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Hippocampal NG2+ pericytes in chronic stressed rodents and depressed patients: a quantitative study.

慢性应激啮齿类动物和抑郁症患者海马 NG2 + 周细胞: 一项定量研究。

  • 影响因子:2.88
  • DOI:10.1080/10253890.2020.1781083
  • 作者列表:"Treccani G","Schlegelmilch AL","Schultz N","Herzog D","Bessa JM","Sotiropoulos I","Muller MB","Wennström M
  • 发表时间:2020-06-17
Abstract

:Objective: The suggested link between major depression disorder (MDD) and blood brain barrier (BBB) alterations supports an impact on the neurovascular unit in this disease condition. Here we investigate how pericytes, a major component in the neurovascular unit, respond to stress, stress hormones, proinflammatory cytokine and depression.Method: Hippocampal sections of chronic unpredictable stressed (CMS) rats, MDD patients and respective controls were immuno-stained against NG2, where the number of NG2+ pericytes in the molecular layer was counted. Proliferation of cultured pericytes after treatment with cortisol and IL-1β was analysed using radioactive labelled thymidine.Findings: The number of NG2+ pericytes was significantly higher in CMS animals than controls. Higher number of NG2+ pericytes was also detected in MDD patients, but the increase did not reach significance. IL-1β, but not cortisol, induced a significant increase in proliferation of cultured pericytes.Conclusion: Our results indicate that exposure to stressful conditions affects the hippocampal pericyte population. These findings add to our knowledge about the impact of stress on the neurovascular unit, which might be relevant for understanding the alterations in BBB found in MDD patients.

摘要

目的: 抑郁症 (MDD) 与血脑屏障 (BBB) 改变之间的联系支持在这种疾病中对神经血管单元的影响。这里我们研究神经血管单元的主要成分周细胞如何对压力、应激激素、促炎细胞因子和抑郁做出反应。方法: 对慢性不可预见性应激 (CMS) 大鼠、 MDD 患者及对照组的海马切片进行 NG2 免疫染色,计数分子层 NG2 + 周细胞数。用放射性标记胸苷分析了用皮质醇和 il-1 β 处理后培养的周细胞的增殖。结果: CMS 动物中 NG2 + 周细胞的数量显著高于对照组。在 MDD 患者中也检测到较高的 NG2 + 周细胞数量,但增加未达到显著性。Il-1 β,而不是皮质醇,诱导了培养周细胞增殖的显著增加。结论: 我们的结果表明,暴露于应激条件会影响海马周细胞群。这些发现增加了我们对压力对神经血管单元影响的了解,这可能与了解 MDD 患者 BBB 的改变有关。

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影响因子:9.56
发表时间:2020-01-24
来源期刊:Molecular psychiatry
DOI:10.1038/s41380-020-0649-0
作者列表:["Li C","Meng F","Garza JC","Liu J","Lei Y","Kirov SA","Guo M","Lu XY"]

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影响因子:5.83
发表时间:2020-01-22
DOI:10.1523/JNEUROSCI.0786-19.2019
作者列表:["Torretta S","Rampino A","Basso M","Pergola G","Di Carlo P","Shin JH","Kleinman JE","Hyde TM","Weinberger DR","Masellis R","Blasi G","Pennuto M","Bertolino A"]

METHODS::Multiple schizophrenia (SCZ) risk loci may be involved in gene co-regulation mechanisms, and analysis of coexpressed gene networks may help to clarify SCZ molecular basis. We have previously identified a dopamine D2 receptor (DRD2) coexpression module enriched for SCZ risk genes and associated with cognitive and neuroimaging phenotypes of SCZ, as well as with response to treatment with antipsychotics. Here we aimed to identify regulatory factors modulating this coexpression module and their relevance to SCZ. We performed motif enrichment analysis to identify transcription factor (TF) binding sites in human promoters of genes coexpressed with DRD2. Then, we measured transcript levels of a group of these genes in primary mouse cortical neurons in basal conditions and upon overexpression and knockdown of predicted TFs. Finally, we analyzed expression levels of these TFs in dorsolateral prefrontal cortex (DLPFC) of SCZ patients. Our in silico analysis revealed enrichment for NURR1 and ERR1 binding sites. In neuronal cultures, the expression of genes either relevant to SCZ risk (Drd2, Gatad2a, Slc28a1, Cnr1) or indexing coexpression in our module (Btg4, Chit1, Osr1, Gpld1) was significantly modified by gain and loss of Nurr1 and Err1. Postmortem DLPFC expression data analysis showed decreased expression levels of NURR1 and ERR1 in patients with SCZ. For NURR1 such decreased expression is associated with treatment with antipsychotics. Our results show that NURR1 and ERR1 modulate the transcription of DRD2 coexpression partners and support the hypothesis that NURR1 is involved in the response to SCZ treatment.SIGNIFICANCE STATEMENT In the present study, we provide in silico and experimental evidence for a role of the TFs NURR1 and ERR1 in modulating the expression pattern of genes coexpressed with DRD2 in human DLPFC. Notably, genetic variations in these genes is associated with SCZ risk and behavioral and neuroimaging phenotypes of the disease, as well as with response to treatment. Furthermore, this study presents novel findings on a possible interplay between D2 receptor-mediated dopamine signaling involved in treatment with antipsychotics and the transcriptional regulation mechanisms exerted by NURR1. Our results suggest that coexpression and co-regulation mechanisms may help to explain some of the complex biology of genetic associations with SCZ.

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影响因子:6.22
发表时间:2020-01-17
DOI:10.1038/s41386-020-0614-2
作者列表:["Chadha R","Meador-Woodruff JH"]

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