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Transcriptome analysis of the larval zebrafish brain

ABSTRACT: We applied zebrafish whole genome microarrays to identify molecular effects of suvorexant, imipramine and a orexin antagonist from natural plant. Behavioral assays were performed to analyze for correlations between altered gene expression with effects on the organism level. Central nervous system drug induced gene expression in larval zebrafish brain was measured at 3 hours after exposure of 1uM suvorexant, 1uM imipramine, 10uM 8beta-(4'-Hydroxytigloyloxy) costunolide or 100uM 8beta-(4'-Hydroxytigloyloxy) costunolide. Three independent experiments were performed.Gene expression profile of brain tissue of 10uM 8beta-(4'-Hydroxytigloyloxy) costunolide treated larva showed closest similarity with suvorexant, as assumed by behavior profile.

ORGANISM(S): Danio rerio

PROVIDER: GSE129812 | GEO | 2019/04/16

REPOSITORIES: GEO

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Project description:Background: Examining transcriptional regulation by existing antidepressants in key neural circuits implicated in depression, and understanding the relationship to transcriptional mechanisms of susceptibility and natural resilience, may help in the search for new therapeutics. Further, given the heterogeneity of treatment response in human populations, examining both treatment response and non-response is critical. Methods: We compared the effects of a conventional monoamine-based tricyclic antidepressant, imipramine (14 daily injections), and a rapidly acting, experimental, non-monoamine-based antidepressant, ketamine (single injection), in mice subjected to chronic social defeat stress, a validated model of depression, and used RNA-sequencing to analyze transcriptional profiles associated with susceptibility, resilience and antidepressant response and non-response in prefrontal cortex (PFC), nucleus accumbens, hippocampus, and amygdala. Results: We identified approximately equal numbers of responder and non-responder mice following ketamine or imipramine treatment. Ketamine induced more expression changes in hippocampus than other brain regions; imipramine induced more expression changes in nucleus accumbens and amygdala. Transcriptional profiles in ketamine and imipramine responders were most similar in PFC, where the least transcriptional regulation occurred for each drug. Non-response reflected both the lack of response-associated gene expression changes and unique gene regulation. In responders, both drugs reversed susceptible associated transcriptional changes as well as induced resilient associated transcription in PFC, with effects varying by drug and brain region studied. Conclusions: We generated a uniquely large resource of gene expression data in four inter-connected limbic brain regions implicated in depression and its treatment with imipramine or ketamine. Our analyses highlight the PFC as a key site of common transcriptional regulation by both antidepressant drugs and in both reversing susceptibility and inducing resilience associated molecular adaptations. In addition, we found region-specific effects of each drug suggesting both common and unique effects of imipramine versus ketamine. mRNA profiles of susceptibility to chronic social defeat stress as well as treatment response were generated across 4 separate brain regions, with a sample size of 3-5 per group.

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Transcriptome analysis of the larval zebrafish brain

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