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

• Published in: Biological psychiatry (1969) 2017-09, Vol.82 (5), p.351-360
• Main Authors: Orozco-Solis, Ricardo, Montellier, Emilie, Aguilar-Arnal, Lorena, Sato, Shogo, Vawter, Marquis P, Bunney, Blynn G, Bunney, William E, Sassone-Corsi, Paolo
• Format: Article
• Language: English
• Subjects: Animals; Anterior cingulate cortex; Antidepressive Agents - pharmacology; Circadian clock; Circadian Rhythm Signaling Peptides and Proteins - metabolism; Computational Biology; Depression; Depressive Disorder - metabolism; Depressive Disorder - therapy; Disease Models, Animal; Gene Expression - drug effects; Gyrus Cinguli - drug effects; Gyrus Cinguli - metabolism; Ketamine; Ketamine - pharmacology; Male; Mice, Inbred C57BL; Microarray Analysis; Psychiatry; Sleep deprivation; Sleep Deprivation - metabolism; Transcriptome; Transcriptome - drug effects; Transcriptome - physiology
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2017.02.1176

Abstract Background Conventional antidepressants usually require several weeks to achieve a full clinical response in patients with major depressive disorder (MDD), an illness associated with dysregulated circadian rhythms and a high incidence of suicidality. Two rapid-acting antidepressants, low-dose ketamine (KT) and sleep deprivation (SD) therapy, dramatically reduce depressive symptoms within 24 hr in a subset of MDD 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 (FST), 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 (GO, KEGG, GSEA) in KT- and SD-treated mice compared to saline-treated controls. 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 down-regulation 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 chrono-pharmacological strategies to treat major depressive disorder.