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Proc Natl Acad Sci U S A. 2019 Feb 12;116(7):2733-2742. doi: 10.1073/pnas.1816456116. Epub 2019 Jan 25.

REM sleep's unique associations with corticosterone regulation, apoptotic pathways, and behavior in chronic stress in mice.

Author information

1
Surrey Sleep Research Centre, Faculty of Health and Medical Sciences, University of Surrey, GU2 7XH Guildford, United Kingdom.
2
Lilly Research Centre, Erl Wood Manor, Eli Lilly and Company, GU20 6PH Windlesham, United Kingdom.
3
Bioinformatics Core Facility, Faculty of Health and Medical Sciences, University of Surrey, GU2 7XH Guildford, United Kingdom.
4
Department of Microbial Sciences, Faculty of Health and Medical Sciences, University of Surrey, GU2 7XH Guildford, United Kingdom.
5
Surrey Sleep Research Centre, Faculty of Health and Medical Sciences, University of Surrey, GU2 7XH Guildford, United Kingdom; d.j.dijk@surrey.ac.uk r.winsky-sommerer@surrey.ac.uk.

Abstract

One of sleep's putative functions is mediation of adaptation to waking experiences. Chronic stress is a common waking experience; however, which specific aspect of sleep is most responsive, and how sleep changes relate to behavioral disturbances and molecular correlates remain unknown. We quantified sleep, physical, endocrine, and behavioral variables, as well as the brain and blood transcriptome in mice exposed to 9 weeks of unpredictable chronic mild stress (UCMS). Comparing 46 phenotypic variables revealed that rapid-eye-movement sleep (REMS), corticosterone regulation, and coat state were most responsive to UCMS. REMS theta oscillations were enhanced, whereas delta oscillations in non-REMS were unaffected. Transcripts affected by UCMS in the prefrontal cortex, hippocampus, hypothalamus, and blood were associated with inflammatory and immune responses. A machine-learning approach controlling for unspecific UCMS effects identified transcriptomic predictor sets for REMS parameters that were enriched in 193 pathways, including some involved in stem cells, immune response, and apoptosis and survival. Only three pathways were enriched in predictor sets for non-REMS. Transcriptomic predictor sets for variation in REMS continuity and theta activity shared many pathways with corticosterone regulation, in particular pathways implicated in apoptosis and survival, including mitochondrial apoptotic machinery. Predictor sets for REMS and anhedonia shared pathways involved in oxidative stress, cell proliferation, and apoptosis. These data identify REMS as a core and early element of the response to chronic stress, and identify apoptosis and survival pathways as a putative mechanism by which REMS may mediate the response to stressful waking experiences.

KEYWORDS:

EEG theta power; anhedonia; depression; machine learning; transcriptome

Conflict of interest statement

Conflict of interest statement: This study was supported by a Lilly Innovation Fellowship Award (to M.N.) and conducted through an academic–industrial partnership between the Surrey Sleep Research Centre of the University of Surrey and Eli Lilly and Company Ltd. K.A.W., A.P.M., K.M., N.L., and M.N. were full-time employees of Eli Lilly and Company Ltd. at the time of the study. D.-J.D. has received research funds and acted as consultant to Eli Lilly and other pharmaceutical companies. R.W.-S. has received research funding from Eli Lilly.

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