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.
An affective disorder in zebrafish with mutation of the glucocorticoid receptor
L. Ziv,A. Muto,P. Schoonheim,Sebastiaan H. Meijsing,Daniel Strasser,H. Ingraham,M. Schaaf,Keith R. Yamamoto,H. Baier
Published 2012 in Molecular Psychiatry
ABSTRACT
PUBLICATION RECORD
- Publication year
2012
- Venue
Molecular Psychiatry
- Publication date
2012-05-14
- Fields of study
Biology, Medicine, Psychology
- Identifiers
- External record
- Source metadata
Semantic Scholar, PubMed
CITATION MAP
EXTRACTION MAP
CLAIMS
CONCEPTS
- corticotropin-releasing hormone
A stress-axis hormone gene whose transcription was assayed in the fish.
Aliases: CRH
- cortisol
A glucocorticoid hormone measured here as a readout of stress-axis activity.
- fluoxetine
A selective serotonin reuptake inhibitor used here as an antidepressant treatment added to the holding water.
- glucocorticoid receptor
A cortisol-responsive nuclear receptor that mediates glucocorticoid-dependent transcription in zebrafish.
Aliases: GR
- mineralocorticoid receptor
A corticosteroid receptor whose transcript abundance was measured in the fish.
Aliases: MR
- novel tank assay
A behavioral test that places fish in an unfamiliar aquarium to assess exploration and stress-related immobility.
Aliases: novel tank
- serotonin transporter
A membrane transporter for serotonin whose transcript abundance was measured in the fish.
Aliases: Serta
- social interactions
Exposure to conspecifics used as an environmental intervention during recovery.
- stress response
The physiological and behavioral reaction to an unfamiliar or stressful stimulus that was tracked through behavior and hormone levels.
- zebrafish mutant
An adult-viable zebrafish line carrying a mutation that eliminates glucocorticoid receptor transcriptional activity.
REFERENCES
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