Active Wakefulness Research Articles

Abstract 10895: Actigraphy-Derived Rest-Activity Rhythms Are Associated With Metabolic Markers and Type 2 Diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA)

Introduction: Individual behaviors in the 24h rest-activity cycle have been linked to cardiometabolic health (CMH). Studies that integrate the overall multidimensional pattern of 24-h rest-activity rhythms (RAR) and evaluate its unique relation with CMH and type 2 diabetes (T2D) are limited. Hypothesis: Disrupted RAR are associated with poorer glycemic control and T2D. Methods: Participants were n=2127 adults (mean age: 69 ± 9 y, 54% women, 62% non-White) in the MESA Sleep Study (2010-13). Interdaily stability (IS), intradaily variability (IV), most active 10 h period (M10) and least active 5 h period (L5) timing and counts, and relative amplitude (RA) (defined in Table) were derived from 7-d actigraphy data using nonparametric rhythm analysis. Multivariable linear and logistic regression was used to examine cross-sectional and prospective associations with glycemic markers and T2D at baseline and after 6 y of follow-up (2016-18). Results: Higher IS (more stable sleep-wake and rest-activity patterns across days), M10 counts (more active wake period), and RA (greater overall RAR robustness) were related to lower fasting glucose, insulin, and HOMA-IR, while higher IV (more fragmented RAR, less efficient sleep) and L5 counts (less restful sleep) were related to higher levels of these metabolic markers (Table). In cross-sectional and prospective analyses, those in the highest vs. lowest quintile of IS, M10 counts, and RA had up to 75% lower odds of T2D, while being in the highest vs. lowest quintile of IV, L5 counts, and L5 midpoint (later sleep period) was associated with up to 79% higher T2D odds with evidence of a dose-response relationship (p-trend <0.05 for all outcomes). Conclusions: A less robust and stable RAR, lower wake time activity, and a less restful and later sleep period are associated with T2D. Targeting the strength, timing, and regularity of rest-activity and sleep-wake patterns to enhance the rhythmicity of diurnal behaviors may enhance CMH and prevent T2D.

Flow past a sphere: Numerical predictions of thixo-viscoelastoplastic wormlike micellar solutions

In this work, we present numerical solutions to the benchmark flow past a sphere problem considering the rheology of semi-diluted and concentrated wormlike micellar viscoelastic solutions using the most recent model-variant of the Bautista–Manero–Puig (BMP) family of fluids, i.e. the BMP+ _ τ p model (López-Aguilar et al., [1] ). This study is performed using our in-house finite volume/element algorithm, stabilised to attain highly-elastic non-linear solutions with two novel constitutive and boundary-condition implementations, i.e. the ABS- f (ABSolute f -functional) and the VGR (Velocity GRadient) corrections (López-Aguilar et al., [2] ). The structuring level of various wormlike micellar fluids with different solute concentrations (from semi-diluted to extremely concentrated solutions) and degrees of strain-hardening is studied with a dynamic dimensionless fluidity that connects the internal structure construction-destruction dynamics with viscoelasticity. In complex flow, a viscoelastic flow-regime unveils the prediction of a flow transition from a stable steady flow (related to a steady sphere settling) to an unsteady quasi-periodic flow regime, in which transient cycles of vortex formation-disappearance behind the sphere are present, resembling experimental findings on negative-wake instabilities and oscillations in the settling velocity for the descend of particles in wormlike micellar solutions. This instability is predicted here for semi-diluted to concentrated wormlike micellar solutions and it is located in flow-rate ranges corresponding to extensional Deborah numbers in the interval of around 26 . 7 ≤ D e e x t ≤ 40 . 3 , as reported experimentally. This behaviour is correlated with a chaotic flow-structure behind the obstacle, for which strong fluctuation in the fluid’s internal-structure is recorded. In the steady viscoelastic flow regime, correlation between the BMP+ _ τ p fluidity structure-variable and its normal-stress response around and downstream of the sphere (in the form of localised extrema) is detected, where interaction between the rheological response of the material and mixed shear-to-extensional deformation provide insights into the forces the fluid elements experiment in the sphere wake. Here, a monotonic decline in the drag-correction factor is observed, this being one of the main experimental manifestations of the steady sphere-settling phase in these materials. These findings may serve to further understand flow transitions and instabilities related to negative wakes in this kind of shear-thinning extensional-hardening fluids (Rothstein and Mohammadigoushki, [3] ). In a plastic regime, complex thixo-viscoelastoplastic BMP+ _ τ p features manifest through the prediction of fore-aft asymmetries promoted by the thixotropic structure construction-destruction and viscoelastic properties of the model under extremely low solute-concentrations. Predicted yield-fronts resemble those reported experimentally by Holenberg et al. [4] for carbopol solutions. • Negative-wake instability predictions in the De -range recorded experimentally. • Correlation between extensional viscosity and normal stresses in the sphere wake. • Localised N 1 and internal-structure f -functional in the sphere wake. • First normal-stress activity in the sphere wake follows extensional viscosity response. • Asymmetric yield-fronts under highly-concentrated gel-like wormlike micellar solutions.

