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Dopamine D2 receptors gate generalization of conditioned threat responses through mTORC1 signaling in the extended amygdala

Molecular Psychiatry volume 21, pages 1545–1553 (2016)Cite this article

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Abstract

Overgeneralization of conditioned threat responses is a robust clinical marker of anxiety disorders. In overgeneralization, responses that are appropriate to threat-predicting cues are evoked by perceptually similar safety-predicting cues. Inappropriate learning of conditioned threat responses may thus form an etiological basis for anxiety disorders. The role of dopamine (DA) in memory encoding is well established. Indeed by signaling salience and valence, DA is thought to facilitate discriminative learning between stimuli representing safety or threat. However, the neuroanatomical and biochemical substrates through which DA modulates overgeneralization of threat responses remain poorly understood. Here we report that the modulation of DA D2 receptor (D2R) signaling bidirectionally regulates the consolidation of fear responses. While the blockade of D2R induces generalized threat responses, its stimulation facilitates discriminative learning between stimuli representing safety or threat. Moreover, we show that controlled threat generalization requires the coordinated activation of D2R in the bed nucleus of the stria terminalis and the central amygdala. Finally, we identify the mTORC1 cascade activation as an important molecular event by which D2R mediates its effects. These data reveal that D2R signaling in the extended amygdala constitutes an important checkpoint through which DA participates in the control of threat processing and the emergence of overgeneralized threat responses.

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Acknowledgements

We thank members of the Valjent laboratory for discussions. We also thank Bo Li for insightful and constructive comments. This work was supported by Inserm (ATIP-Avenir), and the Agence Nationale de la Recherche (ANR-2010-JCJC-1412) to EV. DDB was a recipient of a postdoctoral fellowship from the Fondation pour la Recherche Médicale (FRM). J-AG is supported by an ERC Advanced Grant and is affiliated with the Paris School of Neuroscience and the Bio-Psy Laboratory of excellence.

Author contributions

DDB and EV designed the study. DDB conducted experiments and analyzed the data. CZ and JE assisted with the behavioral experiments. CRG and J-AG provided critical reagents and suggestions. DDB and EV wrote the manuscript.

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  1. D De Bundel

    Present address: 8Current address: Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 103 Laarbeeklaan, Brussels 1090, Belgium.,

Authors and Affiliations

  1. CNRS, UMR 5203, Institut de Génomique Fonctionnelle, Montpellier, France

    D De Bundel, C Zussy, J Espallergues & E Valjent

  2. Inserm U1191, Montpellier, France

    D De Bundel, C Zussy, J Espallergues & E Valjent

  3. UMR 5203, Universités de Montpellier, Montpellier, France

    D De Bundel, C Zussy, J Espallergues & E Valjent

  4. Laboratory of Systems Neuroscience, National Institute of Mental Health, Bethesda, MD, USA

    C R Gerfen

  5. Inserm, UMR-S 839, Paris, France

    J-A Girault

  6. Institut du Fer à Moulin, Paris, France

    J-A Girault

  7. Sorbonne Universités, UPMC, Université Paris 06, Paris, France

    J-A Girault

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  1. D De Bundel
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Correspondence to D De Bundel or E Valjent.

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De Bundel, D., Zussy, C., Espallergues, J. et al. Dopamine D2 receptors gate generalization of conditioned threat responses through mTORC1 signaling in the extended amygdala. Mol Psychiatry 21, 1545–1553 (2016). https://doi.org/10.1038/mp.2015.210

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