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

Research output: Contribution to journalArticle

115 Citations (Scopus)

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-HT 2C receptors (5-HT 2C Rs), 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 (CRF 1 R, also known as CRHR1), 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 â †'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 (US)
Pages (from-to)97-101
Number of pages5
JournalNature
Volume537
Issue number7618
DOIs
StatePublished - Aug 24 2016
Externally publishedYes

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Amygdala
Corticotropin-Releasing Hormone
Fear
Serotonin
Anxiety
Serotonin Uptake Inhibitors
Lateral Hypothalamic Area
Septal Nuclei
Ventral Tegmental Area
Anti-Anxiety Agents
Anxiety Disorders
Neurotransmitter Agents
Emotions
Observation
Learning
Neurons

ASJC Scopus subject areas

  • General

Cite this

Marcinkiewcz, C. A., Mazzone, C. M., D'Agostino, G., Halladay, L. R., Hardaway, J. A., Diberto, J. F., ... Kash, T. L. (2016). Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala. Nature, 537(7618), 97-101. https://doi.org/10.1038/nature19318

Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala. / Marcinkiewcz, Catherine A.; Mazzone, Christopher M.; D'Agostino, Giuseppe; Halladay, Lindsay R.; Hardaway, J. Andrew; Diberto, Jeffrey F.; Navarro, Montserrat; Burnham, Nathan; Cristiano, Claudia; Dorrier, Cayce E.; Tipton, Gregory J.; Ramakrishnan, Charu; Kozicz, Tamas; Deisseroth, Karl; Thiele, Todd E.; McElligott, Zoe A.; Holmes, Andrew; Heisler, Lora K.; Kash, Thomas L.

In: Nature, Vol. 537, No. 7618, 24.08.2016, p. 97-101.

Research output: Contribution to journalArticle

Marcinkiewcz, CA, Mazzone, CM, D'Agostino, G, Halladay, LR, Hardaway, JA, Diberto, JF, Navarro, M, Burnham, N, Cristiano, C, Dorrier, CE, Tipton, GJ, Ramakrishnan, C, Kozicz, T, Deisseroth, K, Thiele, TE, McElligott, ZA, Holmes, A, Heisler, LK & Kash, TL 2016, 'Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala', Nature, vol. 537, no. 7618, pp. 97-101. https://doi.org/10.1038/nature19318
Marcinkiewcz CA, Mazzone CM, D'Agostino G, Halladay LR, Hardaway JA, Diberto JF et al. Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala. Nature. 2016 Aug 24;537(7618):97-101. https://doi.org/10.1038/nature19318
Marcinkiewcz, Catherine A. ; Mazzone, Christopher M. ; D'Agostino, Giuseppe ; Halladay, Lindsay R. ; Hardaway, J. Andrew ; Diberto, Jeffrey F. ; Navarro, Montserrat ; Burnham, Nathan ; Cristiano, Claudia ; Dorrier, Cayce E. ; Tipton, Gregory J. ; Ramakrishnan, Charu ; Kozicz, Tamas ; Deisseroth, Karl ; Thiele, Todd E. ; McElligott, Zoe A. ; Holmes, Andrew ; Heisler, Lora K. ; Kash, Thomas L. / Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala. In: Nature. 2016 ; Vol. 537, No. 7618. pp. 97-101.
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