Breathing modulates gamma synchronization across species.

Nasal respiration influences brain dynamics by phase-entraining neural oscillations at the same frequency as the breathing rate and by phase-modulating the activity of faster gamma rhythms. Despite being widely reported, we still do not understand the functional roles of respiration-entrained oscillations. A common hypothesis is that these rhythms aid long-range communication and provide a privileged window for synchronization. Here we tested this hypothesis by analyzing electrocorticographic (ECoG) recordings in mice, rats, and cats during the different sleep-wake states. We found that the respiration phase modulates the amplitude of cortical gamma oscillations in the three species, although the modulated gamma frequency bands differed with faster oscillations (90-130Hz) in mice, intermediate frequencies (60-100Hz) in rats, and slower activity (30-60Hz) in cats. In addition, our results also show that respiration modulates olfactory bulb-frontal cortex synchronization in the gamma range, in which each breathing cycle evokes (following a delay) a transient time window of increased gamma synchrony. Long-range gamma synchrony modulation occurs during quiet and active wake states but decreases during sleep. Thus, our results suggest that respiration-entrained brain rhythms orchestrate communication in awake mammals.

A More Intense Examination of the Intensity of Physical Activity in People Living with Chronic Obstructive Pulmonary Disease: Insights from Threshold-Free Markers of Activity Intensity.

Physical activity (PA) intensity of people living with chronic obstructive pulmonary disease (COPD) is typically evaluated using intensity thresholds developed in younger, healthier populations with greater exercise capacity and free from respiratory symptoms. This study therefore compared (i) PA differences between COPD and non-COPD controls using both traditional intensity thresholds and threshold-free metrics that represent the volume and intensity of the whole PA profile, and (ii) explored the influence of exercise capacity on observed differences. Moderate-to-vigorous physical activity (MVPA), average acceleration (proxy for volume, mg) and intensity distribution of activity were calculated for 76 individuals with COPD and 154 non-COPD controls from wrist-worn ActiGraph accelerometry. PA profiles representing the minimum intensity (acceleration, mg) during the most active accumulated 5–960 min were plotted. Estimated VO2peak and relative intensity were derived from the incremental shuttle walk test distance. Compared to the non-COPD control group, individuals with COPD recorded fewer MVPA minutes (59 vs. 83 min/day), lower overall waking activity (29.1 vs. 36.4 mg) and a poorer waking intensity distribution (−2.73 vs. −2.57). Individuals with COPD also recorded a lower absolute intensity (acceleration, mg) for their most active 5–960 min, but higher intensity relative to their estimated exercise capacity derived from the ISWT. People with COPD have a lower volume and absolute intensity of PA than controls but perform PA at a higher relative intensity. There is a need to move away from absolute intensity thresholds, and towards personalised or relative-intensity thresholds, to reflect reduced exercise capacity in COPD populations.

Non-sedative cortical EEG signatures of allopregnanolone and functional comparators

