Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Amygdala engaged by Serotonin anxiety and fear-promoting circuit


Nature  537, 97–101 (01 September 2016)

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

Catherine A. Marcinkiewcz,

Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA

Curriculum in Neurobiology, School of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599, USA

Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen AB25 2ZD, UK

National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland 20852-9411, USA

Department of Psychology & Neuroscience, College of Arts and Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA

Department of Bioengineering, Stanford University, Stanford, California 94305, USA

Hayward Genetics Center, Tulane University, New Orleans, Louisiana 70112, USA

Department of Anatomy, Radboud University Nijmegen Medical Center, 6500HB Nijmegen, The Netherlands

Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA

Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA


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.

Given the multiple converging lines of evidence pinpointing 5-HT as a critical neuromodulator of pathological fear learning, we first interrogated the endogenous recruitment of the 5-HTDRN→BNST circuit by an aversive footshock stimulus in mice. Using Fluoro-Gold to retrogradely label BNST-projecting 5-HT neurons in the dorsal raphe nucleus (DRN), we found that c-fos, an immediate-early gene indicative of in vivo neuronal activation, was significantly elevated in 5-HTDRN→BNST neurons after footshock. Using in vivo electrophysiology, we then probed the neuronal dynamics of the BNST during fear conditioning and recall, and found evidence for engagement during both conditioning and recall.

Our data reveal a discrete 5-HT responsive circuit in the BNST that underlies pathological anxiety and fear associated with a hyperserotonergic state. SSRIs are currently a first-line treatment for anxiety and panic disorders, but can acutely exacerbate symptoms, resulting in poor therapeutic compliance. Our results strongly implicate 5-HT engagement of a local BNST-inhibitory microcircuit in acute SSRI-induced aversive behaviours in rodents, and could potentially be involved in the early adverse events seen in clinical populations, emphasizing the need to identify compounds that selectively target both genetically defined and pathway-specific cell populations

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