of miR-146b in controlling behaviors and provide new insights in understanding cell-specific function of miR-146b in the neuronal and astroglial organization of the mouse brain.

show abstract

“…After a week (wk) of transfer adaptation, mice were randomly assigned into 4 groups: Control (Ctr)-Vehicle (Veh) (n = 9), CUS-Veh (n = 9), Ctr-CSF1Ri (n = 10), and CUS-CSF1Ri (n = 10), and subject to CUS/Ctr and CSF1Ri (PLX3397)/Veh treatments. CUS procedure was previously described [42]. PLX3397 (HY-16749/CS-4256, MedChemExpress) was dissolved in DMSO (D8418, Sigma-Aldrich) and freshly diluted with corn oil (#8267, Sigma-Aldrich).…”

Section: Mri Acquisition and Processingmentioning

confidence: 99%

CSF1R Contributes to Vascular Association of Microglia and Stress Regulation in Schizophrenia

Tian

Liu²,

Li³

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Whether and how microglia contribute to stress and anxiety in schizophrenia are not well established. We hypothesized that microglial colony stimulating factor 1 receptor (CSF1R) regulates stress susceptibility in schizophrenia via the hippocampus and associated cortical regions. A cohort of first-episode schizophrenia (FES) patients (n=51) and age- and sex-paired healthy controls (HCs) (n=46) were first recruited. Compared to HCs, FES patients showed higher scores of perceived stress scale (PSS, p<0.01), lower levels of CSF1R mRNA (Log2FC=-0.195, FDR=0.003) and protein (18.31±0.95 vs. 20.49±0.90 µg/ml, p<0.05) in the blood, and smaller volumes of the superiorfrontal gyrus (39.13±0.64 vs. 40.80±0.76 cm3, FDR<0.05) and parahippocampal gyrus (3.51±0.048 vs. 3.72±0.058 cm3, FDR<0.05). CSF1R facilitated the negative superiorfrontal gyral association with PSS (β=6.109, 95% CI: 1.642~10.578, p<0.01) in HCs but not FES patients. CSF1R-associated gene network contributed to brain development. We further studied a chronic unpredictable stress (CUS) mouse model combined with a CSF1R inhibitor (CSF1Ri). Both CUS and CSF1Ri enhanced anxiety in mice (both p<0.001). RNA-seq revealed downregulation of genes for cell adhesion and angiogenesis after CUS-CSF1Ri treatment. Immunostaining showed downregulation of CD31 and preferential loss of vessel-associated IBA1+-microglia induced by CUS or CSF1Ri (p<0.05). Oligodendrocyte precursor cells were however increased after CUS-CSF1Ri treatment (p<0.01). These results suggest that microglial CSF1R showed a protective effect on stress and anxiety in FES patients and CUS mice via contribution to angiogenesis.

show abstract

Sex-Specific Microglial Activation and SARS-CoV-2 Receptor Expression Induced by Chronic Unpredictable Stress

Cited by 13 publications

References 63 publications

Glial receptor PLXNB2 regulates schizophrenia-related stress perception via the amygdala

Glial receptor PLXNB2 regulates schizophrenia-related stress perception via the amygdala

Enhanced Cognition and Neurogenesis in miR-146b Deficient Mice

CSF1R Contributes to Vascular Association of Microglia and Stress Regulation in Schizophrenia

Contact Info

Product

Resources

About