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Fluoxetine ameliorates depressive symptoms by regulating lncRNA expression in the mouse hippocampus

Chuan-Ling Zhang Yi-Jia Li Shuang Lu Ting Zhang Rui Xiao Huai-Rong Luo

Chuan-Ling Zhang, Yi-Jia Li, Shuang Lu, Ting Zhang, Rui Xiao, Huai-Rong Luo. Fluoxetine ameliorates depressive symptoms by regulating lncRNA expression in the mouse hippocampus. Zoological Research, 2021, 42(1): 28-42. doi: 10.24272/j.issn.2095-8137.2020.294
Citation: Chuan-Ling Zhang, Yi-Jia Li, Shuang Lu, Ting Zhang, Rui Xiao, Huai-Rong Luo. Fluoxetine ameliorates depressive symptoms by regulating lncRNA expression in the mouse hippocampus. Zoological Research, 2021, 42(1): 28-42. doi: 10.24272/j.issn.2095-8137.2020.294

氟西汀通过调节小鼠海马组织中长链非编码RNA的表达来改善抑郁症状

doi: 10.24272/j.issn.2095-8137.2020.294

Fluoxetine ameliorates depressive symptoms by regulating lncRNA expression in the mouse hippocampus

Funds: This work was supported by the Scientific Research Projects of Universities in Inner Mongolia Autonomous Region (NJZY111) and Natural Scientific Research Projects of Inner Mongolia Autonomous Region (2020MS03060)
More Information
  • 摘要: 抑郁症是一种与衰老相关的精神障碍疾病,可导致患者发病率和死亡率的增加。目前临床上具有显著抑郁症状的老年抑郁症患者的发病率也在逐年增加。最近的研究表明,在抑郁症发病期间,大脑中长链非编码RNA(lncRNA)表达的改变会影响神经发育,并对抑郁症具有调节功能。但是大多数lncRNA的功能尚未被研究。在本研究中,我们利用慢性不可预知温和应激(CUMS)抑郁小鼠模型,用抗抑郁药氟西汀进行6周干预后,分析了在抑郁样行为小鼠模型以及氟西汀干预后的CUMS小鼠海马组织中lncRNA的表达水平的差异。结果发现,与正常小鼠相比,CUMS诱导的小鼠海马组织中共有282个lncRNA差异表达,其中134个lncRNA在CUMS抑郁样小鼠中表达上调,148个lncRNA在CUMS抑郁样小鼠中表达下调)(P<0.05)。在氟西汀干预后,与CUMS抑郁样小鼠相比,我们发现370个lncRNA呈现差异表达。我们进一步对这些差异表达的lncRNA进行GO功能分析发现,差异表达的lncRNA与蛋白结合,氧结合和转运活性之间存在关联。通过基因和基因组百科全书(KEGG)信号通路分析表明,失调的lncRNA可能参与了炎症反应途径。氟西汀可通过调节海马中lncRNA的表达来有效缓解CUMS诱导的小鼠抑郁症状。本文的发现为老年抑郁症发生的潜在机制提供了有价值的见解。
  • Figure  1.  Behavioral assessments and the schematic diagram of the indcution process of depressive-like hehaviors in mice

    In the SPT assessment (A), mice exposed to CUMS displayed decreased sucrose preference when compared to NOR mice; these effects were ameliorated after fluoxetine treatment. In the FST (B) and TST (C) assessments, immobility time was longer in the CUMS group than in the FLU and the NOR groups. * P-value<0.001. D: Schematic diagram showing the induction process of depressive-like behaviors in mice. Changes in the expression of 5-HT (E) and BDNF (F) in samples from CUMS, FLU, and NOR groups (n=4 per group). A significant decrease in 5-HT concentration was observed in the CUMS group compared to the NOR group. 5-HT concentration was increased after fluoxetine treatment (E). BDNF concentration increased after fluoxetine treatment in the FLU group compared to the CUMS group, in which it was decreased (F). Data indicate mean±SEM. *P-value<0.05. NOR: Normal control group; CUMS: CUMS induced depression group; FLU: Fluoxetine-treated group; SPT: Sucrose preference test; FST: Forced swim test; TST: Tail suspension test.

