Stress and sleep: Novel insights into stress-related sleep disorders from EEG features to neural circuitry.

Sirtuin 1 (SIRT1) is implicated in sleep regulation, but there have been a limited number of sleep studies related to SIRT1. We aim to determine the impacts of the brain-specific loss of SIRT1 on sleep and circadian rhythm. We first characterized circadian periods and sleep phenotypes in baseline and recovery sleep in brain-specific Sirt1 knockout (BKO) and littermate wild-type (WT) mice. We found that there were no differences in sleep architecture, amount of each vigilance state, and sleep homeostasis between genotypes, suggesting that brain SIRT1 functionally plays minor roles in sleep-wake regulation. However, in accordance with prior work, loss of Sirt1 caused decreased delta power during non-REM sleep. In addition, there was no difference in intrinsic circadian periods between genotypes. We also provide the first preclinical evidence of whether nicotinamide mononucleotide (NMN) treatment directly improves sleep by administering it acutely (intraperitoneally for 10 days) and chronically (orally for 2 months). However, neither acute nor chronic treatment changed sleep duration and quality compared to the control session in middle-aged WT and BKO mice. Considering our findings and previous studies, the clinically reported improvement in muscle function and energy metabolism may indirectly contribute to the potential benefits of NMN on sleep quality and fatigue in the elderly.

A unified clearance-based model of homeostatic drive across acute and chronic sleep loss.

IntroductionCannabis use is common in the USA and is associated with adverse outcomes across many domains, including sleep difficulties. Targeting insomnia with an evidence-based treatment could improve sleep and reduce frequent cannabis use. This randomised controlled trial (RCT) will compare evidence-based telemedicine-delivered cognitive-behavioural therapy for insomnia for adults with frequent cannabis use (CBTi-CB) against an active comparator, sleep hygiene education (SHE), for improving insomnia/sleep, associated daytime symptoms and cannabis use. The study will also determine the effects of treatment on sleep mechanisms and their association with clinical outcomes.Methods and analysisThis is a single-site RCT with planned enrolment of 200 adults (21+ years of age) who meet criteria for both chronic insomnia and frequent cannabis use. Eligible participants will be randomised 1:1 to six sessions of CBTi-CB or SHE with clinical assessments conducted at pre-treatment, post-treatment and at 3 and 6 months post-treatment. Overnight polysomnography (PSG) will be conducted before and after treatment. Primary outcomes will include the Insomnia Severity Index, 12-item Short-Form Health Survey Mental Composite Score and cannabis use frequency as assessed by the interview-administered Timeline Follow Back. Electroencephalogram delta activity, derived from overnight PSG, will be the primary end point to assess the sleep homeostasis mechanism.Ethics and disseminationEthical approval for the study has been obtained from the Institutional Review Board of the University of Michigan Medical School (IRBMED #HUM00222302). The results of the investigation will be published in scientific papers. The data from the investigation will be made available through the National Institutes of Health (NIH) National Data Archive, which allows researchers on NIH grants to share and access raw data.Trial registration numberNCT05814822.

Chronic exposure to artificial light at night dampens rhythms in locomotor activity, metabolism, and sleep in female mice.

Slow-wave activity (SWA), a key indicator of sleep homeostasis, is often diminished in individuals with treatment-resistant depression (TRD). Ketamine, a rapid-acting antidepressant, increases SWA during the first period of non-rapid eye movement (NREM1) sleep. However, research into how ketamine affects sleep and its connection to treatment outcomes in TRD has been limited by small sample sizes and a lack of comparison with healthy volunteers (HVs). This placebo-controlled study compared the effects of ketamine on NREM1 SWA in a large sample of unmedicated TRD patients (n = 91; 51 F/40 M) and HVs (n = 42; 23 F/19 M). Linear mixed-effects models and regression analyses, with post-hoc testing (paired ttests and Wilcoxon matched-pairs signed rank tests), were used to assess condition-related effects across baseline, ketamine, and placebo in TRD and HV participants. Age-related moderation of ketamine-associated NREM1 SWA changes and condition-related changes in sleep variables were also examined. At baseline, TRD patients had lower NREM1 SWA than HVs. Ketamine, but not placebo, increased NREM1 SWA in TRD patients, particularly in responders. In contrast, ketamine had no effect on NREM1 SWA in HVs. Following ketamine, TRD patients also showed significant increases in total sleep time and sleep efficiency and a reduction in sleep latency. In TRD patients, the ketamine-related increase in NREM1 SWA diminished with increasing age. Together, the results indicate that ketamine's antidepressant effects appear closely associated with its ability to modulate early SWA. These effects may also be linked to ketamine's ability to improve sleep architecture in TRD. Clinical Trials Identifier: www.clinicaltrials.gov , NCT00088699, NCT01204918.

