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

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 disorders1,2.