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

Abstract

One of sleeps 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 and the brain and blood transcriptome in mice exposed to nine weeks of unpredictable chronic mild stress (UCMS). Comparing 46 phenotypical 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 predictors for specific phenotypes and their overlap. Transcriptomic predictor sets for the inter-individual variation in REMS continuity and theta activity shared many pathways with corticosterone regulation and in particular pathways implicated in apoptosis, including mitochondrial pathways. Predictor sets for REMS and anhedonia, one of the behavioral changes following UCMS, shared pathways involved in oxidative stress, cell proliferation and apoptosis. RNA predictor sets for non-NREMS parameters showed no overlap with other phenotypes. These novel data identify REMS as a core and early element of the response to chronic stress, and identify apoptotic pathways as a putative mechanism by which REMS mediates adaptation to stressful waking experiences.\n\nSignificance StatementSleep is responsive to experiences during wakefulness and is altered in stress-related disorders. Whether sleep changes primarily concern rapid-eye-movement sleep (REMS) or non-REM sleep, and how they correlate with stress hormones, behavioral and transcriptomic responses remained unknown. We demonstrate using unpredictable chronic (9-weeks) mild stress that REMS is the most responsive of all the measured sleep characteristics, and correlates with deficiency in corticosterone regulation. An unbiased machine learning, controlling for unspecific effects of stress, revealed that REMS correlated with RNA predictor sets enriched in apoptosis including mitochondrial pathways. Several pathways were shared with predictors of corticosterone and behavioral responses. This unbiased approach point to apoptosis as a molecular mechanism by which REMS mediates adaptation to an ecologically relevant waking experience.