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^* (Corresponding Author)

^*Corresponding author for this work

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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-HT2C receptors (5-HT2CRs), 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 (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-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 disorders.

Original language	English
Pages (from-to)	97-101
Number of pages	5
Journal	Nature
Volume	537
Early online date	24 Aug 2016
DOIs	https://doi.org/10.1038/nature19318
Publication status	Published - 1 Sep 2016

Keywords

limbic system
neural circuits

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Lora Heisler
- School of Medicine, Medical Sciences & Nutrition, The Rowett Institute of Nutrition and Health - Chair in Human Nutrition
Person: Academic

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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, 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, 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-HT2C receptors (5-HT2CRs), 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 (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-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 disorders.",

keywords = "limbic system, neural circuits",

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.}",

note = "We acknowledge B. Roth for providing DREADD viral constructs and SertCre mice, and B. Lowell for providing CrfCre mice. We also thank A. Lopez, D. Perron, and A. Kendra for technical assistance with stereotaxic surgeries on mice, B. Geenen for technical assistance with immunohistochemistry and E. Dankoski for technical assistance with the FSCV. This work was supported by NIH grants AA019454, AA011605 (T.L.K.), the Wellcome Trust (098012) and the Biotechnology and Biological Sciences Research Council grant (BB/K001418/1) (L.K.H.) and by NIH grant K01AA023555 and the Alcohol Beverage Medical Research Fund (Z.A.M.). C.A.M. was supported by a postdoctoral NIAAA F32 fellowship (AA021319-02). C.M.M. is supported by a predoctoral NIAAA F31 fellowship (F31AA023440).",

year = "2016",

month = sep,

day = "1",

doi = "10.1038/nature19318",

language = "English",

volume = "537",

pages = "97--101",

journal = "Nature",

issn = "0028-0836",

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TY - JOUR

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.

N1 - We acknowledge B. Roth for providing DREADD viral constructs and SertCre mice, and B. Lowell for providing CrfCre mice. We also thank A. Lopez, D. Perron, and A. Kendra for technical assistance with stereotaxic surgeries on mice, B. Geenen for technical assistance with immunohistochemistry and E. Dankoski for technical assistance with the FSCV. This work was supported by NIH grants AA019454, AA011605 (T.L.K.), the Wellcome Trust (098012) and the Biotechnology and Biological Sciences Research Council grant (BB/K001418/1) (L.K.H.) and by NIH grant K01AA023555 and the Alcohol Beverage Medical Research Fund (Z.A.M.). C.A.M. was supported by a postdoctoral NIAAA F32 fellowship (AA021319-02). C.M.M. is supported by a predoctoral NIAAA F31 fellowship (F31AA023440).

PY - 2016/9/1

Y1 - 2016/9/1

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-HT2C receptors (5-HT2CRs), 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 (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-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 disorders.

AB - 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-HT2C receptors (5-HT2CRs), 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 (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-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 disorders.

KW - limbic system

KW - neural circuits

U2 - 10.1038/nature19318

DO - 10.1038/nature19318

M3 - Article

C2 - 27556938

VL - 537

SP - 97

EP - 101

JO - Nature

JF - Nature

SN - 0028-0836

ER -

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

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