Dopamine D2 receptors gate generalization of conditioned threat responses through mTORC1 signaling in the extended amygdala
Open accessAbstract
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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Modulating D2Rs in the central amygdala plays a vital role in fear response consolidation, with stimulation aiding discriminative learning and blockade inducing generalized threat responses.
“Modulating D2Rs in the central amygdala plays a vital role in fear response consolidation, with stimulation aiding discriminative learning and blockade of inducing generalized threat responses (De Bundel et al., 2016).”
From Evidence for the existence of facilitatory interactions between the dopamine D2 receptor and the oxytocin receptor in the amygdala of the rat relevance for anxiolytic actions (2023) · cites this paper as De Bundel et al., 2016
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Dorsal tegmental dopamine neurons gate associative learning of fear
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- Authors
- De Bundel, D., Zussy, C., Espallergues, J., Gerfen, C. R., Girault, J.-A., & Valjent, E.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- National Institutes of Health (US)
- Inserm (FR)
- Venue
- Molecular Psychiatry
- Published
- 2016-01-19
- Volume
- 21
- Issue
- 11
- Pages
- 1545-1553
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC5101541
- OpenAlex
- W2258752721
- Cited by
- 112
- References
- 64
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 13 · 2023: 21 · 2022: 5 · 2021: 17 · 2020: 5 · 2019: 12 · 2018: 13 · 2017: 7 · 2016: 2
- FWCI
- 7.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, other-oa)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (Z01MH002497, ZIAMH002497)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- dopamine D2 receptor, overgeneralization, fear consolidation, discriminative learning, mTORC1 signaling, extended amygdala, bed nucleus of the stria terminalis, central amygdala, anxiety disorders, threat processing, memory encoding
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Amygdala, Animals, Anxiety, Anxiety Disorders, Conditioning, Classical, Cues, Dopamine, Fear, Learning, Male, Mice, Inbred BALB C, Septal Nuclei, Receptors, Dopamine D2, Multiprotein Complexes, Mice, TOR Serine-Threonine Kinases
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