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G9a-Mediated Regulation of OXT and AVP Expression in the Basolateral Amygdala Mediates Stress-Induced Lasting Behavioral Depression and Its Reversal by Exercise

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Abstract

Chronic stress produces behavioral depression. Conversely, physical exercise is held to be beneficial in the treatment of depression. Although genomic mechanisms are likely involved in these behavioral changes, underlying mechanisms are not clearly understood. In the present study, we investigated whether stress effects and their reversal by exercise occur via genomic mechanisms in the amygdala, a core part of the limbic system important for regulating mood states. Mice treated with chronic restraint showed lasting depression-like behaviors, which were counteracted by treatment with scheduled forceful exercise. Microarray analysis identified a number of genes whose expression in the amygdala was either upregulated or downregulated after repeated stress, and these changes were reversed by exercise. Of these genes, the neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) were selected as representative stress-induced and exercise-responded genes in the BLA. Stereotaxic injection of OXT or AVP receptor agonists within the BLA in normal mice produced depression-like behaviors, whereas small interfering RNA (siRNA)-mediated suppression of the OXT or AVP transcripts in the BLA was sufficient to block stress-induced depressive behaviors. Stress-induced depression-like behaviors were accompanied by a global reduction of G9a histone methyltransferase and H3K9me2 at the OXT and AVP promoters. Conversely, repeated exercise increased the levels of G9a and H3K9me2 at the OXT and AVP promoters in the BLA, which was associated with the suppression of OXT and AVP expressions. These results identify G9a-induced histone methylation at the OXT and AVP promoters in the BLA as a mechanism for mediating stress-induced lasting behavioral depression and its reversal by exercise.

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Acknowledgments

This research was supported by a grant (2012R1A2A1A03010177) from the Ministry of Science, ICT and Future Planning, Republic of Korea.

Competing Interests

The authors declare that they have no competing financial interests.

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    Authors and Affiliations

    1. Department of Brain and Cognitive Sciences, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemoon-Gu, Seoul, 120-750, South Korea

      Tae-Kyung Kim, Jung-Eun Lee, Ji-Eun Kim, Jin-Young Park, Juli Choi, Hannah Kim, Eun-Hwa Lee & Pyung-Lim Han

    2. Department of Chemistry and Nano Science, Ewha Womans University, Seoul, South Korea

      Pyung-Lim Han

    3. Brain Disease Research Institute, Ewha Womans University, Seoul, South Korea

      Pyung-Lim Han

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    Tae-Kyung Kim and Jung-Eun Lee contributed equally to this work.

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    Supplemental Table 1

    A list of the genes that were upregulated or downregulated in the amygdala after the 2 h × 14 days RST treatment. A list of the genes whose expressions were upregulated or downregulated in the amygdala by more than 1.2-fold after the 2 h × 14 days RST treatment (CON vs. RST), and follow-up unsupervised clusterings of the respective genes in animal groups treated with imipramine or exercise were overlaid with respect to RST (RST vs. RST + IMI; RST vs. RST + EXE) or control (CON vs. RST + IMI; CON vs. RST + EXE). Average fold changes were presented. CON vs. RST, comparison between control and RST group (the genes that were upregulated or downregulated in the amygdala after the 2 h × 14 days RST); RST vs. RST + IMI, comparison between RST and RST + IMI group (the genes that were downregulated or upregulated by imipramine); RST vs. RST + EXE, comparison between RST and RST + EXE group (the genes that were downregulated or upregulated by exercise); CON vs. RST + IMI, comparison between control and RST + IMI group (the genes that were downregulated or upregulated by imipramine compared to control); CON vs. RST + EXE, comparison between control and RST + EXE group (the genes that were downregulated or upregulated by exercise compared to control). (XLSX 143 kb)

    Supplemental Table 2

    A list of the genes that were upregulated or downregulated in the amygdala after the 2 h × 14 days RST treatment but completely reversed in their expression by exercise. A list of the genes that were upregulated or downregulated in the amygdala by more than 1.2-fold after the 2 h × 14 days RST treatment (CON vs. RST), and then were reversed in their expression in opposite directions beyond the control level after treatment with exercise (E; CON vs. RST + EXE). These groups of the genes correspond to the 3-2 and 4-2 patterns among hypothetical gene expression alterations (G) induced after treatment with exercise. Average fold changes were presented. (XLSX 36 kb)

    Supplemental Table 3

    A list of the genes that were upregulated or downregulated in the amygdala after the 2 h × 14 days RST treatment, but completely reversed in their expression by imipramine. A list of the genes that were upregulated or downregulated in the amygdala by more than 1.2-fold after the 2 h × 14 days RST treatment (CON vs. RST), and then were reversed in their expression in opposite directions beyond the control level after treatment with imipramine (CON vs. RST + IMI). These groups of the genes correspond to the 3-2 and 4-2 patterns among hypothetical gene expression alterations (G) induced after treatment with imipramine. Average fold changes were presented. (XLSX 20.1 kb)

