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mGluR5 in the nucleus accumbens is critical for promoting resilience to chronic stress

Nature Neuroscience volume 18, pages 1017–1024 (2015)Cite this article

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Abstract

Resilience to aversive events has a central role in determining whether stress leads to the development of depression. mGluR5 has been implicated in the pathophysiology of depression, but the effect of mGluR5 activity on stress resilience remains unexplored. We found that mGluR5−/− (also known as Grm5−/−) mice displayed more depression-like behaviors (for example, learned helplessness, social withdrawal and anhedonia) than control mice following exposure to various stressful stimuli. Lentiviral 'rescue' of mGluR5 in the nucleus accumbens (NAc) decreased these depression-like behaviors in mGluR5−/− mice. In the NAc, ΔFosB, whose induction promotes stress resilience, failed to be upregulated by stress in mGluR5−/− mice. Notably, targeted pharmacological activation of mGluR5 in the NAc increased ΔFosB expression. Our findings point to an essential role for mGluR5 in promoting stress resilience and suggest that a defect in mGluR5-mediated signaling in the NAc may represent an endophenotype for stress-induced depression.

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Figure 1: mGluR5−/− mice exhibit depression-like behaviors following exposure to stress in a learned helplessness procedure.
Figure 2: mGluR5−/− mice exhibit enhanced susceptibility to stress-induced social avoidance and anhedonia.
Figure 3: Pharmacological modulation of mGluR5 activity influences depression-like behaviors.
Figure 4: Lentiviral mGluR5 expression in the NAc shell prevents social avoidance in mGluR5−/− mice following a 3-d social defeat stress.
Figure 5: Social avoidance levels after chronic defeat stress are correlated with mGluR5 levels in the NAc shell.
Figure 6: mGluR5 activation mediates the induction of ΔFosB.
Figure 7: Phospho-SRF (S103) mediates the induction of ΔFosB by mGluR5.

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Acknowledgements

We thank the Yonsei-Carl Zeiss Advanced Imaging Center for technical assistance. We thank G. Panagiotakos for her careful and critical reading. This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2014R1A2A1A11051372 & no. 2007-0056092 to C.H.K., no. 2013054004 to D.G.K.), the DGIST R&D Program of the Ministry of Science, ICT and Future Planning (14-BD-16 to C.H.K.), and a faculty research grant from Yonsei University College of Medicine for 2012 (no. 6-2012-0018 to D.G.K.).

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  1. Sora Shin and Obin Kwon: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, BK21 PLUS Project for Medical Science, Brain Research Institute, Yonsei University College of Medicine, Seoul, Korea

    Sora Shin, Obin Kwon, Somin Kwon, Sora Oh, Chul Hoon Kim & Dong Goo Kim

  2. Department of Psychiatry and Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Korea

    Jee In Kang

  3. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea

    Sora Oh & Chul Hoon Kim

  4. Department of Bioindustrial Technologies, College of Animal Bioscience and Technology, Konkuk University, Seoul, Korea

    Jiwon Choi

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Contributions

S.S., O.K., C.H.K. and D.G.K. designed the experiments and analyzed the data. C.H.K. and D.G.K. prepared the manuscript. S.S., O.K., S.O. and J.C. performed the experiments. J.I.K. and S.K. provided scientific input and helped edit the manuscript.

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Correspondence to Chul Hoon Kim or Dong Goo Kim.

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Integrated supplementary information

Supplementary Figure 1 Basic characteristics of mGluR5−/− mice.

