The DOI matches its Crossref record; 25 of the 25 references it cites were found in a registry or an index.
Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala
Open accessAbstract
Serotonin (also known as 5-hydroxytryptamine (5-HT)) is a neurotransmitter that has an essential role in the regulation of emotion. However, the precise circuits have not yet been defined through which aversive states are orchestrated by 5-HT. Here we show that 5-HT from the dorsal raphe nucleus (5-HT DRN) enhances fear and anxiety and activates a subpopulation of corticotropin-releasing factor (CRF) neurons in the bed nucleus of the stria terminalis (CRF BNST) in mice. Specifically, 5-HT DRN projections to the BNST, via actions at 5-HT 2C receptors (5-HT 2C Rs), engage a CRF BNST inhibitory microcircuit that silences anxiolytic BNST outputs to the ventral tegmental area and lateral hypothalamus. Furthermore, we demonstrate that this CRF BNST inhibitory circuit underlies aversive behaviour following acute exposure to selective serotonin reuptake inhibitors (SSRIs). This early aversive effect is mediated via the corticotrophin-releasing factor type 1 receptor (CRF 1 R, also known as CRHR1), given that CRF 1 R antagonism is sufficient to prevent acute SSRI-induced enhancements in aversive learning. These results reveal an essential 5-HT DRN→CRF BNST circuit governing fear and anxiety, and provide a potential mechanistic explanation for the clinical observation of early adverse events to SSRI treatment in some patients with anxiety disorders.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“This suggests these drugs affect multiple 5-HT pathways with distinct and contrasting effects on behavior and highlights the need for new approaches to target specific 5-HT neurons and their outputs (Marcinkiewcz et al., 2016; Urban et al., 2016).”
From Molecular and anatomical organization of the dorsal raphe nucleus (2019) · cites this paper as Marcinkiewcz et al., 2016
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
A robust and high-throughput Cre reporting and characterization system for the whole mouse brain
Madisen, L., Zwingman, T. A., Sunkin, S. M., Oh, S. W., Zariwala, H. A., Gu, H., Ng, L. L., Palmiter, R. D., Hawrylycz, M. J., Jones, A. R., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2467 · Cited by 6,907
Armbruster, B. N., Li, X., Pausch, M. H., Herlitze, S., & Roth, B. L. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0700293104 · Cited by 2,046
Distinct extended amygdala circuits for divergent motivational states
Jennings, J. H., Sparta, D. R., Stamatakis, A. M., Ung, R. L., Pleil, K. E., Kash, T. L., & Stuber, G. D. (2013) · Nature · doi:10.1038/nature12041 · Cited by 704
Diverging neural pathways assemble a behavioural state from separable features in anxiety
Kim, S.-Y., Adhikari, A., Lee, S. Y., Marshel, J. H., Kim, C. K., Mallory, C. S., Lo, M., Pak, S., Mattis, J., Lim, B. K., et al. (2013) · Nature · doi:10.1038/nature12018 · Cited by 666
An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger
Krashes, M. J., Shah, B. P., Madara, J. C., Olson, D. P., Strochlic, D. E., Garfield, A. S., Vong, L., Pei, H., Watabe-Uchida, M., Uchida, N., et al. (2014) · Nature · doi:10.1038/nature12956 · Cited by 603
Targeting cells with single vectors using multiple-feature Boolean logic
Fenno, L. E., Mattis, J., Ramakrishnan, C., Hyun, M., Lee, S. Y., He, M., Tucciarone, J., Selimbeyoglu, A., Berndt, A., Grosenick, L., et al. (2014) · Nature Methods · doi:10.1038/nmeth.2996 · Cited by 557
Dorsal raphe neurons signal reward through 5-HT and glutamate
Liu, Z., Zhou, J., Li, Y., Hu, F., Lu, Y., Ma, M., Feng, Q., Zhang, J.-E., Wang, D., Zeng, J., et al. (2014) · Neuron · doi:10.1016/j.neuron.2014.02.010 · Cited by 469
Subsecond Adsorption and Desorption of Dopamine at Carbon-Fiber Microelectrodes
Bath, B. D., Michael, D. J., Venton, B. J., Joseph, J. D., Runnels, P. L., & Wightman, R. M. (2000) · Analytical Chemistry · doi:10.1021/ac000849y · Cited by 363
Dabrowska, J., Hazra, R., Ahern, T. H., Guo, J.-D., McDonald, A. J., Mascagni, F., Muller, J. F., Young, L. J., & Rainnie, D. G. (2011) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2011.03.003 · Cited by 274
Hefner, K. R., Whittle, N., Juhasz, J., Norcross, M. A., Karlsson, R., Saksida, L. M., Bussey, T. J., Singewald, N., & Holmes, A. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.4904-07.2008 · Cited by 256
Cited by
Sorted by citations
Integration of optogenetics with complementary methodologies in systems neuroscience
Kim, C. K., Adhikari, A., & Deisseroth, K. (2017) · Nature reviews. Neuroscience · doi:10.1038/nrn.2017.15 · Cited by 690
Anatomically defined and functionally distinct dorsal raphe serotonin sub-systems
Ren, J., Friedmann, D., Xiong, J., Liu, C. D., Ferguson, B. R., Weerakkody, T., DeLoach, K. E., Ran, C., Pun, A., Sun, Y., et al. (2018) · Cell · doi:10.1016/j.cell.2018.07.043 · Cited by 498
“Recent studies have begun to target DR subpopulations by utilizing optogenetic activation of serotoninergic terminals at specific targets (Marcinkiewcz et al., 2016) or genetic intersection combined with chemogenetic perturbations (Niederkofler et al.”
