Ucn3 and CRF-R2 in the medial amygdala regulate complex social dynamics

Yair Shemesh; Oren Forkosh; Mathias Mahn; Sergey Anpilov; Yehezkel Sztainberg; Sharon Manashirov; Tamar Shlapobersky; Evan Elliott; Laure Tabouy; Gili Ezra; Elaine S. Adler; Yair J. Ben-Efraim; Shosh Gil; Yael Kuperman; Sharon Haramati; Julien Dine; Matthias Eder; Jan M. Deussing; Elad Schneidman; Ofer Yizhar; Alon Chen

doi:10.1038/nn.4346

Ucn3 and CRF-R2 in the medial amygdala regulate complex social dynamics

Yair Shemesh, Oren Forkosh, Mathias Mahn, Sergey Anpilov, Yehezkel Sztainberg, Sharon Manashirov, Tamar Shlapobersky, Evan Elliott, Laure Tabouy, Gili Ezra, Elaine S. Adler, Yair J. Ben-Efraim, Shosh Gil, Yael Kuperman, Sharon Haramati, Julien Dine, Matthias Eder, Jan M. Deussing, Elad Schneidman, Ofer YizharAlon Chen

Bar-Ilan University - Azrieli Faculty of Medicine

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

84 Scopus citations

Abstract

Social encounters are associated with varying degrees of emotional arousal and stress. The mechanisms underlying adequate socioemotional balance are unknown. The medial amygdala (MeA) is a brain region associated with social behavior in mice. Corticotropin-releasing factor receptor type-2 (CRF-R2) and its specific ligand urocortin-3 (Ucn3), known components of the behavioral stress response system, are highly expressed in the MeA. Here we show that mice deficient in CRF-R2 or Ucn3 exhibit abnormally low preference for novel conspecifics. MeA-specific knockdown of Crfr2 (Crhr2) in adulthood recapitulated this phenotype. In contrast, pharmacological activation of MeA CRF-R2 or optogenetic activation of MeA Ucn3 neurons increased preference for novel mice. Furthermore, chemogenetic inhibition of MeA Ucn3 neurons elicited pro-social behavior in freely behaving groups of mice without affecting their hierarchal structure. These findings collectively suggest that the MeA Ucn3-CRF-R2 system modulates the ability of mice to cope with social challenges.

Original language	English
Pages (from-to)	1489-1496
Number of pages	8
Journal	Nature Neuroscience
Volume	19
Issue number	11
DOIs	https://doi.org/10.1038/nn.4346
State	Published - Nov 2016

Bibliographical note

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© Nature America, Inc., part of Springer Nature. All rights reserved.

Funding

Acknowledgments We thank S. Ovadia for his devoted assistance with animal care. We thank J. Keverne for professional English editing, formatting and scientific input. This work is supported by an FP7 grant from the European Research Council (260463; A.C.); research grants from the Israel Science Foundation (1565/15) (A.C.); research support from Roberto and Renata Ruhman (A.C.); research support from Bruno and Simone Licht; I-CORE Program of the Planning and Budgeting Committee and The Israel Science Foundation (grant no. 1916/12 to A.C.); the Nella and Leon Benoziyo Center for Neurological Diseases (A.C.); the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics (A.C.); the Perlman Family Foundation, founded by Louis L. and Anita M. Perlman (A.C.); the Adelis Foundation (A.C.); the Irving I. Moskowitz Foundation (A.C.); grants from the Israel Science Foundation (1351/12) and the European Commission (ERC StG #337637 and Marie Curie CIG #321919) (O.Y.) and a Human Frontier Program career development award (O.Y.); a Human Frontier Science Program grant (E.S.); European Research Council grant # 311238 (E.S.); an Israel Science Foundation grant #1629/12 (E.S.); research support from Martin Kushner Schnur (E.S.); and Mr. and Mrs. Lawrence Feis (E.S.).

