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Glucocorticoid feedback uncovers retrograde opioid signaling at hypothalamic synapses

Nature Neuroscience volume 16, pages 596–604 (2013)Cite this article

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Abstract

Stressful experience initiates a neuroendocrine response culminating in the release of glucocorticoid hormones into the blood. Glucocorticoids feed back to the brain, causing adaptations that prevent excessive hormone responses to subsequent challenges. How these changes occur remains unknown. We found that glucocorticoid receptor activation in rodent hypothalamic neuroendocrine neurons following in vivo stress is a metaplastic signal that allows GABA synapses to undergo activity-dependent long-term depression (LTDGABA). LTDGABA was unmasked through glucocorticoid receptor–dependent inhibition of Regulator of G protein Signaling 4 (RGS4), which amplified signaling through postsynaptic metabotropic glutamate receptors. This drove somatodendritic opioid release, resulting in a persistent retrograde suppression of synaptic transmission through presynaptic μ receptors. Together, our data provide new evidence for retrograde opioid signaling at synapses in neuroendocrine circuits and represent a potential mechanism underlying glucocorticoid contributions to stress adaptation.

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Figure 1: Stress unmasks long–term plasticity of GABA synapses.
Figure 2: Glucocorticoid receptor activation is necessary and sufficient to unmask LTDGABA.
Figure 3: LTDGABA is expressed presynaptically.
Figure 4: LTDGABA induction is heterosynaptic and requires a retrograde signal.
Figure 5: Glucocorticoid receptor activation modifies mGluR signaling via RGS4.
Figure 6: Presynaptic μ opioid receptors mediate LTDGABA.
Figure 7: LTDGABA is reversible by opioid receptor antagonism.
Figure 8: LTDGABA is not synapse specific.

Change history

  • 14 April 2013

    In the version of this article initially published online, the black trace was missing from Figure 8b, top right pair. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We acknowledge members of the Bains laboratory for thoughtful discussion and C. Sank and R. Cantrup for technical assistance. We thank Q. Pittman and K. Iremonger for helpful comments on the manuscript, and K. Sharkey (University of Calgary) for providing Cnr1−/− mice. We thank the Hotchkiss Brain Institute support of the optogenetics core. J.S.B. is an Alberta Innovates–Health Solutions Senior Scholar. This work was supported by an operating grant from the Canadian Institutes of Health Research (MOP 86501 to J.S.B.). W.I. and T.F. are supported by postdoctoral fellowships, and J.I.W.C. by a PhD scholarship from Alberta Innovates–Health Solutions. W.I. and J.I.W.C. also received fellowship and scholarship support from the Hotchkiss Brain Institute.

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  1. Hotchkiss Brain Institute, Calgary, Alberta, Alberta

    Jaclyn I Wamsteeker Cusulin, Tamás Füzesi, Wataru Inoue & Jaideep S Bains

  2. Department of Physiology and Pharmacology, University of Calgary, Calgary, Canada, Alberta

    Jaclyn I Wamsteeker Cusulin, Tamás Füzesi, Wataru Inoue & Jaideep S Bains

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  1. Jaclyn I Wamsteeker Cusulin
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J.I.W.C. designed and conducted experiments, analyzed the data, and wrote the manuscript. T.F. and W.I. conducted experiments, analyzed data and contributed to manuscript preparation. J.S.B. designed experiments, prepared the manuscript and supervised the project.

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Correspondence to Jaideep S Bains.

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Wamsteeker Cusulin, J., Füzesi, T., Inoue, W. et al. Glucocorticoid feedback uncovers retrograde opioid signaling at hypothalamic synapses. Nat Neurosci 16, 596–604 (2013). https://doi.org/10.1038/nn.3374

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