Neurosteroids that positively modulate GABAA receptors are among a growing list of rapidly acting antidepressants, including ketamine and psychedelics. To develop increasingly specific treatments with fewer side effects, we explored the possibility of EEG signatures in mice, which could serve as a cross-species screening tool. There are few studies of the impact of non-sedative doses of rapid antidepressants on EEG in either rodents or humans. Here we hypothesize that EEG features may separate a rapid antidepressant neurosteroid, allopregnanolone, from other GABAA positive modulators, pentobarbital and diazepam. Further, we compared the actions GABA modulators with those of ketamine, an NMDA antagonist and prototype rapid antidepressant. We examined EEG spectra during active exploration at two cortical locations and examined cross-regional and cross-frequency interactions. We found that at comparable doses, the effects of allopregnanolone, despite purported selectivity for certain GABAAR subtypes, was indistinguishable from pentobarbital during active waking exploration. The actions of diazepam had recognizable common features with allopregnanolone and pentobarbital but was also distinct, consistent with subunit selectivity of benzodiazepines. Finally, ketamine exhibited no distinguishing overlap with allopregnanolone in the parameters examined. Our results suggest that rapid antidepressants with different molecular substrates may remain separated at the level of large-scale ensemble activity, but the studies leave open the possibility of commonalities in more discrete circuits and/or in the context of a dysfunctional brain.

Joint Profiles of Sedentary Time and Physical Activity in Adults and Their Associations with Cardiometabolic Health.

This study aimed to identify and characterize joint profiles of sedentary time and physical activity among adults and to investigate how these profiles are associated with markers of cardiometabolic health. The participants included 3702 of the Northern Finland Birth Cohort 1966 at age 46 yr, who wore a hip-worn accelerometer during waking hours and provided seven consecutive days of valid data. Sedentary time, light-intensity physical activity, and moderate- to vigorous-intensity physical activity on each valid day were obtained, and a data-driven clustering approach ("KmL3D") was used to characterize distinct joint profiles of sedentary time and physical activity intensities. Participants self-reported their sleep duration and performed a submaximal step test with continuous heart rate measurement to estimate their cardiorespiratory fitness (peak heart rate). Linear regression was used to determine the association between joint profiles of sedentary time and physical activities with cardiometabolic health markers, including adiposity markers and blood lipid, glucose, and insulin levels. Four distinct groups were identified: "active couch potatoes" ( n = 1173), "sedentary light movers" ( n = 1199), "sedentary exercisers" ( n = 694), and "movers" ( n = 636). Although sufficiently active, active couch potatoes had the highest daily sedentary time (>10 h) and lowest light-intensity physical activity. Compared with active couch potatoes, sedentary light movers, sedentary exercisers, and movers spent less time in sedentary by performing more physical activity at light-intensity upward and had favorable differences in their cardiometabolic health markers after accounting for potential confounders (1.1%-25.0% lower values depending on the health marker and profile). After accounting for sleep duration and cardiorespiratory fitness, waking activity profiles characterized by performing more physical activity at light-intensity upward, resulting in less time spent in sedentary, were associated with better cardiometabolic health.

Respiratory entrainment of units in the mouse parietal cortex depends on vigilance state

Synchronous oscillations are essential for coordinated activity in neuronal networks and, hence, for behavior and cognition. While most network oscillations are generated within the central nervous system, recent evidence shows that rhythmic body processes strongly influence activity patterns throughout the brain. A major factor is respiration (Resp), which entrains multiple brain regions at the mesoscopic (local field potential) and single-cell levels. However, it is largely unknown how such Resp-driven rhythms interact or compete with internal brain oscillations, especially those with similar frequency domains. In mice, Resp and theta (θ) oscillations have overlapping frequencies and co-occur in various brain regions. Here, we investigated the effects of Resp and θ on neuronal discharges in the mouse parietal cortex during four behavioral states which either show prominent θ (REM sleep and active waking (AW)) or lack significant θ (NREM sleep and waking immobility (WI)). We report a pronounced state-dependence of spike modulation by both rhythms. During REM sleep, θ effects on unit discharges dominate, while during AW, Resp has a larger influence, despite the concomitant presence of θ oscillations. In most states, unit modulation by θ or Resp increases with mean firing rate. The preferred timing of Resp-entrained discharges (inspiration versus expiration) varies between states, indicating state-specific and different underlying mechanisms. Our findings show that neurons in an associative cortex area are differentially and state-dependently modulated by two fundamentally different processes: brain-endogenous θ oscillations and rhythmic somatic feedback signals from Resp.

Mistimed sleep and waking activity in humans disrupts glucocorticoid signalling transcripts and SP1, but not plasma cortisol rhythms.

