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* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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-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-HT2C receptors (5-HT2CRs), 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 (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-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.

Original languageEnglish
Pages (from-to)97-101
Number of pages5
JournalNature
Volume537
Early online date24 Aug 2016
DOIs
Publication statusPublished - 1 Sept 2016

Bibliographical note

We acknowledge B. Roth for providing DREADD viral constructs and SertCre mice, and B. Lowell for providing CrfCre mice. We also thank A. Lopez, D. Perron, and A. Kendra for technical assistance with stereotaxic surgeries on mice, B. Geenen for technical assistance with immunohistochemistry and E. Dankoski for technical assistance with the FSCV. This work was supported by NIH grants AA019454, AA011605 (T.L.K.), the Wellcome Trust (098012) and the Biotechnology and Biological Sciences Research Council grant (BB/K001418/1) (L.K.H.) and by NIH grant K01AA023555 and the Alcohol Beverage Medical Research Fund (Z.A.M.). C.A.M. was supported by a postdoctoral NIAAA F32 fellowship (AA021319-02). C.M.M. is supported by a predoctoral NIAAA F31 fellowship (F31AA023440).

Keywords

  • limbic system
  • neural circuits

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