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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amygdala / drug effects
  • Amygdala / metabolism*
  • Animals
  • Anxiety / chemically induced
  • Anxiety / metabolism*
  • Anxiety Disorders / chemically induced
  • Corticotropin-Releasing Hormone / metabolism*
  • Dorsal Raphe Nucleus / drug effects
  • Dorsal Raphe Nucleus / metabolism
  • Fear / drug effects
  • Fear / physiology*
  • Female
  • Fluoxetine / adverse effects
  • Fluoxetine / pharmacology
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism
  • Male
  • Mice
  • Neurons / drug effects
  • Neurons / metabolism
  • Optogenetics
  • Receptors, Corticotropin-Releasing Hormone / metabolism
  • Selective Serotonin Reuptake Inhibitors / adverse effects
  • Selective Serotonin Reuptake Inhibitors / pharmacology
  • Serotonin / metabolism*
  • Thalamus / drug effects
  • Thalamus / metabolism*
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / metabolism

Substances

  • Receptors, Corticotropin-Releasing Hormone
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • Serotonin
  • CRF receptor type 1
  • Corticotropin-Releasing Hormone