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Plasma and CSF Proteomic Signatures of Acutely Sleep-Deprived Humans: An Exploratory Study

ABSTRACT: Study objectives: Acute sleep deprivation affects both central and peripheral biological processes. Prior research has mainly focused on specific proteins or biological pathways that are dysregulated in the setting of sustained wakefulness. This pilotexploratory study’s objective wasaimed to provide a comprehensive view of the biological processes and proteins impacted by acute sleep deprivation in both plasma and cerebrospinal fluid (CSF). Methods: We collected plasma and CSF from human participants during one night of sleep deprivation and control normal sleep conditions. 1300 proteins were measured at hour 0 and hour 24 using a high-scale aptamer-based proteomics platform (SOMAomascan) and a systematics biological database tool (Metascape) was used to reveal dysregulated biological pathways. Results: Acute sleep deprivation lead to opposite effects in plasma and CSF, decreasingdecreased the number of upregulated and downregulated differential protein expression and biological pathways and proteins in plasma but increased upregulated and downregulated protein and biological pathwayssing them in CSF. Predominantly affected pProteins and n pathways were associated with that were predominantly affected by sleep deprivation included immune response, inflammation, phosphorylation, membrane signaling, cell-cell adhesion, and extracellular matrix organization. Conclusions: The identified modification across biofluids adds to evidence that acute sleep deprivation has important impacts on biological pathways and proteins that can negatively affect human health. As a hypothesis-driving study, these findings may help with the exploration of novel mechanisms that mediate sleep loss and associated conditions, drive the discovery of new sleep loss biomarkers, and ultimately aid in the identification of new targets for intervention to human diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244817 | GEO | 2023/12/14

REPOSITORIES: GEO

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Project description:Sleep insufficiency is associated with various disorders (cardiovascular disease, neurodegenerative diseases, immunological disorders.) but the molecular bases for these associations are largely unknown. We used multiple omics techniques to examine changes in the blood of healthy male and female adults voluntarily subjected to 24 h of sleep deprivation followed by up to one day of recovery with normal sleep routines. Thirty-two (14 males, 18 females) healthy adults 22-27 years old donated fasting blood samples prior to (Day 1) and following (Days 2 and 3) a 24-hour period of sleep deprivation. Blood samples were subjected to cell, biochemical, transcriptomic, proteomic and metabolomic analyses. Multi-omics integration analysis showed that sleep deprivation caused marked molecular changes (46.4% transcript genes, 59.3% proteins and 55.6% metabolites) that had not been restored by Day 2. Transient sleep deprivation had the greatest impact on the immune system and, in particular, on neutrophil-mediated immune processes. Correlation analysis with neutrophils suggested the plasma level of superoxidase dismustase-1 (SOD1) and the primary blood mononuclear cell transcriptional profile of the S100A8 gene could be used as biomarkers reflecting the sleep deprivation-associated disordered immunological state. An increased number of immune cells (leukocytes, neutrophils, monocytes, eosinophils, CD4+T), inflammatory factors (TNF-α, INF-γ, Il-6, IL-10, IL-12) and c-reactive protein in blood plasma further demonstrated the dysregulation of the immune system associated with short-term sleep deprivation. Other important findings associated with sleep deprivation included a significant decrease in the plasma melatonin level and an enrichment of molecules in signaling pathways associated with brain disorders, including schizophrenia and neurodegenerative diseases. Taken in concert, these points suggest that disrupted sleep, such as may occur in shift work, perturbs immunological status and may increase the risk for brain disorders in later life.

Project description:Sleep deprivation (SD) in young adults is associated with metabolic, stress and cognitive responses that are also characteristic of brain aging. Given that sleep architecture changes with age, including increased fragmentation and decreased slow wave activity, it seems reasonable to investigate potential molecular relationships between SD and aging in brain tissue. Here, we tested the hypothesis that young rats exposed to 24 or 72 hour SD would respond with stress and aging-like shifts in brain hippocampal CA1 gene expression. SD animals showed blood corticosterone and weight changes consistent with a stress response. Microarray results, validated by Western blot and comparison to prior SD studies, pointed to disruptions in neurotransmission, sleep pressure signaling, and macromolecular synthesis. In a separate experiment, animals exposed to 24 or 72 hour novel environment stress recapitulated nearly one third of the SD transcriptional profile, particularly upregulated apoptotic and immune signaling pathways. Compared to aging (based on three previously published independent hippocampal aging studies), SD transcriptional profiles agreed for neurogenesis and energy pathways. However, immune signaling, glial activity, macromolecular synthesis and neuronal function all showed an SD profile that was, at least in part, opposed by aging. We conclude that while stress and SD have discrete molecular signatures, they do show a subset of highly similar changes. However, the same could not be said of aging and SD, where a similar subset of genes is changed, but in partially divergent directions. Finally, this work identifies presynaptic vesicular release and intercellular adhesion molecular signatures as novel targets for future SD-countering therapeutics. Subjects: Male Fischer 344 rats (3-5 months old, Harlan, Indianapolis): 37 in cohort 1 and 32 in cohort 2. Subjects were assigned to one of 5 treatment groups: Home Cage-HC n =17; 24 hour sleep deprivation- 24SD n = 16; 72 hour sleep deprivation- 72SD n = 20; 24 hour novel environment stress- 24NES n = 10; 72 hour novel environment stress- 72NES n = 6. Cohorts 1 and 2 were combined for microarray analyses. Sleep Deprivation: The multiple platform modification (Coenen and van Luijtelaar, 1985) of the classic 'flower pot' (Mendelson et al., 1974) technique in which animals are placed on an elevated platform over water was used. Pairs of SD animals (cage mates) were sleep deprived for 24 or 72 hours. Novel Environment Stress (NES): NES animals were exposed to a novel environment, but were not constrained from sleeping. These NES animals paralleled the sleep deprivation exposure duration (24 hour- n = 10, and 72 hour- n = 6). Tissue Isolation: On the day that animals were removed from the SD chambers, they were anesthetized with CO2 gas and decapitated. Brains were removed and immediately placed in oxygenated artificial cerebrospinal fluid (aCSF) containing (in mM) 114NaCl, 2.5 KCl, 2MgCl2, 30 NaHCO3, 10 Glucose and 2.2CaCl2. Hippocampi were dissected as described previously (Blalock et al., 2003; Kadish et al., 2009). Briefly, dissected hippocampi were immersed in 0C oxygenated aCSF and placed on a chilled glass petri dish. The CA1 region was dissected along the long axis of the hippocampus. CA1 tissue was flash frozen and stored at -80C until further use. Microarray Protocol: GCOS quality control measures of background signal (74.9 ¬± 2.1 cohort 1; 59.8 ¬± 2.3 cohort 2) and RawQ (2.3 ¬± 0.1 cohort 1; 1.9 ¬± 0.1 cohort 2), as well as a chip x chip correlation matrix of signal intensity data pointed to a global decrease in background signal intensity in Cohort 2. To control for this, each gene expression values for HC, 24SD and 72SD was standardized separately within cohort 1 and cohort 2, and then the two cohorts were combined. This retained the variability of each cohort, but removed the 'cohort effect' from the data. Pre-statistical filtering retained 'A' grade probe sets that were uniquely annotated (Affymetrix, June 2011) with gene symbols and had at least 6 presence calls across all 71 chips. This criterion was selected based on factorial analysis demonstrating < 5% probability of 6 or more chips being rated present for a given probe set by chance (Blalock, unpublished observations).

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Plasma and CSF Proteomic Signatures of Acutely Sleep-Deprived Humans: An Exploratory Study

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