The off-label use of cannabidiol (CBD) has outpaced investigation. We assessed the effects of CBD in Angelman syndrome model mice lacking the Ube3a gene and found that chronic injection of CBD increased rapid-eye movement sleep during the dark cycle, restored "Siesta", improved sleep homeostasis, and reduced spontaneous seizures following flurothyl kindling.

Insomnia is the most prevalent sleep disorder worldwide and results from multiple factors. While Limosilactobacillus fermentum PS150 (PS150) improves sleep in animal models, its effects on insomnia remain unclear. In this study, a caffeine-induced insomnia mouse model was established to evaluate the effects of live PS150 and its heat-treated form (HT-PS150). Mice were supplemented with PS150 or HT-PS150 for 21 days, and caffeine was administered during the final week to induce insomnia-like symptoms. Sleep parameters, including sleep latency, duration, and recovery time, were subsequently evaluated using a pentobarbital-induced sleep test. Compared with the vehicle control group, caffeine significantly increased sleep latency, which was reversed by HT-PS150 but showed only a trend toward improvement with PS150. The sleep duration remained unchanged; however, both forms significantly shortened the recovery time. These results indicate the potential of PS150 to alleviate caffeine-induced sleep disturbance. In contrast, the caffeine-treated group exhibited increased adenosine A1 receptor expression, activation of protein kinase A-cAMP response element-binding protein signaling, upregulation of Per2, Cry1, and Cry2, and disrupted GABAergic balance in the prefrontal cortex, a key region involved in sleep homeostasis. PS150 and HT-PS150 reversed these alterations, thereby normalizing circadian and GABAergic signaling. Moreover, both treatments modified the gut microbiota composition, suggesting potential involvement of the microbiota-gut-brain axis. PS150 and HT-PS150 may ameliorate caffeine-induced sleep disturbances through mechanisms potentially associated with circadian modulation, regulation of GABAergic signaling, and alterations in gut microbiota composition. These findings highlight their potential as functional food ingredients or dietary supplements for supporting sleep health.

Diabetes is a metabolic condition characterized by increased blood glucose levels resulting from defects in insulin secretion, utilization, or both. Sleep deprivation (SD) can alter homeostasis, while the consequences of diabetes can disrupt sleep homeostasis. These findings support the hypothesis of a bidirectional interaction between sleep homeostasis, metabolic disorders, and neurological or behavioral disorders. The present study aims to investigate the bidirectional interaction between chronic REM-SD and metabolic disorders in rats by combining assessments of affective and cognitive behaviors (anxiety, depression, and memory function), metabolic (glucose homeostasis, glucose tolerance, insulin sensitivity), oxidative, cholinergic, cytotoxic, neuroinflammatory parameters, and histopathological change in hippocampus (HP), hypothalamus (HYP), and prefrontal cortex (PFC) in male Wistar rats. Eighteen male Wistar rats were divided into three groups (CON, WP, and CSD). The REM-SD was carried out for 18h a day (from 4:00 p.m. to 10:00 a.m.) over a period of five weeks, using the modified multi-platform method (MMPM). Glucose (ipGTT) and insulin tolerance (ipITT), corticosterone and blood hs-CRP levels were evaluated, along with affective behaviors (anxiety- and depression-like) and cognitive functions, including spatial learning, recognition memory, working memory, and long-term memory. We also measured acetylcholinesterase (AchE) activity, neurotoxicity, and oxidative stress markers, as well as histopathological changes in the HP, HYP, and PFC of male Wistar rats. The results demonstrated that chronic REM-SD induced glucose intolerance and insulin resistance, leading to hyperglycemia, which was accompanied by low-grade inflammation and activation of the HPA axis. Regarding behavioral conditions, REM-SD induced anxiety, depression, and learning and memory impairments. Specifically, in relation to the brain region, REM-SD exhibited disruption in cholinergic neurotransmission, oxidative stress balance (increase in NO, MDA, and decrease in CAT and SOD activity), and neurotoxicity (increase in LDH levels). The r-Spearman correlation analysis showed that AchE activity and memory performance were strongly correlated in sleep-deprived rats. In addition, histological examination demonstrates that chronic REM-SD induced structural atrophy, neuronal degeneration, and a marked decrease in neuronal density in the PFC, HYP, and HP, specifically in the CA3 and DG. Briefly, this finding provides novel insight into the bidirectional interplay pathway between SD and metabolic disorders, and between the mechanisms linking sleep health, diabetes, and behavioral disorders. Consequently, our future studies aim to examine the effect of pharmacological treatments and sleep recovery on biochemical and neurobiochemical parameters, cholinergic neurotransmission, and brain architecture.