    Supplemental Fig. 1

    Real-time PCR analysis for expression levels of HATs, HDACs and HMTs in the amygdala after the 2 h × 14 days RST treatment. (A) Experimental design for treatment with 2 h × 14 days RST and following tissue preparation (arrow). (B) Real-time PCR analysis for expression levels of HATs, HDACs and HMTs in the amygdala after the 2 h × 14 days RST treatment. HAT, histone acetyltransferases (CREB-binding protein(CBP) and p300); HDAC2 and HDAC5, histone deacetyltransferase-2 and deacetyltransferase-5; HMT, histone methyltransferase (G9a and GLP). Data are presented as the mean ± SEM (n = 6 animals for each). Student t test. *p < 0.05 for the difference between indicated group. Primers used were 5′-CGCAACATCACCCATCTG-3′ and 5′-TCATACCAGCATCGGATACT-3′ for G9a, 5′-GACTGAGCAGCGATAATG-3′ and 5′-CAAGGTGTCTCTAGTGTATG-3′for p300, 5′-GGTTGCCTATGCTAAGAAAGT-3′ and 5′-GATGCCTTGCTTATGTAAACG-3′ for CBP, 5′-GGGACAGGCTTGGTTGTTTC-3′ and 5′-GAGCATCAGCAATGGCAAGT-3′ for HDAC2, 5′-TGTCACCGCCAGATGTTTTG-3′ and 5′-TGAGCAGAGCCGAGACACAG-3′ for HDAC5, 5′-CCAAGCAAGAGACCAAGCAG-3′ and 5′-CTTCCTGTGGGCTAGCTCTT-3′ for GLP, 5′-AGAAGGTGGTGAAGCAGGCATC-3′ and 5′-CGAAGGTGGAAGAGTGGGAGTTG-3′ for GAPDH, and 5′-GCTGCCATCTGTTTTACGG-3′ and 5′-TGACTGGTGCCTGATGAACT-3′ for L32. (GIF 32 kb)

    High resolution image (TIFF 1332 kb)

    Supplemental Fig. 2

    Representative amplification plots for ChIP assays quantified by real-time PCR and relative enrichments of G9a and H3K9me2 at the OXT and AVP promoters. (A, B) The promoter regions (P1 and P2) of the OXT(D) and AVP(E) genes used for ChIP analysis were indicated. tss, transcription start site of each gene. (C–F) Representative amplification plots for ChIP assays quantified by real-time PCR. Relative fluorescence levels were plotted over PCR cycle numbers. The Tc value of immunoprecipitated products with normal anti-IgG was observed later than the Tc value of immunoprecipitated products with anti-DimeH3K9 or anti-G9a in all promoter cases examined. These results indicate that ChIPs reacted with DimeH3K9 or G9a antibody were enriched for the OXT and AVP promoters, thus were dissociated from ChIPs produced by normal IgG in the test condition. (G–J) Relative enrichments of G9a and H3K9me2 at the P1 and P2 promoter regions of the OXT (G, H) and AVP (I, J). ChIP reactions were conducted with anti-DimeH3K9, anti-G9a, or normal IgG for each experiment group, and obtained ChIP products in each reaction were quantified for the indicated promoter region by real-time PCR. The data presented were normalized by the input DNA. CON, control; RST, treatment with 2 h × 14 days restraint; RST + IMI, treatment with RST and imipramine; RST + EXE, treatment with RST and exercise. Data are presented as the mean ± SEM (n = 18 animals for each, 3 repeats of ChIP). One-way ANOVA and Newman-Keuls post hoc test. *p < 0.05 and **p < 0.01 for the difference between the control and indicated groups. # p < 0.05 and ## p < 0.01, respectively for the difference between RST and indicated groups. (K–R) Representative amplification plots for DimeH3K or G9a ChIP assays showing the differential enrichments of H3K9me2 (K–N) or G9a (O–R) at the P1 and P2 promoter regions of the OXT (K, L, O, P) and AVP (M, N, Q, R) in different experimental groups. Compared to the control at all promoter regions examined, exercise group was detected earlier than the control, while stress group appeared later than the control. The higher the occupancy of DimeH3K or G9a at each promoter region, the earlier the PCR cycle at which the amplification reaches threshold fluorescence. CON, naïve control; RST, mice treated with 2 h × 14 days restraint; RST + IMI, mice treated with 2 h × 14 days RST, followed by imipramine; RST + EXE, mice treated with 2 h × 14 days RST, followed by exercise (GIF 93 kb)

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    Kim, TK., Lee, JE., Kim, JE. et al. G9a-Mediated Regulation of OXT and AVP Expression in the Basolateral Amygdala Mediates Stress-Induced Lasting Behavioral Depression and Its Reversal by Exercise. Mol Neurobiol 53, 2843–2856 (2016). https://doi.org/10.1007/s12035-015-9160-z

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