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An affective disorder in zebrafish with mutation of the glucocorticoid receptor.
- Source :
-
Molecular psychiatry [Mol Psychiatry] 2013 Jun; Vol. 18 (6), pp. 681-91. Date of Electronic Publication: 2012 May 29. - Publication Year :
- 2013
-
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.
- Subjects :
- Analysis of Variance
Animals
Animals, Genetically Modified
Anti-Anxiety Agents pharmacology
Anti-Anxiety Agents therapeutic use
Arginine genetics
Brain metabolism
Cell Line, Transformed
Chlorocebus aethiops
Corticotropin-Releasing Hormone genetics
Corticotropin-Releasing Hormone metabolism
Cysteine genetics
Diazepam pharmacology
Diazepam therapeutic use
Disease Models, Animal
Escape Reaction drug effects
Escape Reaction physiology
Exploratory Behavior drug effects
Exploratory Behavior physiology
Fluoxetine pharmacology
Fluoxetine therapeutic use
Freezing Reaction, Cataleptic physiology
Hormone Antagonists pharmacology
Humans
Hydrocortisone blood
Interpersonal Relations
Mifepristone pharmacology
Mood Disorders diet therapy
Mood Disorders metabolism
Mood Disorders pathology
Psychomotor Agitation genetics
Psychomotor Agitation pathology
Radioimmunoassay
Receptors, Glucocorticoid metabolism
Serotonin genetics
Serotonin metabolism
Transfection
Zebrafish
Mood Disorders genetics
Mutation genetics
Receptors, Glucocorticoid genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5578
- Volume :
- 18
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Molecular psychiatry
- Publication Type :
- Academic Journal
- Accession number :
- 22641177
- Full Text :
- https://doi.org/10.1038/mp.2012.64