Summary: A new study finds that repeated mild daily stress leads to a clear increase in REM (rapid eye movement) sleep. This REM increase correlates with altered expression of genes linked to cell death and survival, shedding light on how stress may contribute to mood disorders through sleep changes.
Source: University of Surrey.
Daily mild stress causes a distinct rise in REM sleep and is associated with gene pathways that regulate cell death and survival, a study published in PNAS reports.
REM sleep—often called paradoxical sleep—is the stage when most dreaming occurs and plays a key role in emotion regulation and memory consolidation. Disturbances of REM sleep are commonly observed in mood disorders such as depression, but the molecular links between stress-driven sleep changes and brain biology have been unclear.
In this nine-week study, researchers from the Surrey Sleep Research Centre at the University of Surrey, in collaboration with Eli Lilly, exposed mice to an unpredictable series of mild stressors, including cues such as the odor of a predator. Over the course of the protocol, mice developed behavioral signs consistent with a depression-like state: reduced self-grooming, decreased interest in pleasurable foods, and diminished social exploration toward unfamiliar conspecifics.
Continuous sleep monitoring revealed that stressed mice showed a pronounced increase in the duration and continuity of REM sleep and in REM-specific brain oscillations, while deep non-REM sleep (NREM) remained largely unchanged. These REM alterations were tightly linked to impaired regulation of the stress hormone corticosterone. At the same time, exposure to mild stress produced changes in gene expression across brain regions.
To explore connections among stress, hormone regulation, sleep and gene expression, the team used a machine-learning approach to identify sets of genes that best predict observed sleep, hormonal and behavioral outcomes. This analysis showed that parameters of REM sleep, corticosterone dysregulation, and a behavioral marker of anhedonia were strongly associated with molecular pathways governing cellular apoptosis and survival—particularly within the hippocampus.
These results indicate that increased REM sleep may activate signaling pathways that allow the brain to adapt—or maladapt—to repeated mild stress. In particular, engagement of apoptosis and survival pathways suggests a mechanism by which REM sleep could influence cellular remodeling in response to stressful waking events, potentially contributing to the development of mood disturbances.
Lead author Dr. Mathieu Nollet commented that combining behavioral, sleep and gene-expression analyses provides strong evidence for REM sleep’s central role in the brain’s response to stress. Senior author Dr. Raphaelle Winsky-Sommerer, Reader in Sleep & Circadian Rhythms at the University of Surrey, noted that the behavioral and sleep alterations observed in the mice resemble features of human depression, supporting the potential relevance of these molecular changes to human stress responses and mood disorders.
Professor Derk-Jan Dijk, who directs the Surrey Sleep Research Centre, emphasized that sleep serves as a sensitive and early indicator of how the brain reacts to daytime challenges and highlighted the importance of studying how sleep contributes to recovery after stress.
Funding: Supported by a Lilly Innovation Fellowship Award from Eli Lilly and Company Ltd.
Source: Natasha Meredith – University of Surrey
Publisher: Organized by NeuroscienceNews.com.
Image: NeuroscienceNews.com image in the public domain.
Original research: REM sleep’s unique associations with corticosterone regulation, apoptotic pathways, and behavior in chronic stress in mice. Authors: Mathieu Nollet, Harriet Hicks, Andrew P. McCarthy, Huihai Wu, Carla S. Möller-Levet, Emma E. Laing, Karim Malki, Nathan Lawless, Keith A. Wafford, Derk-Jan Dijk, and Raphaelle Winsky-Sommerer. Published in PNAS, January 25, 2019. DOI: 10.1073/pnas.1816456116
REM sleep’s unique associations with corticosterone regulation, apoptotic pathways, and behavior in chronic stress in mice
Sleep is believed to help the brain adapt to waking experiences. Chronic mild stress is a frequent waking challenge, but which sleep features are most responsive—and how those changes relate to behavior and molecular biology—has been unclear. In mice subjected to nine weeks of unpredictable chronic mild stress (UCMS), researchers measured sleep, physical and behavioral markers, endocrine responses, and brain and blood transcriptomes. Across 46 measured phenotypes, REM sleep, corticosterone regulation and coat state were most responsive to UCMS. REM theta oscillations were enhanced while NREM delta activity remained unaffected. Gene transcripts altered by UCMS in the prefrontal cortex, hippocampus, hypothalamus and blood were linked to inflammatory and immune responses. Machine-learning analyses identified transcriptomic predictor sets for REM parameters enriched across nearly 200 pathways—including those related to stem cells, immune response, and apoptosis and survival—whereas very few pathways predicted NREM measures. Predictor sets for REM continuity and theta activity overlapped with corticosterone regulation pathways, notably those involved in apoptosis and mitochondrial apoptotic machinery. Predictor sets linking REM and anhedonia implicated oxidative stress, cell proliferation and apoptosis pathways. Together, these findings position REM sleep as an early and central element of the response to chronic stress and point to apoptosis and survival pathways as candidate mechanisms by which REM may mediate brain adaptations to stressful waking experiences.