Funders	Funder number
Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics
Human Frontier Program career development
Irving I. Moskowitz Foundation	1351/12
Nella and Leon Benoziyo Center for Neurological Diseases
Roberto and Renata Ruhman	1916/12
Achelis Foundation
Seventh Framework Programme
Perlman Family Foundation
Marie Curie	321919
European Commission
European Commission	260463, 337637
Human Frontier Science Program	311238, 1629/12
Israel Science Foundation	1565/15

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Shemesh, Y., Forkosh, O., Mahn, M., Anpilov, S., Sztainberg, Y., Manashirov, S., Shlapobersky, T., Elliott, E., Tabouy, L., Ezra, G., Adler, E. S., Ben-Efraim, Y. J., Gil, S., Kuperman, Y., Haramati, S., Dine, J., Eder, M., Deussing, J. M., Schneidman, E., ... Chen, A. (2016). Ucn3 and CRF-R2 in the medial amygdala regulate complex social dynamics. Nature Neuroscience, 19(11), 1489-1496. https://doi.org/10.1038/nn.4346

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title = "Ucn3 and CRF-R2 in the medial amygdala regulate complex social dynamics",

abstract = "Social encounters are associated with varying degrees of emotional arousal and stress. The mechanisms underlying adequate socioemotional balance are unknown. The medial amygdala (MeA) is a brain region associated with social behavior in mice. Corticotropin-releasing factor receptor type-2 (CRF-R2) and its specific ligand urocortin-3 (Ucn3), known components of the behavioral stress response system, are highly expressed in the MeA. Here we show that mice deficient in CRF-R2 or Ucn3 exhibit abnormally low preference for novel conspecifics. MeA-specific knockdown of Crfr2 (Crhr2) in adulthood recapitulated this phenotype. In contrast, pharmacological activation of MeA CRF-R2 or optogenetic activation of MeA Ucn3 neurons increased preference for novel mice. Furthermore, chemogenetic inhibition of MeA Ucn3 neurons elicited pro-social behavior in freely behaving groups of mice without affecting their hierarchal structure. These findings collectively suggest that the MeA Ucn3-CRF-R2 system modulates the ability of mice to cope with social challenges.",

author = "Yair Shemesh and Oren Forkosh and Mathias Mahn and Sergey Anpilov and Yehezkel Sztainberg and Sharon Manashirov and Tamar Shlapobersky and Evan Elliott and Laure Tabouy and Gili Ezra and Adler, {Elaine S.} and Ben-Efraim, {Yair J.} and Shosh Gil and Yael Kuperman and Sharon Haramati and Julien Dine and Matthias Eder and Deussing, {Jan M.} and Elad Schneidman and Ofer Yizhar and Alon Chen",

year = "2016",

month = nov,

doi = "10.1038/nn.4346",

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Shemesh, Y, Forkosh, O, Mahn, M, Anpilov, S, Sztainberg, Y, Manashirov, S, Shlapobersky, T, Elliott, E, Tabouy, L, Ezra, G, Adler, ES, Ben-Efraim, YJ, Gil, S, Kuperman, Y, Haramati, S, Dine, J, Eder, M, Deussing, JM, Schneidman, E, Yizhar, O & Chen, A 2016, 'Ucn3 and CRF-R2 in the medial amygdala regulate complex social dynamics', Nature Neuroscience, vol. 19, no. 11, pp. 1489-1496. https://doi.org/10.1038/nn.4346

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AU - Forkosh, Oren

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AU - Anpilov, Sergey

AU - Sztainberg, Yehezkel

AU - Manashirov, Sharon

AU - Shlapobersky, Tamar

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AU - Ezra, Gili

AU - Adler, Elaine S.

AU - Ben-Efraim, Yair J.

AU - Gil, Shosh

AU - Kuperman, Yael

AU - Haramati, Sharon

AU - Dine, Julien

AU - Eder, Matthias

AU - Deussing, Jan M.

AU - Schneidman, Elad

AU - Yizhar, Ofer

AU - Chen, Alon

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AB - Social encounters are associated with varying degrees of emotional arousal and stress. The mechanisms underlying adequate socioemotional balance are unknown. The medial amygdala (MeA) is a brain region associated with social behavior in mice. Corticotropin-releasing factor receptor type-2 (CRF-R2) and its specific ligand urocortin-3 (Ucn3), known components of the behavioral stress response system, are highly expressed in the MeA. Here we show that mice deficient in CRF-R2 or Ucn3 exhibit abnormally low preference for novel conspecifics. MeA-specific knockdown of Crfr2 (Crhr2) in adulthood recapitulated this phenotype. In contrast, pharmacological activation of MeA CRF-R2 or optogenetic activation of MeA Ucn3 neurons increased preference for novel mice. Furthermore, chemogenetic inhibition of MeA Ucn3 neurons elicited pro-social behavior in freely behaving groups of mice without affecting their hierarchal structure. These findings collectively suggest that the MeA Ucn3-CRF-R2 system modulates the ability of mice to cope with social challenges.

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Ucn3 and CRF-R2 in the medial amygdala regulate complex social dynamics

Abstract

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