Sleep need is associated with both circuit dynamics and widespread synaptic plasticity, yet the specific synaptic changes underlying sleep homeostasis remain incompletely understood. In Drosophila, sleep loss has been shown to trigger plasticity of the presynaptic active zone, marked by increasing levels of the ELKS-family scaffold protein Bruchpilot (BRP). By titrating brp gene copy number, we previously established a presynapse-specific, dosage-dependent paradigm that modulates sleep pressure. Here, to elucidate the molecular landscape of this plasticity, we performed synapse-enriched integrated-omics. Proteomic and bioinformatic analyses revealed changes in immune and stress response pathways and local translation control. Strikingly, phospho-proteomic analysis uncovered a global shift toward hypophosphorylation, particularly in presynaptic proteins, indicating a reprogramming of the phosphorylation-dephosphorylation balance. This presynaptic hypophosphorylation is likely contributed by reduced activity of Protein Kinase A (PKA) and enhanced substrate affinity of Protein Phosphatase 1 (PP1) mediated by its regulatory subunit Spinophilin (Spn). Manipulating either PKA or PP1 activity was sufficient to suppress BRP-modulated sleep phenotypes. We propose that presynaptic hypophosphorylation constitutes a molecular signature of local synaptic remodeling that adaptively tunes sleep need via reversible posttranslational modification, a mechanism likely conserved across species.

ABSTRACTSleep disruption is an early and pervasive feature of Alzheimer’s disease (AD), yet the circuit mechanisms linking tau pathology to sleep-wake dysfunction remain unresolved. Here, we identify melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus (LH) as a critical node disrupted in tauopathy. Longitudinal EEG/EMG recordings inPS19mice reveal progressive impairments in sleep architecture and homeostasis. Histological analyses revealed significant degeneration of both MCH neurons and the neighboring hypocretin (Hcrt) neuronal population in the LH at late stages of tauopathy.In vivofiber photometry recordings demonstrated a selective functional impairment of MCH neurons, characterized by reduced activity during REM sleep, whereas Hcrt neuronal activity remained largely preserved. In addition, cell-autonomous expression of mutant tau in MCH neurons recapitulates sleep disruption, establishing a causal role. Despite tauopathy-induced neuronal loss and reduced endogenous activity, optogenetic and chemogenetic activation show that MCH neurons retain functional capacity, and their activation restores sleep in agedPS19mice. Together, these findings define a circuit mechanism linking tau pathology to sleep and identify MCH neurons as a tractable therapeutic target.

A Rhodiola-derived acidic glycopeptide maintains sleep homeostasis by regulating brain lipid metabolism in Drosophila.

This review examines the bidirectional relationship between sleep regulation and the gut microbiome within the gut-brain axis, with particular attention to mechanistic pathways, disorder-associated dysbiosis patterns, and microbiome-targeted interventions in insomnia, obstructive sleep apnea, circadian disruption, and sleep loss-related states. We critically synthesized evidence from both human and preclinical studies, focusing on microbial metabolites, neuroimmune and neuroendocrine signaling, circadian regulation, and intervention-based approaches. Rather than only summarizing individual studies, we aimed to distinguish associative human findings from mechanistic evidence derived mainly from animal models. Current evidence supports a bidirectional link between sleep and the gut microbiome. Microbiota-derived metabolites, particularly short-chain fatty acids, tryptophan-related metabolites, and gamma-aminobutyric acid, appear to influence sleep homeostasis through effects on intestinal barrier integrity, inflammatory tone, stress-axis regulation, and central signaling pathways. Across sleep disorders, recurrent microbial patterns include reduced abundance of potentially beneficial taxa such as Bifidobacterium and Faecalibacterium and enrichment of pro-inflammatory or stress-associated taxa, although these signatures are not yet fully consistent across cohorts or disorders. In humans, most data remain observational and support association rather than causation, whereas stronger mechanistic support comes from experimental models of sleep deprivation, intermittent hypoxia, and microbiota transfer. Early intervention studies suggest that selected probiotics, prebiotics, dietary modulation, and related microbiome-directed strategies may improve sleep-related outcomes, but the magnitude and reproducibility of these effects remain uncertain. The gut microbiome represents a promising mechanistic and therapeutic target in sleep medicine, but clinical translation is still constrained by heterogeneity in microbiome profiling, sleep phenotyping, intervention design, and strain-specific effects. Future work should prioritize longitudinal human studies, standardized outcome measures, and mechanistically informed trials capable of identifying clinically actionable and biologically credible microbiome signatures.