Cortisol is a robust circadian signal that synchronises peripheral circadian clocks with the central clock in the suprachiasmatic nucleus via glucocorticoid receptors that regulate peripheral gene expression. Misalignment of the cortisol rhythm with the sleep–wake cycle, as occurs in shift work, is associated with negative health outcomes, but underlying molecular mechanisms remain largely unknown. We experimentally induced misalignment between the sleep–wake cycle and melatonin and cortisol rhythms in humans and measured time series blood transcriptomics while participants slept in-phase and out-of-phase with the central clock. The cortisol rhythm remained unchanged, but many glucocorticoid signalling transcripts were disrupted by mistimed sleep. To investigate which factors drive this dissociation between cortisol and its signalling pathways, we conducted bioinformatic and temporal coherence analyses. We found that glucocorticoid signalling transcripts affected by mistimed sleep were enriched for binding sites for the transcription factor SP1. Furthermore, changes in the timing of the rhythms of SP1 transcripts, a major regulator of transcription, and changes in the timing of rhythms in transcripts of the glucocorticoid signalling pathways were closely associated. Associations between the rhythmic changes in factors that affect SP1 expression and its activity, such as STAT3, EP300, HSP90AA1, and MAPK1, were also observed. We conclude that plasma cortisol rhythms incompletely reflect the impact of mistimed sleep on glucocorticoid signalling pathways and that sleep–wake driven changes in SP1 may mediate disruption of these pathways. These results aid understanding of mechanisms by which mistimed sleep affects health.

Glutamatergic neurons in paraventricular nucleus of the thalamus regulate the recovery from isoflurane anesthesia

ObjectivesPrevious studies have demonstrated that the paraventricular nucleus of the thalamus (PVT) is a key wakefulness-controlling nucleus in the thalamus. Therefore, PVT may also be involved in the process of general anesthesia. This study intends to explore the role of PVT in isoflurane anesthesia.MethodsIn the present study, we used the expression of c-Fos to observe the neuronal activity of PVT neurons under isoflurane anesthesia. We further recorded the effect of isoflurane anesthesia on the calcium signal of PVT glutamatergic neurons in real time with the help of calcium fiber photometry. We finally used chemogenetic technology to specifically regulate PVT glutamatergic neurons, and observed its effect on isoflurane anesthesia and cortical electroencephalography (EEG) in mice.ResultsWe found that glutamatergic neurons of PVT exhibited high activity during wakefulness and low activity during isoflurane anesthesia. Activation of PVT glutamatergic neuronal caused an acceleration in emergence from isoflurane anesthesia accompanied with a decrease in EEG delta power (1–4 Hz). Whereas suppression of PVT glutamatergic neurons induced a delay recovery of isoflurane anesthesia, without affecting anesthesia induction.ConclusionsAssuming a pharmacokinetic explanation for results can be excluded, these results demonstrate that the PVT is involved in regulating anesthesia emergence.

Knockout of Katnal2 Leads to Autism-like Behaviors and Developmental Delay in Zebrafish.

KATNAL2 mutations have been associated with autism spectrum disorder (ASD) and other related neurodevelopmental disorders (NDDs) such as intellectual disability (ID) in several cohorts. KATNAL2 has been implicated in brain development, as it is required for ciliogenesis in Xenopus and is required for dendritic arborization in mice. However, a causative relationship between the disruption of Katnal2 function and behavioral defects has not been established. Here, we generated a katnal2 null allele in zebrafish using CRISPR/Cas9-mediated genome editing and carried out morphological and behavioral characterizations. We observed that katnal2-/- embryos displayed delayed embryonic development especially during the convergence and extension (CE) movement. The hatched larvae showed reduced brain size and body length. In the behavioral tests, the katnal2-/- zebrafish exhibited reduced locomotor activity both in larvae and adults; increased nocturnal waking activity in larvae; and enhanced anxiety-like behavior, impaired social interaction, and reduced social cohesion in adults. These findings indicate an important role for katnal2 in development and behavior, providing an in vivo model to study the mechanisms underlying the ASD related to KATNAL2 mutations.

Enhanced Visual Cortex Activation in People With Narcolepsy Type 1 During Active Sleep Resistance: An fMRI-EEG Study.

