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Local Interleukin-18 System in the Basolateral Amygdala Regulates Susceptibility to Chronic Stress

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An Erratum to this article was published on 07 October 2016

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Abstract

Interleukin-18 (IL18) is a multifunctional cytokine that has been implicated in increased susceptibility to depression; however, the underlying mechanism remains unknown. We found that the IL18 system in the basolateral amygdala (BLA) determined susceptibility to chronic stress. Mice subjected to chronic restraint stress or chronic foot-shock stress demonstrated increased expression of IL18 in the BLA, and exhibited depression-like behaviors, whereas IL18 knockout (KO) mice were resilient to these chronic stresses. IL18 and IL18 receptors in the BLA were expressed in glutamatergic and GABAergic neurons in addition to glial cells. Local inhibition of IL18 and IL18 receptors in the BLA by stereotaxic injection of siRNA-IL18 or siRNA-IL18 receptor-1α was sufficient to suppress stress-induced depression-like behaviors. Following chronic stress, the downstream mediator of IL18 receptor activation, phospho-NF-kB, was increased in BLA neurons expressing IL18 receptors. Furthermore, siRNA-mediated inhibition of NF-kB in the BLA significantly suppressed stress-induced depression-like behaviors, and NF-kB KO mice were resilient to chronic stress. The siRNA-mediated inhibition of NF-kB in the BLA downregulated stress-induced increased expression of Hcrt, MCH, OXT, AVP, and TRH, the neuropeptides that were induced by chronic stress in the BLA and promoted depression-like behaviors. These results suggest that the local IL18 and its receptor system in the BLA function as molecular regulators promoting susceptibility to chronic stress.

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  • 07 October 2016

    An erratum to this article has been published.

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Acknowledgments

This research was supported by grants (2015R1A2A2A01003413; WCI 2009-002) from the Ministry of Science, ICT and Future Planning, Republic of Korea, and KRIBB Research Initiative Program.

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Authors and Affiliations

  1. Department of Brain and Cognitive Sciences, Ewha Womans University, Seoul, 120-750, Republic of Korea

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

  2. World Class Institute, Korea Research Institute of Bioscience & Biotechnology, Science Park, Cheongwon, 363-883, South Korea

    Bo Yeon Kim

  3. Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul, 120-749, South Korea

    Young J. Oh

  4. Chemistry and Nano Science, Ewha Womans University, Seoul, Republic of Korea

    Pyung-Lim Han

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Additional information

An erratum to this article is available at https://doi.org/10.1007/s12035-016-0139-1.

Electronic Supplementary Material

Supplemental Fig. S1

Shock sensitivity and shock-escaping tests of IL18 KO mice. a Experimental design for the shock sensitivity test and subsequent shock-escaping test. b Behavioral responses in the shock sensitivity test. Mice grouped to be subjected to the foot-shock regime were individually exposed to a single 0.8-mA electrical shock 2 s in duration through a shock grid floor in a shock chamber. Shock responders were defined as mice showing jumping, high-pitched vocalization, and/or saccadic movement in response to an electrical shock. Non-responders were defined as mice showing none of these behavioral responses to the single shock trial. c, d Behavioral responses in the shock-escaping test. Mice were subjected to a single 0.8-mA electrical shock 2 s in duration through a shock grid floor in the shock chamber containing an escaping block in a corner (c). In response to shock, mice normally jumped onto the escaping block. The mice who failed to escape were given a second electrical shock 10 s after the first trial, and escaping responses were recorded. Animals that escaped on the first and second trials were counted as percentage of successful shock escapes (d). All IL18 KO mice tested were successfully escaped on the first or second trial. (GIF 138 kb)

High resolution image (TIFF 6480 kb)

Supplemental Figure S2

GFAP-positive cells in the BLA were rare. a, b Photomicrographs showing anti-GFAP staining in the hippocampus (a) and BLA (b). Numerous anti-GFAP-stained cells were present in the hippocampus, while anti-GFAP-stained cells were relatively rare in the BLA. However, the surrounding areas of the BLA contained a number of anti-GFAP-stained cells. CA1 hippocampal CA1, DG dentate gyrus, BLA basolateral amygdala. (GIF 270 kb)

High resolution image (TIFF 7588 kb)

Supplemental Fig. S3

Expression of IL18 and IL18 receptors in the BLA. a Photomicrograph showing the location (white rectangle) for high magnification images in panels (b)–(i) and the area in the BLA used for quantifications (blue circle). CeA central amygdala, BLA basolateral amygdala. Scale bar = 200 μm. b–i Expressions of proIL18 (b–e) and IL18Rα (f–i) in the BLA. Photomicrographs representing the co-localization of proIL18 and GAD67 (b), proIL18 and Glu-4 (c), IL18Rα and GAD67 (f), and IL18Rα and Glu-4 (g) in the BLA of mice treated with 2 h × 14 d RST. Venn diagrams for the quantification of co-localization of proIL18 and GAD67 (d), proIL18 and Glu-4 (e), IL18Rα and GAD67 (h), IL18Rα and Glu-4 (i), and the number of counted cells of each marker. The specificity of proIL18 and IL18Rα antibodies was verified using BLA sections of IL18 KO mice and BLA sections injected with siRNA-IL18Rα, respectively. Scale bars = 100 μm. (GIF 610 kb)

High resolution image (TIFF 16402 kb)