The role of 5-HT receptors in depression
Yohn, C. N., Gergues, M. M., & Samuels, B. A. (2017) · Molecular Brain · doi:10.1186/s13041-017-0306-y · Cited by 485
“showed that 5-HT release from the dorsal raphe nucleus enhances fear and anxiety through activation of 5-HT2CRs on a subpopulation of corticotropin-releasing factor (CRF) neurons in the bed nucleus of the stria terminalis (BNST) [86].”
BackgroundInfluentialGut microbiome and depression: what we know and what we need to know
Winter, G., Hart, R. A., Charlesworth, R. P. G., & Sharpley, C. F. (2018) · Reviews in the Neurosciences · doi:10.1515/revneuro-2017-0072 · Cited by 394
The Roles of Serotonin in Neuropsychiatric Disorders
Pourhamzeh, M., Moravej, F. G., Arabi, M., Shahriari, E., Mehrabi, S., Ward, R. T., Ahadi, R., & Joghataei, M. T. (2021) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-021-01064-9 · Cited by 409
Metadata
- Authors
- Marcinkiewcz, C. A., Mazzone, C. M., D’Agostino, G., Halladay, L. R., Hardaway, J. A., DiBerto, J. F., Navarro, M., Burnham, N., Cristiano, C., Dorrier, C. E., Tipton, G. J., Ramakrishnan, C., Kozicz, T., Deisseroth, K., Thiele, T. E., McElligott, Z. A., Holmes, A., Heisler, L. K., & Kash, T. L.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- University of Aberdeen (GB)
- National Institutes of Health (US)
- Stanford University (US)
- Corresponding author
- Kash, Thomas L.
- ORCID
- Venue
- Nature
- Published
- 2016-08-24
- Volume
- 537
- Issue
- 7618
- Pages
- 97-101
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5124365
- OpenAlex
- W2516878167
- Cited by
- 456
- References
- 25
- Citations by year
- 2026: 45 · 2025: 41 · 2024: 41 · 2023: 48 · 2022: 53 · 2021: 46 · 2020: 51 · 2019: 45 · 2018: 46 · 2017: 35 · 2016: 3
- FWCI
- 24.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Aberdeen University Research Archive (Aberdeen University) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- Wellcome Trust (098012)
- National Institutes of Health (5f32aa021319-02, AA011605)
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council (BB/K001418/1)
- National Institute on Alcohol Abuse and Alcoholism (P50AA011605, AA019454, AA011605, F31AA023440, F32-AA021319, K01AA023555, P60AA011605, R01AA019454)
- National Institute of Mental Health (T32MH076694)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- serotonin, anxiety, fear, extended amygdala, bed nucleus of the stria terminalis, dorsal raphe nucleus, corticotropin-releasing hormone neurons, 5-HT2C receptor, CRF1 receptor, fluoxetine, selective serotonin reuptake inhibitors, adverse drug reactions, ventral tegmental area, lateral hypothalamus, aversive learning
- MeSH terms
- CRF Receptor, Type 1, Amygdala, Animals, Anxiety, Anxiety Disorders, Corticotropin-Releasing Hormone, Fear, Female, Fluoxetine, Hypothalamus, Male, Neurons, Serotonin, Thalamus, Selective Serotonin Reuptake Inhibitors, Ventral Tegmental Area, Receptors, Corticotropin-Releasing Hormone, Mice, Optogenetics, Dorsal Raphe Nucleus
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
