title: Dopamine D2 receptors gate generalization of conditioned threat responses through mTORC1 signaling in the extended amygdala.
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.
authors.affiliation: CNRS, UMR 5203, Institut de Génomique Fonctionnelle, Montpellier, France.|Inserm U1191, Montpellier, France.|UMR 5203, Universités de Montpellier, Montpellier, France.
authors.forename: D
authors.initials: D
authors.lastname: De Bundel
authors.affiliation: CNRS, UMR 5203, Institut de Génomique Fonctionnelle, Montpellier, France.|Inserm U1191, Montpellier, France.|UMR 5203, Universités de Montpellier, Montpellier, France.
authors.forename: C
authors.initials: C
authors.lastname: Zussy
authors.affiliation: CNRS, UMR 5203, Institut de Génomique Fonctionnelle, Montpellier, France.|Inserm U1191, Montpellier, France.|UMR 5203, Universités de Montpellier, Montpellier, France.
authors.forename: J
authors.initials: J
authors.lastname: Espallergues
authors.affiliation: Laboratory of Systems Neuroscience, National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Gerfen
authors.affiliation: Inserm, UMR-S 839, Paris, France.|Institut du Fer à Moulin, Paris, France.|Sorbonne Universités, UPMC, Université Paris 06, Paris, France.
authors.forename: J-A
authors.initials: JA
authors.lastname: Girault
authors.affiliation: CNRS, UMR 5203, Institut de Génomique Fonctionnelle, Montpellier, France.|Inserm U1191, Montpellier, France.|UMR 5203, Universités de Montpellier, Montpellier, France.
authors.forename: E
authors.initials: E
authors.lastname: Valjent
mesh_terms: D000679:Amygdala / Q000502:physiology*; D000818:Animals; D001007:Anxiety / Q000378:metabolism / Q000503:physiopathology; D001008:Anxiety Disorders / Q000209:etiology / Q000378:metabolism; D003214:Conditioning, Classical; D003463:Cues; D004298:Dopamine / Q000378:metabolism; D005239:Fear / Q000502:physiology*; D007858:Learning / Q000502:physiology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008807:Mice, Inbred BALB C; D046912:Multiprotein Complexes / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D012686:Septal Nuclei / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D017448:Receptors, Dopamine D2; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D004298:Dopamine