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MicroRNA-204-5p reduction in rat hippocampus contributes to stress-induced pathology via targeting RGS12 signaling pathway

Lan, Tian, Li, Ye, Fan, Cuiqin, Wang, Liyan, Wang, Wenjing, Chen, Shihong, Yu, Shu Yan·2021·Journal of Neuroinflammation
DOI 10.1186/s12974-021-02299-5PMC PMC8532383
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Abstract

Background: Neuroinflammation occupies a pivotal position in the pathogenesis of most nervous system diseases, including depression. However, the underlying molecular mechanisms of neuroinflammation associated with neuronal injury in depression remain largely uncharacterized. Therefore, identifying potential molecular mechanisms and therapeutic targets would serve to better understand the progression of this condition. Methods: Chronic unpredictable stress (CUS) was used to induce depression-like behaviors in rats. RNA-sequencing was used to detect the differentially expressed microRNAs. Stereotactic injection of AAV virus to overexpress or knockdown the miR-204-5p. The oxidative markers and inflammatory related proteins were verified by immunoblotting or immunofluorescence assay. The oxidative stress enzyme and products were verified using enzyme-linked assay kit. Electron microscopy analysis was used to observe the synapse and ultrastructural pathology. Finally, electrophysiological recording was used to analyze the synaptic transmission. Results: Here, we found that the expression of miR-204-5p within the hippocampal dentate gyrus (DG) region of rats was significantly down-regulated after chronic unpredicted stress (CUS), accompanied with the oxidative stress-induced neuronal damage within DG region of these rats. In contrast, overexpression of miR-204-5p within the DG region of CUS rats alleviated oxidative stress and neuroinflammation by directly targeting the regulator of G protein signaling 12 (RGS12), effects which were accompanied with amelioration of depressive-like behaviors in these CUS rats. In addition, down-regulation of miR-204-5p induced neuronal deterioration in DG regions and depressive-like behaviors in rats. Conclusion: Taken together, these results suggest that miR-204-5p plays a key role in regulating oxidative stress damage in CUS-induced pathological processes of depression. Such findings provide evidence of the involvement of miR-204-5p in mechanisms underlying oxidative stress associated with depressive phenotype. Graphical Abstract:

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Fig. 1 Oxidative damage as observed in the hippocampal DG region and vmPFC of CUS rats. A Behavioral responses of FST and SPT in control rats and CUS model rats (N = 50 per group). B Activity of antioxidant enzymes SOD and T-AOC. Contents of MDA and LDH were analyzed and levels were normalized to total protein content (N = 5–6 per group). C Representative western blot images showing relative protein levels NOX1 and NOX4 (N = 6 per group). D Q-PCR analysis of NOX1 and NOX4 mRNA levels of each group. Band intensities were normalized to GAPDH (N = 6 per group). E Representative images of DHE staining (red) within the DG area from each group of rats following ROS analysis (N = 6 per group). Nuclei (blue) are stained with DAPI. Scale bar is 50 μm. F ROS relative intensity analysis after DHE staining in each group *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, vs Control group. Data are presented as means ± SEMs. Student t-tests were employed for comparisons between the two groups