Unpredictable work schedules (UWSs), which are characterized by last-minute schedule changes, on-call shifts, and short advance notice, have become increasingly common and have been linked to disrupted circadian rhythms, impaired sleep homeostasis, and poor health. However, evidence from South Korea, where long hours and low schedule autonomy are prevalent, remains scarce. This study examined the association between UWS and insomnia symptoms among wage workers in South Korea. Data from 20,534 wage workers aged 20-64 years were obtained from the 2020 Korean Working Conditions Survey. UWS was defined using three items: sudden callbacks, advance notice of schedule changes, and control over working hours. Insomnia symptoms were measured using the minimal insomnia symptom scale, with scores ≥ 6 indicating insomnia. Weighted multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for insomnia by UWS status after adjusting for demographic, socioeconomic, occupational, and psychosocial factors. Sensitivity analyses applied alternative UWS definitions (sudden recall, combined, strict, and lenient definitions). The prevalence of insomnia symptoms was 16.10% (157/975) in UWS and 7.25% (1418/19559) in non-UWS (p < 0.001). In the unweighted analysis, UWS was associated with higher odds of insomnia symptoms in the crude model (OR 2.46, 95% CI 2.05-2.94). Moreover, the association remained significant after adjustment for demographic and work-related covariates (Model 1: OR 2.15, 95% CI 1.78-2.59; Model 2: OR 1.64, 95% CI 1.34-2.01). Sensitivity analysis using alternative UWS definitions showed a consistent, statistically significant association in both crude and adjusted models. In the weighted analysis, the association remained significant after full adjustment (OR 2.30, 95% CI 1.74-3.05). UWS was found to be associated with higher odds of insomnia symptoms among Korean wage workers. Improving the predictability of schedules and ensuring the provision of advance notices may help improve sleep health. Longitudinal studies are needed to clarify causal relationships and to further investigate potential underlying pathways.

Phosphorylation of Thr221 (T221) in salt-inducible kinase 3 (SIK3) is a key determinant of its catalytic activity, with broad implications ranging from sleep homeostasis to tumorigenesis. Despite its physiological significance, however, the underlying molecular mechanism by which this phosphorylation event regulates enzymatic activity remains poorly understood. Here, we combine all-atom molecular dynamics (MD) simulations, quantum mechanics/molecular mechanics (QM/MM)-based steered molecular dynamics (SMD) simulations, molecular mechanics/generalized Born surface area (MM/GBSA) binding free-energy calculations, protein contact network (PCN) analysis, and principal component analysis (PCA) to systematically elucidate the allosteric effects of T221 phosphorylation. We show that a highly occupied pT221-Arg112 salt bridge stabilizes the αC-helix in its "in" conformation and strengthens the conserved Glu113(αC-helix)-Lys95(β3-strand) interaction, thereby biasing the conformational ensemble toward active-like states. This inward orientation of the αC-helix, directed toward both the ATP-binding pocket and the catalytic center, further positions Lys109 to maintain a persistent and energetically favorable salt bridge with ATP, consistent with enhanced ATP affinity. Consistent with these atomistic observations, PCA and MM/GBSA analyses reveal a phosphorylation-induced population shift toward a lower free-energy ensemble and substantially stronger ATP binding, jointly indicating a coordinated allosteric enhancement of catalytic activity. Further QM/MM MD simulations indicate that T221 phosphorylation pre-organizes the SIK3 active site to position HDAC4-Ser245(Oγ) closer to the ATP γ-phosphate in a reaction-competent arrangement, thereby facilitating Ser245-O-P phosphoester bond formation and promoting Ser245 phosphorylation. Taken together, these findings define-at atomic resolution-the detailed structural and dynamic principles by which T221 phosphorylation regulates SIK3 function, thus providing mechanistic insight into sleep-need homeostasis and offering a foundation for structure-guided development of SIK3-targeted cancer therapeutics.

From sleep homeostasis to cellular constraints in neurons.