(a) At 16 week of age, mGluR5−/− mice showed reduced body weights compared with wild-type mice (n = 14 mice for mGluR5+/+ and 12 for each mGluR5+/– and mGluR5−/−, respectively). One-way ANOVA (F(2,35) = 6.661, P = 0.004) followed by Bonferroni post hoc test for multiple comparisons; **P = 0.003 compared with wild-type mice. (b) Locomotor activity was monitored for 15 min and analyzed in 3 min bins (n = 10 mice for each mGluR5+/+ and mGluR5+/– and 11 for mGluR5−/−, respectively). (c) Total distance traveled during the 15 min test period. No significant difference in locomotor activity was observed between genotypes. (d) Rearing counts (vertical activity) were unchanged in mGluR5+/– and mGluR5−/− mice (n = 8 mice for mGluR5+/+ and 7 for each mGluR5+/– and mGluR5−/−, respectively). Data are expressed as the mean ± SEM. (e) Western blot analysis of whole brain lysates and crude synaptosomal fractions from mGluR5+/+, mGluR5+/–, and mGluR5−/− mice. mGluR5−/− mice showed normal levels of other subtypes of mGluRs (mGluR1, mGluR2/3, and mGluR7), ionotropic glutamate receptors (GluR1, GluR2, NR2A, and NR2B), and synaptic scaffold proteins (PSD-95, PICK1, Pan-MAGUK, Chapsyn-110, and SAP-102). The experiment was successfully repeated three times. Full-length blots are presented in Supplementary Figure 9.

Supplementary Figure 2 mGluR5−/− mice exhibit depression-like behaviors in two-day FST and TST.

(a,b) FST over two consecutive days. Immobility (a) and struggling time (b) were measured during the last 4 min of the 6-min swim test period on day 1 and day 2 respectively (n = 8 mice for mGluR5+/+ and 7 for mGluR5–/–). Two-sided t-test (day2 mGluR5+/+ vs mGluR5–/–, t(13) = –2.504 in a and t(13) = 2.899 in b); P < 0.05 compared with wild-type mice on day 2. (c) Tail suspension test (TST) over two consecutive days. Immobility time was measured during the last 4 min of the 6-min suspension test period on day 1 and day 2 respectively. Two-sided t-test (day2 mGluR5+/+ vs mGluR5–/–, t(10) = –2.236); *P = 0.049 compared with wild-type mice on day 2. (d,e) Time spent immobile per 1-min interval within the 6-min TST session on day 1 (d) and day 2 (e) (n = 7 mice for mGluR5+/+ and 5 for mGluR5–/–). Two-way RM ANOVA (in e, genotype × time interaction F(5,50) = 1.552, P = 0.191) followed by Bonferroni post hoc test for multiple comparisons; *P < 0.05 compared with wild-type mice at each time point. Data are expressed as the mean ± SEM.

Supplementary Figure 3 Validation of mGluR5-expressing lentivirus and verification of correct injection site in the NAc shell and core.

(a) Diagram of the lentiviral vector used to rescue mGluR5. (b) Validation of the mGluR5-lentivirus. Western blot analysis of mGluR5 expression in HEK293FT cells 6 days after transduction of the control-LV (lentivirus) or mGluR5-LV with low, medium, and high concentrations. Full-length blots are presented in Supplementary Figure 10. The experiment was successfully repeated two times. (c) Immunohistochemistry of mGluR5 overlapping ZsGreen in the NAc shell of mice injected with mGluR5-LV. Scale bars, 50 μm. The experiment was successfully repeated three times. (d) Immunofluorescence of ZsGreen in the NAc shell (left) and NAc core (right) of mice injected with control-LV. ac, anterior commissure; AcbC, nucleus accumbens core; Acbsh, nucleus accumbens shell. Scale bars, 100 μm. The experiment was successfully repeated three times.

Supplementary Figure 4 ‘Rescue’ of mGluR5 in the NAc shell normalizes sucrose preference.

(a) Localized expression of mGluR5 within the NAc shell reversed the 3-day restraint stress-induced anhedonia observed in mGluR5−/− mice (n = 9, 5, and 6 mice for WT-control LV, KO-control LV and KO-mGluR5 LV, respectively). Two-way RM ANOVA (group × stress interaction F(2,17) = 9.042, P = 0.002) followed by Fisher LSD post hoc test for multiple comparisons; ##P = 0.001 compared with the WT-control LV following restraint stress; ††P = 0.004 compared with the respective pre-stressed mice; §P = 0.028 compared with the KO-control LV following restraint stress. (b) Rescue of mGluR5 in the NAc shell did not alter total liquid intake (water plus sucrose solution) before and after the 3-day restraint stress. Data are expressed as the mean ± SEM.