    Figure  2.  Transcriptome-wide identification and characterization of lncRNAs

    A: A total of 8 281 lncRNAs were identified using the CNCI, CPC2, Pfam Scan, and PhyloCSF tools. B: Identified lncRNAs were mainly classified as lincRNA, anti-sense lncRNA, and intronic lncRNA. C: Conservation comparison of the identified lncRNAs, mRNAs, and predicted novel lncRNAs. D, E: The exon number (D) and length (E) of lncRNAs identified were comparatively shorter than mRNA transcripts. F: Length of ORF in most identified lncRNAs was less than 300 bp.

    Figure  3.  Differentially expressed lncRNAs (DElnRNAs) comparison between CUMS vs. NOR groups and FLU vs. CUMS groups

    A, B: Volcano map of 282 and 370 differentially regulated lncRNAs based on a group-wise comparison of CUMS vs. NOR groups (A), and FLU vs. CUMS groups (B), respectively (P-value<0.05). C: Venn map showing 95 commonly expressed lncRNAs identified in a comparison between FLU vs. CUMS groups and CUMS vs. NOR groups (P-value<0.05). D: Three lncRNAs (LNC_004212, LNC_001203, and ENSMUST00000148687.1) with contrasting expression patterns between FLU and CUMS groups vs. CUMS and NOR groups based on RNA-seq analysis (Q-value<0.05).

    Figure  4.  Chromosomal distribution and hierarchical clustering analysis of DElnRNAs in CUMS, FLU and NOR mice

    A: Distribution of DElnRNAs on all chromosomes in CUMS vs. NOR groups. Among the 282 DElnRNAs, the 134 up-regulated and 148 down-regulated lncRNAs were enriched on chromosome 1, 2, 7, 9, 10, 11 and 2, 4, 5, 8, 10, 12, 15, respectively. B: Distribution of DElnRNAs on all chromosomes in FLU vs. CUMS groups. After fluoxetine treatment, the 236 up-regulated and 134 down-regulated lncRNAs mapped to chromosomes 4, 6, 10, 11, 17 and 2, 7, 9, 11, 17, respectively. P-value<0.05. C: Hierarchical clustering showing that lncRNAs differentially expressed (P-value<0.05) in FLU vs. CUMS and CUMS vs. NOR groups were clustered into four main categories. DElnRNAs in the same category may participate in similar processes resulting in depressive-like behaviors. Samples from the same group were clustered together, indicating minimal variation in samples from the same group.

    Figure  5.  GO analysis of putative target genes

    A: GO analysis of mRNAs co-localized with DElnRNAs between FLU and CUMS mice. A total of 154 co-localized differentially expressed transcripts were found to be enriched with the GO terms of organismal development, intracellular part, organelle, and macromolecular complex binding when comparing FLU and CUMS groups. B: GO analysis of mRNAs co-expressed with DElnRNAs between FLU and CUMS mice. A total of 679 co-expressed transcripts indicated an association with the GO terms of response to stimulus, intracellular part, organelle or cytoplasm of the cell, and protein binding. C, D: GO annotation of mRNA targets co-localized with 48 DElnRNAs which were up-regulated in CUMS-induced mice compared to NOR mice, and down-regulated in FLU treated compared to CUMS mice. These 48 lncRNA transcripts were predicted to be associated with oxygen binding and transport activity. E: Validation of lncRNA expressions in the hippocampus of CUMS, FLU, and NOR mice by qRT-PCR. Six of eight randomly selected lncRNAs were up-regulated, whereas Tmem134 and LNC_004971 were down-regulated in CUMS mice compared to NOR controls. Up-regulated lncRNAs in CUMS mice compared to NOR controls were down-regulated after fluoxetine treatment, thereby validating the RNA-seq results.