Supplemental Fig. S4

IL18Rα was expressed in BLA cells positive for proHcrt, proMCH, proOXT, proAVP, or proTRH. a Photomicrograph showing the location (red rectangle) in the BLA for high magnifications of panels (b)–(f). CeA central amygdala, BLA basolateral amygdala. Scale bar = 200 μm. b–f Photomicrographs representing the co-localization of IL18Rα and proHcrt (b), IL18Rα and proMCH (c), IL18Rα and proOXT (d), IL18Rα and proAVP (e), and IL18Rα and proTRH (f) in BLA neurons. Scale bar = 20 μm. (GIF 489 kb)

High resolution image (TIFF 13440 kb)

Supplemental Fig. S5

Stress-induced c-Fos expression in glutamatergic and GABAergic neurons in the BLA. a Experimental design for the treatment of mice with daily 2-h restraint for 7 days (gray squares), following 1-h restraint (gray rectangle) on day 8, and tissue preparation (arrow). b–d Photomicrographs showing the co-staining of c-Fos (green) and GAD67 (red) (b), c-Fos (green) and PAV (red) (c), and c-Fos (green) and Glu-4 (red) (d) in the BLA of mice exposed to restraint stress. Arrowheads—co-stained cells. Scale bar = 100 μm. e–g Venn diagrams for the quantification of co-localization of c-Fos and GAD67 (e), c-Fos and PAV (f), and c-Fos and Glu-4 (g), and the number of counted cells of each marker. (GIF 487 kb)

High resolution image (TIFF 14727 kb)

Supplemental Fig. S6

Stress-induced c-Fos expression in IL18- or IL18 receptor-expressing cells in the BLA. a Experimental design for the treatment of mice with daily 2-h restraint for 7 days (gray squares), following 1-h restraint (gray rectangle) on day 8, and tissue preparation (arrow). b, c Photomicrographs showing the co-staining of proIL18 (green) and c-Fos (red) (a), and IL18Rα (green) and c-Fos (red) (b) in the BLA of mice exposed to restraint stress. Arrowheads—co-stained cells. Scale bar = 100 μm. (GIF 220 kb)

High resolution image (TIFF 7058 kb)

Supplemental Fig. S7

Phospho-NF-kB p65 and phospho-STAT3 were detected in GABAergic and glutamatergic cells in the BLA. a Photomicrograph showing the location (white rectangle) for high magnifications in panels (b)–(g). CeA central amygdala, BLA basolateral amygdala. Scale bar = 200 μm. b, c Photomicrographs showing the co-localization of phospho-NF-kB p65 (p-NF-kB; green) and NeuN (red) (b) and phospho-STAT3 (p-STAT3; green) and NeuN (red) (c) in the BLA of mice treated with 2 h × 14 d RST. Scale bar = 20 μm. d, e Photomicrographs representing the co-localization of p-NF-kB p65 (p-NF-kB; green) and GAD67 (red) (d), and p-NF-kB p65 (p-NF-kB; green) and Glu-4 (red) (e) in the BLA of mice treated with 2 h × 14 d RST. Scale bar = 20 μm. f, g Photomicrographs showing the co-localization of p-STAT3 (green) and GAD67 (red) (f), and p-STAT3 (green) and Glu-4 (red) (g) in the BLA of mice treated with 2 h × 14 d RST. Scale bar = 20 μm. (GIF 549 kb)

High resolution image (TIFF 14006 kb)

Supplemental Fig. S8

Shock sensitivity and shock-escaping tests of NF-kB KO mice. a Experimental design for the shock sensitivity test and shock-escaping test. b Prescreening of mice based on the shock sensitivity test. Mice grouped to be subjected to the foot-shock regime were individually exposed to a single 0.8-mA electrical shock 2 s in duration through a shock grid floor in a shock chamber. Shock responders were defined as mice showing jumping, high-pitched vocalizations, and/or saccadic movements in response to an electrical shock, and non-responders as mice showing none of these behavioral responses. c, d Shock-escaping behaviors of WT and NF-kB KO mice. Mice were subjected to a single 0.8-mA electrical shock 2 s in duration through a shock grid floor in the shock chamber containing an escaping block in a corner (c). In response to shock, mice normally jumped onto the escaping block. The mice who failed to escape were given a second electrical shock 10 s after the first trial, and successful escapes were recorded. Animals that escaped on the first and second trials were counted as percentage of successful shock escapes (d). All NF-kB KO mice tested were successfully escaped on the first or second trial. (GIF 141 kb)

High resolution image (TIFF 6443 kb)

Supplemental Fig. S9

Potential NF-kB and STAT3 binding sites in the promoter regions of Hcrt, MCH, OXT, AVP, and TRH genes. Schematic representation of potential NF-kB and STAT3 binding sites on the promoter regions of Hcrt, MCH, OXT, AVP, and TRH genes. The 1000 base-pair proximal promoter region of Hcrt, MCH, OXT, and AVP genes contains a NF-kB binding site (red box), while the TRH promoter region contains a STAT3 binding site (blue box). Numbers represent the distance from the transcription start site (TSS) of each gene. (GIF 17 kb)

High resolution image (TIFF 688 kb)

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Kim, TK., Kim, JE., Choi, J. et al. Local Interleukin-18 System in the Basolateral Amygdala Regulates Susceptibility to Chronic Stress. Mol Neurobiol 54, 5347–5358 (2017). https://doi.org/10.1007/s12035-016-0052-7

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