Supplementary Figure 5 Learned helplessness level after electric foot shock is correlated with mGluR5 level in NAc shell.

(a) Susceptible mice showed higher mean escape latency compared to non-defeat control mice, while resilient mice did not (n = 5, 8, and 12 mice for unshocked, susceptible, and resilient group, respectively). One-way ANOVA (F(2,22) = 72.955, P < 0.001) followed by Fisher LSD post hoc test for multiple comparisons; ***P < 0.001 compared with control group; †††P < 0.001 compared with resilient group. (b) Mean escape latency during 5-trial blocks. Two-way RM ANOVA (group × number of block interaction F(10,110) = 1.440, P = 0.172) followed by Fisher LSD post hoc test for multiple comparisons; ***P < 0.001 compared with unshocked mice; †††P < 0.001 compared with resilient group at each trial block. (c) Western blot images and quantification analysis of mGluR5 level in the NAc of susceptible mice following learned helplessness paradigm showed lower level compared to that of control mice, while resilient mice did not. One-way ANOVA (F(2,22) = 4.042, P = 0.032) followed by Fisher LSD post hoc test for multiple comparisons; *P = 0.046 compared with control group; †P = 0.014 compared with resilient group. Data are expressed as the mean ± SEM. Full-length blots are presented in Supplementary Figure 10. (d) There was a significant correlation between mean escape latency and mGluR5 level in the NAc; Pearson correlation.

Supplementary Figure 6 Lentiviral ΔFosB expression in the NAc shell prevents social avoidance in mGluR5−/− mice following a 3-day social defeat stress.

(a) Diagram of the lentiviral vector used to express ΔFosB. Scale bar, 50 μm. For each mouse used, precise delivery of the virus was confirmed by visualizing ZsGreen1-expressing cells. (b) Validation of the ΔFosB-lentivirus. Western blot analysis of ΔFosB expression in HEK293FT cells 6 days after transduction of the control-LV (lentivirus) or ΔFosB-LV. Full-length blots are presented in Supplementary Figure 10. (c,d) mGluR5−/− mice that received ΔFosB LV in the NAc shell exhibited times spent in the interaction zone (c) and the corner zone (d) that were comparable to those of control LV-injected mGluR5+/+ mice (n = 4, 6, and 9 mice for WT-control LV, KO-control LV and KO-ΔFosB LV, respectively). Two-way RM ANOVA (in c, group × target interaction F(2,16) = 3.821, P = 0.044) followed by Bonferroni post hoc test for multiple comparisons; #P = 0.012, ##P = 0.006 compared with the WT-control LV in the presence of a target; †P = 0.046, ††P = 0.004 compared with the respective no-target conditions; §P = 0.028, §§P = 0.002 compared with the KO-control LV in the presence of a target. Data are expressed as the mean ± SEM.

Supplementary Figure 7 Phospho-SRF (Ser103) mediates the induction of ΔFosB by mGluR5 after 3-day social defeat stress.

Representative double immunohistochemistry of the NAc shell of wild-type and mGluR5–/– mice following a 3-day social defeat stress (lower 2 rows) or not (upper 2 rows). Scale bars, 50 μm. The experiment was successfully repeated three times.

Supplementary Figure 8 Un-cropped blot images in the main figures.

Supplementary Figure 9 Un-cropped blot images in the supplementary figure 1.

Supplementary Figure 10 Un-cropped blot images in the supplementary figures 3,5,6.

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Shin, S., Kwon, O., Kang, J. et al. mGluR5 in the nucleus accumbens is critical for promoting resilience to chronic stress. Nat Neurosci 18, 1017–1024 (2015). https://doi.org/10.1038/nn.4028

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