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  An affective disorder in zebrafish with mutation of the glucocorticoid receptor

Ziv, L., Muto, A., Schoonheim, P. J., Meijsing, S. H., Strasser, D., Ingraham, H. A., et al. (2012). An affective disorder in zebrafish with mutation of the glucocorticoid receptor. Molecular Psychiatry, 18(6), 681-91. doi:10.1038/mp.2012.64.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0014-7B80-E Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0014-7BA3-F
Genre: Journal Article

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 Creators:
Ziv, L.1, 2, Author
Muto, A.1, 3, Author
Schoonheim, P. J.1, 4, Author
Meijsing, S. H.5, 6, Author              
Strasser, D.7, Author
Ingraham, H. A.6, Author
Schaaf, M. J.4, Author
Yamamoto, K. R.6, Author
Baier, H.1, 8, Author
Affiliations:
1Department of Physiology, Programs in Neuroscience, Genetics, and Developmental and Stem Cell Biology, University of California , San Francisco, CA, USA, ou_persistent22              
2Cancer Research Center, Sheba Medical Center , Tel Hashomer, Israel, ou_persistent22              
3Division of Molecular and Developmental Biology, National Institute of Genetics , Mishima, Shizuoka 411-8540, Japan, ou_persistent22              
4Institute of Biology, Leiden University , Leiden, The Netherlands, ou_persistent22              
5Mechanisms of Transcriptional Regulation (Sebastiaan H. Meijsing), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, Berlin, Germany, ou_1479641              
6Department of Cellular and Molecular Pharmacology, University of California , San Francisco, CA, USA, ou_persistent22              
7Institute of Chemistry, Hebrew University of Jerusalem , Institute of Chemistry, Hebrew University of Jerusalem, Jerusalem, Israel, ou_persistent22              
8Department Genes, Circuits and Behavior, Max Planck Institute of Neurobiology , Martinsried, Germany, ou_persistent22              

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Free keywords: anxiety; depression; fish model; glucocorticoid; serotonin; stress
 Abstract: Upon binding of cortisol, the glucocorticoid receptor (GR) regulates the transcription of specific target genes, including those that encode the stress hormones corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone. Dysregulation of the stress axis is a hallmark of major depression in human patients. However, it is still unclear how glucocorticoid signaling is linked to affective disorders. We identified an adult-viable zebrafish mutant in which the negative feedback on the stress response is disrupted, due to abolition of all transcriptional activity of GR. As a consequence, cortisol is elevated, but unable to signal through GR. When placed into an unfamiliar aquarium ('novel tank'), mutant fish become immobile ('freeze'), show reduced exploratory behavior and do not habituate to this stressor upon repeated exposure. Addition of the antidepressant fluoxetine to the holding water and social interactions restore normal behavior, followed by a delayed correction of cortisol levels. Fluoxetine does not affect the overall transcription of CRH, the mineralocorticoid receptor (MR), the serotonin transporter (Serta) or GR itself. Fluoxetine, however, suppresses the stress-induced upregulation of MR and Serta in both wild-type fish and mutants. Our studies show a conserved, protective function of glucocorticoid signaling in the regulation of emotional behavior and reveal novel molecular aspects of how chronic stress impacts vertebrate brain physiology and behavior. Importantly, the zebrafish model opens up the possibility of high-throughput drug screens in search of new classes of antidepressants.

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Language(s): eng - English
 Dates: 2012-05-29
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1038/mp.2012.64
ISSN: 1476-5578 (Electronic)1359-4184 (Print)
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Title: Molecular Psychiatry
Source Genre: Journal
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Publ. Info: Houndmills, Hampshire, UK : Stockton Press
Pages: - Volume / Issue: 18 (6) Sequence Number: - Start / End Page: 681 - 91 Identifier: ISSN: 1359-4184
CoNE: /journals/resource/954925619131