Serotonin Engages an Anxiety and Fear-promoting Circuit in the Extended Amygdala

Overview

Journal Nature

Specialty Science

Date 2016 Aug 25

PMID 27556938

Citations 215

Authors

Catherine A Marcinkiewcz

Christopher M Mazzone

Giuseppe DAgostino

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

Affiliations

Soon will be listed here.

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

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