A Circadian Genomic Signature Common to Ketamine and Sleep Deprivation in the Anterior Cingulate Cortex

🥈 Top 2% JournalApr 12, 2017Biological psychiatry

Daily Gene Activity Patterns Shared by Ketamine and Sleep Deprivation in the Brain's Emotion and Decision Area

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Abstract

Sixty-four genes show shared expression changes in response to low-dose ketamine and sleep deprivation treatments.

Both low-dose ketamine and sleep deprivation lead to similar changes in gene expression associated with the circadian clock.
Key clock genes, including Ciart, Per2, Npas4, Dbp, and Rorb, are downregulated in treated mice compared to controls.
The findings suggest that rapid antidepressant effects may involve shared regulatory mechanisms related to circadian rhythms.
Distinct elements of the circadian clock and neuronal plasticity processes are implicated in the response to these treatments.

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BACKGROUND: Conventional antidepressants usually require several weeks to achieve a full clinical response in patients with major depressive disorder, an illness associated with dysregulated circadian rhythms and a high incidence of suicidality. Two rapid-acting antidepressant strategies, low-dose ketamine (KT) and sleep deprivation (SD) therapies, dramatically reduce depressive symptoms within 24 hours in a subset of major depressive disorder patients. However, it is unknown whether they exert their actions through shared regulatory mechanisms. To address this question, we performed comparative transcriptomics analyses to identify candidate genes and relevant pathways common to KT and SD.

METHODS: We used the forced swim test, a standardized behavioral approach to measure antidepressant-like activity of KT and SD. We investigated gene expression changes using high-density microarrays and pathway analyses (Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Gene Set Enrichment Analysis) in KT- and SD-treated mice compared with saline-treated control male mice.

RESULTS: We show that KT and SD elicit common transcriptional responses implicating distinct elements of the circadian clock and processes involved in neuronal plasticity. There is an overlap of 64 genes whose expression is common in KT and SD. Specifically, there is downregulation of clock genes including Ciart, Per2, Npas4, Dbp, and Rorb in both KT- and SD-treated mice.

CONCLUSIONS: We demonstrate a potential involvement of the circadian clock in rapid antidepressant responses. These findings could open new research avenues to help design chronopharmacological strategies to treat major depressive disorder.

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