title: Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala.
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-HTDRNprojections to the BNST, via actions at 5-HT2Creceptors (5-HT2CRs), engage a CRFBNSTinhibitory microcircuit that silences anxiolytic BNST outputs to the ventral tegmental area and lateral hypothalamus. Furthermore, we demonstrate that this CRFBNSTinhibitory 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→CRFBNSTcircuit 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.
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Marcinkiewcz
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Curriculum in Neurobiology, School of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Mazzone
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen AB25 2ZD, UK.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: D'Agostino
authors.affiliation: National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD 20852-9411, USA.
authors.forename: Lindsay R
authors.initials: LR
authors.lastname: Halladay
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Hardaway
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: DiBerto
authors.affiliation: Department of Psychology & Neuroscience, College of Arts and Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Navarro
authors.affiliation: Department of Psychology & Neuroscience, College of Arts and Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Burnham
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen AB25 2ZD, UK.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cristiano
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Cayce E
authors.initials: CE
authors.lastname: Dorrier
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tipton
authors.affiliation: Department of Bioengineering, Stanford University, Stanford CA 94305, USA.
authors.forename: Charu
authors.initials: C
authors.lastname: Ramakrishnan
authors.affiliation: Hayward Genetics Center, Tulane University, New Orleans, LA 70112, USA.|Department of Anatomy, Radboud University Nijmegen Medical Center, 6500HB Nijmegen, The Netherlands.
authors.forename: Tamas
authors.initials: T
authors.lastname: Kozicz
authors.affiliation: Department of Bioengineering, Stanford University, Stanford CA 94305, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Deisseroth
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Department of Psychology & Neuroscience, College of Arts and Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Thiele
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Zoe A
authors.initials: ZA
authors.lastname: McElligott
authors.affiliation: National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD 20852-9411, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Holmes
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen AB25 2ZD, UK.
authors.forename: Lora K
authors.initials: LK
authors.lastname: Heisler
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Curriculum in Neurobiology, School of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.|Department of Psychology & Neuroscience, College of Arts and Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Kash
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000378:metabolism*; D001008:Anxiety Disorders / Q000139:chemically induced; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D065847:Dorsal Raphe Nucleus / Q000187:drug effects / Q000378:metabolism; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005473:Fluoxetine / Q000009:adverse effects / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D062308:Optogenetics; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D013788:Thalamus / Q000187:drug effects / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism; D000099052:CRF Receptor, Type 1
chemical_list: D003346:Corticotropin-Releasing Hormone; D005473:Fluoxetine; D018019:Receptors, Corticotropin-Releasing Hormone; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D000099052:CRF Receptor, Type 1