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

doi:10.1038/nature19318

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

Medical Genetics

Research output: Contribution to journal › Article › peer-review

183 Scopus citations

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 language	English (US)
Pages (from-to)	97-101
Number of pages	5
Journal	Nature
Volume	537
Issue number	7618
DOIs	https://doi.org/10.1038/nature19318
State	Published - Aug 24 2016

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Marcinkiewcz, C. A., Mazzone, C. M., D'Agostino, G., Halladay, L. R., Hardaway, J. A., Diberto, J. F., Navarro, M., Burnham, N., Cristiano, C., Dorrier, C. E., Tipton, G. J., Ramakrishnan, C., Kozicz, T., Deisseroth, K., Thiele, T. E., McElligott, Z. A., Holmes, A., Heisler, L. K., & 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

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

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title = "Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala",

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 {\^a} †'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.",

author = "Marcinkiewcz, {Catherine A.} and Mazzone, {Christopher M.} and Giuseppe D'Agostino and Halladay, {Lindsay R.} and Hardaway, {J. Andrew} and Diberto, {Jeffrey F.} and Montserrat Navarro and Nathan Burnham and Claudia Cristiano and Dorrier, {Cayce E.} and Tipton, {Gregory J.} and Charu Ramakrishnan and Tamas Kozicz and Karl Deisseroth and Thiele, {Todd E.} and McElligott, {Zoe A.} and Andrew Holmes and Heisler, {Lora K.} and Kash, {Thomas L.}",

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doi = "10.1038/nature19318",

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T1 - Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala

AU - Marcinkiewcz, Catherine A.

AU - Mazzone, Christopher M.

AU - D'Agostino, Giuseppe

AU - Halladay, Lindsay R.

AU - Hardaway, J. Andrew

AU - Diberto, Jeffrey F.

AU - Navarro, Montserrat

AU - Burnham, Nathan

AU - Cristiano, Claudia

AU - Dorrier, Cayce E.

AU - Tipton, Gregory J.

AU - Ramakrishnan, Charu

AU - Kozicz, Tamas

AU - Deisseroth, Karl

AU - Thiele, Todd E.

AU - McElligott, Zoe A.

AU - Holmes, Andrew

AU - Heisler, Lora K.

AU - Kash, Thomas L.

PY - 2016/8/24

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N2 - 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.

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ER -

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

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