The brain activation patterns related to sleep resistance remain to be discovered in health and disease. The maintenance of wakefulness test (MWT) is an objective neuropsychological assessment often used to assess an individual’s ability to resist sleep. It is frequently used in narcolepsy type 1, a disorder characterized by impaired sleep-wake control and the inability to resist daytime sleep. We investigated the neural correlates of active sleep resistance in 12 drug-free people with narcolepsy type 1 and 12 healthy controls. Simultaneous fMRI-EEG measurements were recorded during five cycles of two alternating conditions of active sleep resistance and waking rest. Cleaned EEG signals were used to verify wakefulness and task adherence. Pooling both subject groups, significantly higher fMRI activation when actively resisting sleep was seen in the brainstem, superior cerebellum, bilateral thalamus and visual cortices. In controls the activation clusters were generally smaller compared to patients and no significant activation was seen in the brainstem. Formal comparison between groups only found a significantly higher left primary visual cortex activation in patients during active sleep resistance. The active sleep resistance paradigm is a feasible fMRI task to study sleep resistance and induces evident arousal- and visual-related activity. Significantly higher left primary visual cortical activation in patients could be caused by an enhanced need of visual focus to resist sleep, or reflecting a more rapid descent in their level of alertness when resting.

The effect of interference, offline sleep, and wake on spatial statistical learning

Statistical learning, the ability of the human brain to uncover patterns organized according to probabilistic relationships between elements and events of the environment, is a powerful learning mechanism underlying many cognitive processes. Here we examined how memory for statistical learning of probabilistic spatial configurations is impacted by interference at the time of initial exposure and varying degrees of wakefulness and sleep during subsequent offline processing. We manipulated levels of interference at learning by varying the time between exposures of different spatial configurations. During the subsequent offline period, participants either remained awake (active wake or quiet wake) or took a nap comprised of either non-rapid eye movement (NREM) sleep only or NREM and rapid eye movement (REM) sleep. Recognition of the trained spatial configurations, as well as a novel configuration exposed after the offline period, was tested approximately 6–7 h after initial exposure. We found that the sleep conditions did not provide any additional memory benefit compared to wakefulness for spatial statistical learning with low interference. For high interference, we found some evidence that memory may be impaired following quiet wake and NREM sleep only, but not active wake or combined NREM and REM sleep. These results indicate that learning conditions may interact with offline brain states to influence the long-term retention of spatial statistical learning.

Sleep affects higher-level categorization of speech sounds, but not frequency encoding

Sleep can increase consolidation of new knowledge and skills. It is less clear whether sleep plays a role in other aspects of experience-dependent neuroplasticity, which underlie important human capabilities such as spoken language processing. Theories of sensory learning differ in their predictions; some imply rapid learning at early sensory levels, while other propose a slow, progressive timecourse such that higher-level categorical representations guide immediate, novice learning, while lower-level sensory changes do not emerge until later stages. In this study, we investigated the role of sleep across both behavioural and physiological indices of auditory neuroplasticity. Forty healthy young human adults (23 female) who did not speak a tonal language participated in the study. They learned to categorize non-native Mandarin lexical tones using a sound-to-category training paradigm, and were then randomly assigned to a Nap or Wake condition. Polysomnographic data were recorded to quantify sleep during a 3 h afternoon nap opportunity, or equivalent period of quiet wakeful activity. Measures of behavioural performance accuracy revealed a significant improvement in learning the sound-to-category training paradigm between Nap and Wake groups. Conversely, a neural index of fine sound encoding fidelity of speech sounds known as the frequency-following response (FFR) suggested no change due to sleep, and a null model was supported, using Bayesian statistics. Together, these results support theories that propose a slow, progressive and hierarchical timecourse for sensory learning. Sleep's effect may play the biggest role in the higher-level learning, although contributions to more protracted processes of plasticity that exceed the study duration cannot be ruled out.

Theta Activity During Encoding Interacts With NREM Sleep Oscillations to Predict Memory Generalization.

Relatively little is known regarding the interaction between encoding-related neural activity and sleep-based memory consolidation. One suggestion is that a function of encoding-related theta power may be to “tag” memories for subsequent processing during sleep. This study aimed to extend previous work on the relationships between sleep spindles, slow oscillation-spindle coupling, and task-related theta activity with a combined Deese-Roediger-McDermott (DRM) and nap paradigm. This allowed us to examine the influence of task- and sleep-related oscillatory activity on the recognition of both encoded list words and associative theme words. Thirty-three participants (29 females, mean age = 23.2 years) learned and recognised DRM lists separated by either a 2 h wake or sleep period. Mixed-effects modelling revealed the sleep condition endorsed more associative theme words and fewer list words in comparison to the wake group. Encoding-related theta power was also found to influence sleep spindle density, and this interaction was predictive of memory outcomes. The influence of encoding-related theta was specific to sleep spindle density, and did not appear to influence the strength of slow oscillation-spindle coupling as it relates to memory outcomes. The finding of interactions between wakeful and sleep oscillatory-related activity in promoting memory and learning has important implications for theoretical models of sleep-based memory consolidation.

