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

Catherine A Marcinkiewcz; Christopher M Mazzone; Giuseppe D’Agostino; Lindsay R Halladay; J. Andrew Hardaway; Jeffrey F DiBerto; Montserrat Navarro; Nathan Burnham; Claudia Cristiano; Cayce E Dorrier; Gregory J Tipton; Charu Ramakrishnan; Tamas Kozicz; Karl Deisseroth; Todd E Thiele; Zoe A McElligott; Andrew Holmes; Lora K Heisler; Thomas L Kash

doi:10.1038/nature19318

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

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

Catherine A Marcinkiewcz, Christopher M Mazzone, Giuseppe D’Agostino, Lindsay R Halladay, J. Andrew Hardaway, Jeffrey F DiBerto, Montserrat Navarro, Nathan Burnham, Claudia Cristiano, Cayce E Dorrier, …

Nature (London), Vol.537(7618), pp.97-101

09/01/2016

DOI: 10.1038/nature19318

PMCID: PMC5124365

PMID: 27556938

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Abstract

Serotonin (5-hydroxytryptamine; 5-HT) is a neurotransmitter that has an essential role in the regulation of emotion. The precise circuits through which aversive states are orchestrated by 5-HT, however, have not yet been defined. 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 ). 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 (VTA) and lateral hypothalamus (LH). Further, we demonstrate that this CRF BNST inhibitory circuit underlies aversive behavior 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) 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 1 , 2 .

anxiety

BNST

VTA

Serotonin

CRF

5-HT2C receptor

fear

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Title: Subtitle: Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala
Creators: Catherine A Marcinkiewcz - Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Christopher M Mazzone - Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Giuseppe D’Agostino - Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen AB25 2ZD, UK
Lindsay R Halladay - National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD 20852-9411, USA
J. Andrew Hardaway - Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Jeffrey F DiBerto - Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Montserrat Navarro - Department of Psychology & Neuroscience, College of Arts and Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Nathan Burnham - Department of Psychology & Neuroscience, College of Arts and Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Claudia Cristiano - Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen AB25 2ZD, UK
Cayce E Dorrier - Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Gregory J Tipton - Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Charu Ramakrishnan - Department of Bioengineering, Stanford University, Stanford CA 94305, USA
Tamas Kozicz - Hayward Genetics Center, Tulane University, New Orleans, LA 70112, USA
Karl Deisseroth - Department of Bioengineering, Stanford University, Stanford CA 94305, USA
Todd E Thiele - Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Zoe A McElligott - Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Andrew Holmes - National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD 20852-9411, USA
Lora K Heisler - Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen AB25 2ZD, UK
Thomas L Kash - Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Resource Type: Journal article
Publication Details: Nature (London), Vol.537(7618), pp.97-101
DOI: 10.1038/nature19318
PMID: 27556938
PMCID: PMC5124365
NLM abbreviation: Nature
ISSN: 0028-0836
eISSN: 1476-4687
Language: English
Date published: 09/01/2016
Academic Unit: Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9984040355202771

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