1. Dopamine D2 receptors gate generalization of conditioned threat responses through mTORC1 signaling in the extended amygdala
- Author
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Charleine Zussy, Julie Espallergues, Charles R. Gerfen, Jean-Antoine Girault, Emmanuel Valjent, Dimitri De Bundel, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Institut du Fer à Moulin, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Pharmaceutical Chemistry, Drug Analysis and Drug Information, Pharmaceutical and Pharmacological Sciences, Faculty of Medicine and Pharmacy, and Experimental Pharmacology
- Subjects
Male ,0301 basic medicine ,Dopamine ,[SDV]Life Sciences [q-bio] ,Conditioning, Classical ,Stimulation ,Anxiety ,Mechanistic Target of Rapamycin Complex 1 ,Amygdala ,Article ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Extended amygdala ,Dopamine receptor D2 ,medicine ,Animals ,Learning ,Molecular Biology ,ComputingMilieux_MISCELLANEOUS ,Mice, Inbred BALB C ,Receptors, Dopamine D2 ,TOR Serine-Threonine Kinases ,Septal nuclei ,Fear ,Anxiety Disorders ,Psychiatry and Mental health ,Stria terminalis ,030104 developmental biology ,medicine.anatomical_structure ,Multiprotein Complexes ,Septal Nuclei ,Cues ,medicine.symptom ,Psychology ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - 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.Molecular Psychiatry advance online publication, 19 January 2016; doi:10.1038/mp.2015.210.
- Published
- 2016
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