Fig. 1 Oxidative damage as observed in the hippocampal DG region and vmPFC of CUS rats. A Behavioral responses of FST and SPT in control rats and CUS model rats (N = 50 per group). B Activity of antioxidant enzymes SOD and T-AOC. Contents of MDA and LDH were analyzed and levels were normalized to total protein content (N = 5–6 per group). C Representative western blot images showing relative protein levels NOX1 and NOX4 (N = 6 per group). D Q-PCR analysis of NOX1 and NOX4 mRNA levels of each group. Band intensities were normalized to GAPDH (N = 6 per group). E Representative images of DHE staining (red) within the DG area from each group of rats following ROS analysis (N = 6 per group). Nuclei (blue) are stained with DAPI. Scale bar is 50 μm. F ROS relative intensity analysis after DHE staining in each group *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, vs Control group. Data are presented as means ± SEMs. Student t-tests were employed for comparisons between the two groupsCC BY · PubMed Central
Fig. 2 MiR-204-5p is reduced in the hippocampal DG region of CUS rats. A Heat map of differentially expressed miRNAs in hippocampal DG regions. B Relative expression levels of miR-204-5p, miR-1298, miR-143-3p and miR-34c-5p in the DG region (N = 7–8 per group). **P < 0.01, ****P < 0.0001, vs Control group. C Bar graphs represent magnitudes of significant correlations for miR-204-5p mediated signaling pathways as indicated by respective P-values (− log10 scaled). D Bioinformatical prediction of miR-204-5p target genes. E Predicted putative seed-matching sites between miR-204-5p and RGS12. F Luciferase reporter assay results as performed on 293Tcells to detect relative luciferase activities of WT and MUT RGS12 reporters (N = 3/group). **P < 0.01 vs WT + NC. &P < 0.05 vs WT + rno-miR-204-5p. Data are presented as means ± SEMs. Student t-tests were employed for comparisons between the two groups. One-way ANOVA followed by Tukey’s post-hoc test was used for multiple comparisons involving > 2 groups
Fig. 2 MiR-204-5p is reduced in the hippocampal DG region of CUS rats. A Heat map of differentially expressed miRNAs in hippocampal DG regions. B Relative expression levels of miR-204-5p, miR-1298, miR-143-3p and miR-34c-5p in the DG region (N = 7–8 per group). **P < 0.01, ****P < 0.0001, vs Control group. C Bar graphs represent magnitudes of significant correlations for miR-204-5p mediated signaling pathways as indicated by respective P-values (− log10 scaled). D Bioinformatical prediction of miR-204-5p target genes. E Predicted putative seed-matching sites between miR-204-5p and RGS12. F Luciferase reporter assay results as performed on 293Tcells to detect relative luciferase activities of WT and MUT RGS12 reporters (N = 3/group). **P < 0.01 vs WT + NC. &P < 0.05 vs WT + rno-miR-204-5p. Data are presented as means ± SEMs. Student t-tests were employed for comparisons between the two groups. One-way ANOVA followed by Tukey’s post-hoc test was used for multiple comparisons involving > 2 groupsCC BY · PubMed Central
Fig. 3 Effects of changes in miR-204-5p expression within the hippocampal DG region of normal and CUS rats. A Schematics of AAV vectors engineered to overexpress miR-204-5p, knock-down miR-204-5p and their corresponding controls. B Experimental paradigm for determining behavioral responses of rats infected with the virus. C Illustration of AAV viral infusion into the DG region. Scale bar is 1 mm. D The infection efficiency of AAV-miR-204-5p sponge and AAV-miR-204. Expression level of miR-204-5p in the DG region infected with AAV-204-5p or AAV-204-5p sponge (N = 10 per group). Behavioral responses in the (E) FST (N = 20 per group), (F) SPT (N = 20 per group) and (G) MWM of rats expressing various viral constructs within the DG region (N = 6 per group). *P < 0.05, **P < 0.01 ***P < 0.001, ****P < 0.0001, control + AAV-control vs control + AAV-miR-204-5p sponge; &P < 0.05, &&P < 0.01, &&&P < 0.001, &&&&P < 0.0001, CUS + AAV-control vs CUS + AAV-miR-204-5p. Data are presented as means ± SEMs. Student t-tests were employed for comparisons between the two groups. One-way ANOVA followed by Tukey’s post-hoc test was used for D. Two-way ANOVA was used for E–F