    Table  1.   qRT-PCR primers used for validation of lncRNA expression identified from RNA-seq

    lncRNA transcript IDTranscript symbol nameForward primer sequence (5'–3')Reverse primer sequence (5'–3')PCR product size (bp)
    LNC_007274CTTGGTCAGAAGCATCTGGAAAGAACAGGCTTCGAGAACG273
    ENSMUST00000148687.1Gm16638ATCCAGCAGACAGCACTATGGTTGCCTCTGTGTTCAGAAG278
    LNC_001203CACAGTTGCTTCTAAGCCAGATACAGAGAGCGCAGCATTC259
    LNC_004971TGGTGACATTCTTCAGCTCCATTGCAGAAGAGGCCGATAG145
    ENSMUST00000139987.8Tmem134GATCTTCATCTACTGCGCTGCAGGTGTAGGTTGGAGGAAT159
    ENSMUST00000182520.1Gm26917AATGGTGCTACCGGTCATTCACACCTCTCTTATCCGCTCT194
    ENSMUST00000152663.74933431E20RikGACTCAGATCCATCCGTTCACAGTGTCTGGACCTGTTCAT280
    ENSMUST00000174808.1Malat1CCTTCCTGTGTGGCAAGAATCTGCAAGCACAACTTGAGGT223
    –: Not available.
    下载: 导出CSV

    Table  2.   DElnRNAs between CUMS-induced mice and normal controls (adjusted P-value <0.05)

    LncRNA transcript_idCUMS/NOR fold change (log2 ratio)P-valueQ-value
    LNC_001649–13.699 28.93E–050.029 085
    LNC_002578–13.348 50.0001020.031 665
    LNC_007352–10.429 33.50E–050.014 861
    LNC_001657–9.480 776.31E–050.022 996
    LNC_007186–8.750 248.35E–070.000 832
    LNC_004212–8.231 643.01E–060.002 228
    LNC_003004–7.265 230.000180.045 952
    LNC_002630–7.001 840.0001740.044 864
    LNC_003171–5.972 240.0001180.034 934
    LNC_0018713.741 1925.21E–050.020 057
    LNC_0025765.643 556.22E–060.004 041
    LNC_0055057.062 690.0001960.048 071
    LNC_0006487.296 8179.84E–050.030 782
    LNC_0020567.889 7651.61E–050.008 33
    ENSMUST00000139987.87.965 8730.0001050.032 184
    LNC_0012038.904 7713.63E–050.015 174
    ENSMUST00000148687.18.997 0711.36E–050.007 63
    LNC_0036999.458 8575.65E–050.021 329
    LNC_00716410.498 721.48E–050.007 939
    下载: 导出CSV

    Table  3.   DELnRNAs between fluoxetine-treated CUMS-induced mice and CUMS-induced mice (adjusted P-value <0.05)

    LncRNA transcript_idFLU/CUMS fold change (log2 ratio)P-valueQ-value
    LNC_000804–12.589 27.49E–162.95E–12
    LNC_004168–11.758 12.41E–125.29E–09
    LNC_007274–10.935 34.54E–060.001 971
    LNC_005854–10.426 81.12E–050.003 987
    ENSMUST00000148687.1–9.016 461.63E–050.005 382
    LNC_004971–8.843 160.000 2040.036 612
    LNC_004518–7.637 877.27E–050.017 453
    LNC_001203–7.069 030.000 1510.029 595
    LNC_0011383.050 8373.00E–083.39E–05
    LNC_0043473.307 2263.81E–060.001 737
    ENSMUST00000182520.15.833 6581.36E–232.54E–19
    LNC_0072416.265 0494.08E–050.011 235
    LNC_0031267.047 6280.000 2640.043 714
    LNC_0021867.188 6450.000 1820.034 032
    LNC_0038227.450 2470.000 1150.02 4392
    LNC_0073587.570 9220.000 1330.027 026
    LNC_0042127.790 2584.21E–050.011 393
    LNC_0038218.000 8361.37E–050.004 665
    LNC_0008728.030 347.94E–060.00 313
    LNC_0013928.045 1960.000 210.037 484
    LNC_0011058.478 2543.56E–117.19E–08
    LNC_0002388.580 2480.000 3090.048 759
    LNC_0029418.760 410.000 2510.042 275
    LNC_0075369.109 9740.000 1960.035 421
    ENSMUST00000123998.110.423 951.09E–050.003 939
    LNC_00302311.197 152.82E–060.001 406
    LNC_00080613.241 014.17E–050.011 379
    ENSMUST00000174808.116.987 893.93E–050.010 935
    下载: 导出CSV
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  • 收稿日期:  2020-11-25
  • 录用日期:  2021-01-06
  • 网络出版日期:  2021-01-08
  • 刊出日期:  2021-01-18

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