JACUZI-SD: An automated, high-throughput, minimally stressful approach to sleep depriving larval zebrafish

Caffeine is the most widely consumed psychoactive stimulant worldwide and acts primarily through antagonism of adenosine A1 and A2A receptors, thereby reducing sleep pressure and promoting wakefulness. Although its alerting and performance-enhancing effects are well established, its influence on sleep-related electroencephalography (EEG) has been investigated across diverse paradigms with substantial methodological heterogeneity. This systematic and mechanistic review aimed to synthesize human evidence on how caffeine affects sleep architecture, quantitative sleep EEG, and neurophysiological markers of sleep homeostasis, and to interpret these findings within current models of adenosine-mediated sleep-wake regulation. A systematic search of PubMed/MEDLINE, Web of Science, Scopus, Embase, PsycINFO, ResearchGate, and Google Scholar was conducted for studies published between January 1980 and January 2026, with the final search performed on 10 January 2026. Eligible studies were original human investigations examining caffeine exposure or administration and reporting sleep-related EEG outcomes, including polysomnographic sleep staging, spectral EEG analyses, or other EEG-derived sleep metrics. Two reviewers independently screened records and assessed eligibility, with disagreements resolved by consensus. Data on study design, participant characteristics, caffeine interventions, EEG methodology, and outcomes were extracted using a predefined form. Risk of bias was evaluated using the RoB 2 and ROBINS-I tools. Owing to marked heterogeneity across studies, findings were synthesized narratively within a mechanistic interpretive framework. Thirty-two studies were included. Across highly heterogeneous paradigms-including acute bedtime or evening dosing, daytime or repeated caffeine use before nocturnal sleep, administration during prolonged wakefulness followed by recovery sleep, withdrawal protocols, and ambulatory/home EEG monitoring-the most consistent finding was suppression of low-frequency NREM EEG activity, particularly slow-wave activity and the lowest delta frequencies. Caffeine frequently increased faster EEG activity, including sigma/spindle and beta ranges, producing a lighter, more aroused, and more wake-like sleep EEG profile. These effects were especially prominent during early-night NREM sleep and in recovery sleep after sleep deprivation, where caffeine attenuated the expected homeostatic rebound in low-frequency power. REM-related effects were less consistent, but some studies reported delayed REM timing and subtler alterations in REM EEG. Emerging evidence further suggests that caffeine increases EEG complexity and shifts sleep dynamics toward a more excitation-dominant state. Several studies indicated that quantitative EEG measures were more sensitive than conventional sleep-stage variables in detecting caffeine-related sleep disruption. Dose, timing, habitual caffeine use, withdrawal state, age, circadian context, and adenosinergic genetic variation, particularly involving ADORA2A, moderated the magnitude of effects. We also highlighted the connection between current results and sports and sports science. Caffeine reliably alters the neurophysiological architecture of human sleep in a direction consistent with reduced sleep depth and weakened homeostatic recovery. The overall evidence supports a mechanistic model centered on adenosine receptor antagonism, attenuation of sleep-pressure build-up and expression, and a shift toward greater cortical arousal during sleep. Sleep EEG appears to be a sensitive marker of these effects, often revealing physiological disruption even when conventional sleep architecture changes are modest. Future research should prioritize larger and more diverse samples, pharmacokinetic and pharmacogenetic characterization, and ecologically valid high-resolution sleep monitoring to clarify the real-world and functional consequences of caffeine-induced EEG changes.

Sleep biomarkers of sudden unexpected death in epilepsy: Data from the Kv1.1 mouse model.

Abstract Unsuitable physical environments are increasingly recognised not just as a nuisance, but also as a significant determinant in the pathophysiology of sleep disorders and chronic illness. According to the literature, even little environmental changes can have a significant impact on sleep homeostasis: persistent exposure to background noise above 30 decibels causes autonomic arousal associated to cardiovascular disease, but even low-level artificial light (5–10 lux) suppresses melatonin and disrupts metabolic homeostasis. When paired with thermal stress outside the ideal 18–21 $$^\circ $$ ∘ C, window or ventilation deficiencies enabling carbon dioxide to increase over 1,000 ppm, these environmental stressors affect sleep architecture and impede long-term cognitive recovery. This paper introduces an innovative approach to automatically regulating environmental conditions to ensure proper sleep. This approach leverages an integrated framework of model predictive control, fuzzy logic, and reinforcement learning. To validate this deterministic approach, the study utilises a high-fidelity digital twin of student accommodations at the Mărăşti Student Campus of the Technical University of Cluj-Napoca. Experimental results demonstrate that the proposed Meta-Controller significantly enhances physiological outcomes, yielding a notable 10.06% improvement in objective sleep quality metrics and a 5.41% reduction in health risk indicators associated with sleep deprivation. By achieving an optimised sleep score in 99.24% of cases, the study underscores the efficacy of merging heuristic logic with predictive and adaptive control paradigms. This work provides a pioneering contribution to the field of cyber-physical systems, laying a robust foundation for future advancements in environmental modelling and the development of intelligent, health-centric living spaces through advanced system dynamics.