Fig. 3 Effects of changes in miR-204-5p expression within the hippocampal DG region of normal and CUS rats. A Schematics of AAV vectors engineered to overexpress miR-204-5p, knock-down miR-204-5p and their corresponding controls. B Experimental paradigm for determining behavioral responses of rats infected with the virus. C Illustration of AAV viral infusion into the DG region. Scale bar is 1 mm. D The infection efficiency of AAV-miR-204-5p sponge and AAV-miR-204. Expression level of miR-204-5p in the DG region infected with AAV-204-5p or AAV-204-5p sponge (N = 10 per group). Behavioral responses in the (E) FST (N = 20 per group), (F) SPT (N = 20 per group) and (G) MWM of rats expressing various viral constructs within the DG region (N = 6 per group). *P < 0.05, **P < 0.01 ***P < 0.001, ****P < 0.0001, control + AAV-control vs control + AAV-miR-204-5p sponge; &P < 0.05, &&P < 0.01, &&&P < 0.001, &&&&P < 0.0001, CUS + AAV-control vs CUS + AAV-miR-204-5p. Data are presented as means ± SEMs. Student t-tests were employed for comparisons between the two groups. One-way ANOVA followed by Tukey’s post-hoc test was used for D. Two-way ANOVA was used for E–FCC BY · PubMed Central
Fig. 4 MiR-204-5p knock-down within the hippocampal DG region results in neuronal inflammation and oxidative stress in normal rats. A Representative confocal microscopic images showing expressions of 4-HNE in the DG region after AAV-miR-204-5p sponge infusion (N = 6 per group). Scale bar is 50 μm. B Representative images of Mito-Sox staining (red). Nuclei (blue) are stained with DAPI. Neurons (green) are stained with Anti-NeuN. Scale bar is 50 μm. (N = 6 per group). C Representative images of 8-oHdG staining (red). Scale bar is 50 μm. (N = 6 per group) D Immunofluorescent staining of Iba1 positive microglial cells within the DG region. Scale bar is 50 μm. (N = 6 per group) E Western bolt assays of protein expression levels of NOX1 and NOX4 within the DG region (N = 6 per group). F Q-PCR assays of mRNA expression levels of IL1β, TNF-α and IFN-γ within the DG region. Band intensities were normalized to GAPDH (N = 6 per group). **P < 0.01 ***P < 0.001, ****P < 0.0001, control + AAV-control vs control + AAV-miR-204-5p sponge. Data are presented as means ± SEMs. Student t-tests were employed for comparisons between the two groups
Fig. 4 MiR-204-5p knock-down within the hippocampal DG region results in neuronal inflammation and oxidative stress in normal rats. A Representative confocal microscopic images showing expressions of 4-HNE in the DG region after AAV-miR-204-5p sponge infusion (N = 6 per group). Scale bar is 50 μm. B Representative images of Mito-Sox staining (red). Nuclei (blue) are stained with DAPI. Neurons (green) are stained with Anti-NeuN. Scale bar is 50 μm. (N = 6 per group). C Representative images of 8-oHdG staining (red). Scale bar is 50 μm. (N = 6 per group) D Immunofluorescent staining of Iba1 positive microglial cells within the DG region. Scale bar is 50 μm. (N = 6 per group) E Western bolt assays of protein expression levels of NOX1 and NOX4 within the DG region (N = 6 per group). F Q-PCR assays of mRNA expression levels of IL1β, TNF-α and IFN-γ within the DG region. Band intensities were normalized to GAPDH (N = 6 per group). **P < 0.01 ***P < 0.001, ****P < 0.0001, control + AAV-control vs control + AAV-miR-204-5p sponge. Data are presented as means ± SEMs. Student t-tests were employed for comparisons between the two groupsCC BY · PubMed Central
