Urocortin-1 and-2 double-deficient mice show robust anxiolytic phenotype and modified serotonergic activity in anxiety circuits

A. Neufeld-Cohen, A. K. Evans, D. Getselter, A. Spyroglou, A. Hill, S. Gil, M. Tsoory, F. Beuschlein, C. A. Lowry, W. Vale, A. Chen

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

The urocortin (Ucn) family of neuropeptides is suggested to be involved in homeostatic coping mechanisms of the central stress response through the activation of corticotropin-releasing factor receptor type 2 (CRFR2). The neuropeptides, Ucn1 and Ucn2, serve as endogenous ligands for the CRFR2, which is highly expressed by the dorsal raphe serotonergic neurons and is suggested to be involved in regulating major component of the central stress response. Here, we describe genetically modified mice in which both Ucn1 and Ucn2 are developmentally deleted. The double knockout mice showed a robust anxiolytic phenotype and altered hypothalamic-pituitary-adrenal axis activity compared with wild-type mice. The significant reduction in anxiety-like behavior observed in these mice was further enhanced after exposure to acute stress, and was correlated with the levels of serotonin and 5-hydroxyindoleacetic acid measured in brain regions associated with anxiety circuits. Thus, we propose that the Ucn/CRFR2 serotonergic system has an important role in regulating homeostatic equilibrium under challenge conditions.

Original languageEnglish
Pages (from-to)426-441
Number of pages16
JournalMolecular Psychiatry
Volume15
Issue number4
DOIs
StatePublished - Apr 2010
Externally publishedYes

Funding

We thank Dr C Kenyon and Dr E Aldujaili (Endocrinology Unit, Centre for Cardiovascular Science, The Queen’s Medical Research Institute, Edinburgh), for providing specific corticosterone antibody and guiding us through the enzyme-linked immunosorbent assay protocol they developed. AC is incumbent of the Philip Harris and Gerald Ronson Career Development Chair. WV is a Clayton Medical Research Foundation Senior Investigator and is the Helen McLoraine Professor of Molecular Neurobiology. This work is supported by a research grant from The German Israeli Foundation for Scientific Research and Development; a research grant from the Israel Science Foundation; a research grant from the Institute for the Study of Affective Neuroscience; a research grant from the Israel Ministry of Health; a research grant from Roberto and Renata Ruhman; a grant from Mr and Mrs Mike Kahn; a research grant from Mr Jorge David Ashkenazi, a research grant from Mr and Mrs Barry Wolfe; a research grant from The Irving B Harris Foundation; a research grant from Green Irwin Alzheimer’s Research; a research grant from The Joseph D Shane Fund for Neuroscience; a grant from the Estate of Ernst and Anni Deutsch (RPH Promotor Stiftung); a grant from the Hana and Julius Rosen Fund; a grant from the Mel and Joyce Eisenberg Keefer Professional Chair for New Scientists; a research grant from Mr and Mrs Gerhard and Hannah Bacharach; a research grant from Nella and Leon Benoziyo Center for Neurosciences; a grant from Fondation Fernande et Jean Gaj; a research grant from the Woman’s Health Research Center; a research grant from Abisch–Frenkel Foundation for the Promotion of Life Sciences; and a research Grant from the Carl and Micaela Einhorn–Dominic Institute for Brain Research. CAL is supported by a NARSAD 2007 Young Investigator Award.

FundersFunder number
Abisch–Frenkel Foundation for the Promotion of Life Sciences
Carl and Micaela Einhorn–Dominic Institute for Brain Research
Estate of Ernst and Anni Deutsch
Fondation Fernande et Jean Gaj
Green Irwin Alzheimer’s Research
Hana and Julius Rosen Fund
Irving B Harris Foundation
Joseph D Shane Fund for Neuroscience
Mr Jorge David Ashkenazi
Mr and Mrs Barry Wolfe
Mr and Mrs Gerhard and Hannah Bacharach
Mr and Mrs Mike Kahn
RPH
Woman’s Health Research Center
National Institute of Diabetes and Digestive and Kidney DiseasesP01DK026741
National Alliance for Research on Schizophrenia and Depression
German-Israeli Foundation for Scientific Research and Development
Israel Science Foundation
Institute for the Study of Affective Neuroscience
Ministry of Health, State of Israel

    Keywords

    • Anxiety
    • CRF receptors
    • Serotonin
    • Stress
    • Urocortin-1
    • Urocortin-2

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