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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. (2013). An affective disorder in zebrafish with mutation of the glucocorticoid receptor. Molecular Psychiatry, 18, 681-691. doi:10.1038/mp.2012.64.

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 Creators:
Ziv, L., Author
Muto, A., Author
Schoonheim, P. J., Author
Meijsing, S. H., Author
Strasser, D., Author
Ingraham, H. A., Author
Schaaf, M. J. M., Author
Yamamoto, K. R., Author
Baier, Herwig1, Author           
Affiliations:
1Department: Genes-Circuits-Behavior / Baier, MPI of Neurobiology, Max Planck Society, ou_1128545              

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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: 2013
 Publication Status: Issued
 Pages: 11
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/mp.2012.64
 Degree: -

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Title: Molecular Psychiatry
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: Houndmills, Hampshire, UK : Stockton Press
Pages: - Volume / Issue: 18 Sequence Number: - Start / End Page: 681 - 691 Identifier: ISSN: 1359-4184
CoNE: https://pure.mpg.de/cone/journals/resource/954925619131