Fig. 5 MiR-204-5p overexpression within the hippocampal DG region alleviates neuronal inflammation and oxidative stress in CUS rats. A Representative confocal microscopic images showing expressions of 4-HNE in the DG region after AAV-miR-204-5p infusion (N = 6 per group). Scale bar is 50 μm. B Representative images of Mito-Sox staining (red). Nuclei (blue) are stained with DAPI. Neurons (green) are stained with Anti-NeuN. Scale bar is 50 μm. (N = 6 per group) C Representative confocal microscopic images of immunostainings for 8-oHdG in the DG region. Scale bar = 50 μm. (N = 6 per group) D Immunofluorescent staining of Iba1 positive microglial cells within the DG region. Scale bar is 50 μm. (N = 6 per group) E Western bolt assays of protein expression levels of NOX1 and NOX4 within the DG region (N = 6 per group). F Q-PCR showing mRNA levels of pro-inflammatory cytokines, Band intensities were normalized to GAPDH. N = 6 per group, ****P < 0.0001, CUS + AAV-control vs CUS + AAV-miR-204-5p. Data are presented as means ± SEMs. Student t-tests were employed for comparisons between the two groups. One-way ANOVA followed by Tukey’s post-hoc test was used for multiple comparisons involving > 2 groups
Fig. 5 MiR-204-5p overexpression within the hippocampal DG region alleviates neuronal inflammation and oxidative stress in CUS rats. A Representative confocal microscopic images showing expressions of 4-HNE in the DG region after AAV-miR-204-5p infusion (N = 6 per group). Scale bar is 50 μm. B Representative images of Mito-Sox staining (red). Nuclei (blue) are stained with DAPI. Neurons (green) are stained with Anti-NeuN. Scale bar is 50 μm. (N = 6 per group) C Representative confocal microscopic images of immunostainings for 8-oHdG in the DG region. Scale bar = 50 μm. (N = 6 per group) D Immunofluorescent staining of Iba1 positive microglial cells within the DG region. Scale bar is 50 μm. (N = 6 per group) E Western bolt assays of protein expression levels of NOX1 and NOX4 within the DG region (N = 6 per group). F Q-PCR showing mRNA levels of pro-inflammatory cytokines, Band intensities were normalized to GAPDH. N = 6 per group, ****P < 0.0001, CUS + AAV-control vs CUS + AAV-miR-204-5p. Data are presented as means ± SEMs. Student t-tests were employed for comparisons between the two groups. One-way ANOVA followed by Tukey’s post-hoc test was used for multiple comparisons involving > 2 groupsCC BY · PubMed Central
Fig. 6 MiR-204-5p inhibits the occurrence of oxidative stress within the hippocampal DG region via the RGS12/Nrf2-NF-κB pathway. A Representative images of RGS12 (red) and MAP2 (green) staining. Nuclei (blue) are stained with DAPI. Scale bar is 50 μm. (N = 6 per group) B, C Representative western blot images showing relative protein levels of RGS12, Nrf2, NQO1, HO-1 and NF-κB p65 in AAV-miR-204-5p sponge virus infected DGs (N = 6 per group). (D-E) Representative western blot images showing relative protein levels in AAV-miR-204-5p virus infected DGs (N = 6 per group). **P < 0.01 ***P < 0.001, ****P < 0.0001, control + AAV-control vs control + AAV-miR-204-5p sponge; &&P < 0.01, &&&P < 0.001, &&&&P < 0.0001, CUS + AAV-control vs CUS + AAV-miR-204-5p. Data are presented as means ± SEMs. Student t-tests were employed for comparisons between the two groups. Two-way ANOVA was used for Fig. 6A. One-way ANOVA followed by Tukey’s post-hoc test was used for C and E
Fig. 6 MiR-204-5p inhibits the occurrence of oxidative stress within the hippocampal DG region via the RGS12/Nrf2-NF-κB pathway. A Representative images of RGS12 (red) and MAP2 (green) staining. Nuclei (blue) are stained with DAPI. Scale bar is 50 μm. (N = 6 per group) B, C Representative western blot images showing relative protein levels of RGS12, Nrf2, NQO1, HO-1 and NF-κB p65 in AAV-miR-204-5p sponge virus infected DGs (N = 6 per group). (D-E) Representative western blot images showing relative protein levels in AAV-miR-204-5p virus infected DGs (N = 6 per group). **P < 0.01 ***P < 0.001, ****P < 0.0001, control + AAV-control vs control + AAV-miR-204-5p sponge; &&P < 0.01, &&&P < 0.001, &&&&P < 0.0001, CUS + AAV-control vs CUS + AAV-miR-204-5p. Data are presented as means ± SEMs. Student t-tests were employed for comparisons between the two groups. Two-way ANOVA was used for Fig. 6A. One-way ANOVA followed by Tukey’s post-hoc test was used for C and ECC BY · PubMed Central
