Longitudinal transcriptome-wide gene expression analysis of sleep deprivation treatment shows involvement of circadian genes and immune pathways

Michael Deuschle,Jens Treutlein,Christian C. Witt,Nina Trautmann,Josef Frank,Carolina De La Torre,Andreas Meyer-Lindenberg,Lea Sirignano,Jerome C. Foo,Steffen Conrad von Heydendorff,Bertram Müller-Myhsok,Junfang Chen,Fabian Streit,Stephanie H. Witt,Maria Gilles,Carsten Sticht,Marcella Rietschel

doi:10.1038/s41398-019-0671-7

Abstract

Therapeutic sleep deprivation (SD) rapidly induces robust, transient antidepressant effects in a large proportion of major mood disorder patients suffering from a depressive episode, but underlying biological factors remain poorly understood. Research suggests that these patients may have altered circadian molecular genetic ‘clocks’ and that SD functions through ‘resetting’ dysregulated genes; additional factors may be involved, warranting further investigation. Leveraging advances in microarray technology enabling the transcriptome-wide assessment of gene expression, this study aimed to examine gene expression changes accompanying SD and recovery sleep in patients suffering from an episode of depression. Patients (N = 78) and controls (N = 15) underwent SD, with blood taken at the same time of day before SD, after one night of SD and after recovery sleep. A transcriptome-wide gene-by-gene approach was used, with a targeted look also taken at circadian genes. Furthermore, gene set enrichment, and longitudinal gene set analyses including the time point after recovery sleep, were conducted. Circadian genes were significantly affected by SD, with patterns suggesting that molecular clocks of responders and non-responders, as well as patients and controls respond differently to chronobiologic stimuli. Notably, gene set analyses revealed a strong widespread effect of SD on pathways involved in immune function and inflammatory response, such as those involved in cytokine and especially in interleukin signalling. Longitudinal gene set analyses showed that in responders these pathways were upregulated after SD; in non-responders, little response was observed. Our findings emphasize the close relationship between circadian, immune and sleep systems and their link to etiology of depression at the transcriptomic level.

Highlights

Therapeutic sleep deprivation (SD) rapidly induces robust antidepressant effects in a large proportion of major mood disorder patients suffering from a depressive episode[1,2,3,4,5]
Here, we report the first longitudinal transcriptomewide study of SD treatment in major mood disorder patients suffering from a major depressive episode
Widespread differential gene expression was observed after SD; circadian genes were differentially expressed, and enrichment in pathways related to immune function, inflammatory response and sleep regulation was observed

Summary

Introduction

Therapeutic sleep deprivation (SD) rapidly induces robust antidepressant effects in a large proportion of major mood disorder patients suffering from a depressive episode[1,2,3,4,5]. Work in humans[12,13,14,15] as well as animals[16,17,18] consistently documents the effects of mistimed or insufficient sleep and sleep deprivation on circadian gene expression (such as CLOCK, ARNTL [BMAL1], PER1, PER2, PER3, etc.) as well as on genes involved in related biological processes such as inflammatory, immune and stress response[19,20]. A prominent hypothesis about the antidepressant mechanism underlying SD is that it restores circadian rhythmicity, which is often dysregulated in depression, via resetting clock gene transcription[21,22]. The well-controlled nature and rapidity of response to SD treatment[23] renders it a promising context to investigate associated biological measures such as gene expression

Objectives

Methods

Results

Conclusion