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Nature. 2016 Sep 1;537(7618):97-101. doi: 10.1038/nature19318. Epub 2016 Aug 24.

Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala.

Author information

1
Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
2
Curriculum in Neurobiology, School of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
3
Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen AB25 2ZD, UK.
4
National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD 20852-9411, USA.
5
Department of Psychology & Neuroscience, College of Arts and Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
6
Department of Bioengineering, Stanford University, Stanford CA 94305, USA.
7
Hayward Genetics Center, Tulane University, New Orleans, LA 70112, USA.
8
Department of Anatomy, Radboud University Nijmegen Medical Center, 6500HB Nijmegen, The Netherlands.
9
Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
10
Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
#
Contributed equally

Abstract

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-HTDRN) enhances fear and anxiety and activates a subpopulation of corticotropin-releasing factor (CRF) neurons in the bed nucleus of the stria terminalis (CRFBNST) in mice. Specifically, 5-HTDRN projections to the BNST, via actions at 5-HT2C receptors (5-HT2CRs), engage a CRFBNST inhibitory microcircuit that silences anxiolytic BNST outputs to the ventral tegmental area and lateral hypothalamus. Furthermore, we demonstrate that this CRFBNST 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 (CRF1R, also known as CRHR1), given that CRF1R antagonism is sufficient to prevent acute SSRI-induced enhancements in aversive learning. These results reveal an essential 5-HTDRN→CRFBNST 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.

PMID:
27556938
PMCID:
PMC5124365
[Available on 2017-02-24]
DOI:
10.1038/nature19318
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no financial conflict of interest.

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