Fig. 7 MiR-204-5p regulates synaptic plasticity of DG neurons in rats. A Representative traces of sEPSCs in DG neurons of rats infected with the virus. B Cumulative fraction plots of sEPSCs amplitudes and frequencies. C Cumulative fraction plots of mEPSCs amplitudes and frequencies. D Representative traces of mEPSCs in DG neurons of rats infected with the virus. N = 18 neurons from six rats in each group. E Representative electron micrographs and summary of data showing the number of synapsis. Arrows indicate neuronal synapses. Scale bar is 1 μm. (N = 6 per group). F Representative electron micrograph of DG neurons in rats from each group (N = 6 per group). Arrows indicate neuronal synapses. Scale bar is 0.2 μm. **P < 0.01 ***P < 0.001, ****P < 0.0001, control + AAV-control vs control + AAV-miR-204-5p sponge; &&P < 0.01, &&&&P < 0.0001, CUS + AAV-control vs CUS + AAV-miR-204-5p. Data are presented as means ± SEMs. Student t-tests were employed for comparisons between the two groups. Two-way ANOVA was used for multiple comparisons involving > 2 groups
Fig. 7 MiR-204-5p regulates synaptic plasticity of DG neurons in rats. A Representative traces of sEPSCs in DG neurons of rats infected with the virus. B Cumulative fraction plots of sEPSCs amplitudes and frequencies. C Cumulative fraction plots of mEPSCs amplitudes and frequencies. D Representative traces of mEPSCs in DG neurons of rats infected with the virus. N = 18 neurons from six rats in each group. E Representative electron micrographs and summary of data showing the number of synapsis. Arrows indicate neuronal synapses. Scale bar is 1 μm. (N = 6 per group). F Representative electron micrograph of DG neurons in rats from each group (N = 6 per group). Arrows indicate neuronal synapses. Scale bar is 0.2 μm. **P < 0.01 ***P < 0.001, ****P < 0.0001, control + AAV-control vs control + AAV-miR-204-5p sponge; &&P < 0.01, &&&&P < 0.0001, CUS + AAV-control vs CUS + AAV-miR-204-5p. Data are presented as means ± SEMs. Student t-tests were employed for comparisons between the two groups. Two-way ANOVA was used for multiple comparisons involving > 2 groupsCC BY · PubMed Central

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Metadata

Authors
Lan, T., Li, Y., Fan, C., Wang, L., Wang, W., Chen, S., & Yu, S. Y.
ORCID
Yu, Shu Yan
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2021-10-21
Volume
18
Issue
1
ISSN
1742-2094
DOI
10.1186/s12974-021-02299-5
PMC
PMC8532383
Cited by
38
References
5
Language
en
Licence
Funders
  • national natural science foundation of china (NSFC81873796, NSFC82071513)
  • natural science foundation of shandong province (ZR2020ZD25)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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How to cite

Cite CoChat for the checks on this page, and the paper for its own findings.

This page
CoChat. (2026). Citation check: MicroRNA-204-5p reduction in rat hippocampus contributes to stress-induced pathology via targeting RGS12 signaling pathway. https://app.cochat.ai/papers/10.1186/s12974-021-02299-5
The paper
Lan, T., Li, Y., Fan, C., Wang, L., Wang, W., Chen, S., & Yu, S. Y. (2021). MicroRNA-204-5p reduction in rat hippocampus contributes to stress-induced pathology via targeting RGS12 signaling pathway. Journal of Neuroinflammation. https://doi.org/10.1186/s12974-021-02299-5