REM Sleep Rebound Following Acute Intermittent Hypoxia in Freely Behaving Rats

Core components of the circadian clock and molecules involved in neuroplasticity elicited by acute intermittent hypoxia (AIH) exhibit 24‐hour rhythms in gene expression in the phrenic/diaphragm motor system. Ongoing investigations of time‐of‐day effects on AIH‐induced motor plasticity must account for changes in time spent across vigilance states since sleep architecture profoundly influences other biological rhythms across the rest‐active cycle. Previous investigations from our group reported a marginal increase in wakefulness during the AIH exposure in unanesthetized rats (10, 5‐min hypoxic episodes; 5 min intervals). Following AIH, we also observed a prolonged increase in slow‐wave sleep lasting hours, but changes in REM were not assessed (Terada et al., J. Appl. Physiol., 2011). Given the significant effects disruptions of the sleep‐wake cycle can have on daily biological rhythms, further characterization of sleep architecture following AIH is needed. In this preliminary analysis, from an extensive study of diaphragm long‐term facilitation (LTF) in rats at opposite stages of the diurnal cycle (mid‐active vs. mid‐rest), we added second set of intracortical EEG leads (ECoG) not used by Terada et al. (2011) to enhance detection of hippocampal theta bursts and sleep spindling. In 8 unanesthetized, instrumented rats exposed to AIH, ECoG, and nuchal EMG signals acquired via radiotelemetry were analyzed in 10‐second epochs using Fast Fourier transformation spectral analysis. Power spectra were averaged in frequency bands: delta (1.5‐4.0Hz), theta (4.0‐10.0Hz), beta (10.0‐30.0 Hz), and sigma (10.0‐14.0Hz). We assessed vigilance state at baseline, during AIH, and 90 minutes post‐AIH; there were significant effects of AIH protocol period (p < 0.05) and sleep state (p<0.001). There were marginal, non‐significant trends towards increased active wakefulness during AIH, with decreased quiet wakefulness, slow‐wave sleep, and REM. Time spent in REM sleep rebounded to levels nearly two‐fold above baseline at 60 and 90 min post‐AIH; there were non‐significant trends towards reduced quiet wakefulness without apparent change in NREM sleep post‐AIH. In this preliminary analysis, we report an acute AIH protocol (3, 5 min hypoxic episodes, 13% O2; 5‐min normoxic intervals) has minimal impact on NREM sleep during or following AIH but increases REM post‐AIH. Additional analyses will be performed during and following AIH during the mid‐active and mid‐rest phases, using the 5‐min AIH protocol and a modified protocol with similar cumulative duration of hypoxia (15, 1 min hypoxic episodes; 1 min intervals) often used in human studies of repetitive AIH as a neurotherapeutic modality to improve breathing and non‐respiratory motor function in humans living with chronic spinal cord injury and ALS. REM sleep is essential for mechanisms of neuroplasticity in neural networks controlling diverse physiological systems. These results warrant future research to delineate the influence REM may play in initiating and maintaining memory in the respiratory system.

Platycladus orientalis seed extract as a potential triple reuptake MAO inhibitor rescue depression phenotype through restoring monoamine neurotransmitters

Ethnopharmacology relevancePlatycladus orientalis seeds are recorded in traditional Chinese medicine (TCM) formulations for modulation of mood and physical activity in “Shen Nong Ben Cao Jing” and “Compendium of Materia Medica” and so on. Recently, we identified its extracting components and looked for the potentials in treatment for depression by improving the function of monoamine neurotransmitters. Aim of the studyWe investigated the mechanism of action of the seed extracts of P. orientalis (S4) to rescue depressive behavior in a chronic, unpredicted, mild stress (CUMS)-induced model in rats. Materials and methodsWe used ultra-fast liquid chromatography coupled with triple quadrupole-time of flight tandem mass spectrometry to analyze the chemical constituents in S4. An assay platform in zebrafish and molecular docking were used to analyze if S4 regulated rest/wake behavior and predict the biological targets which correlated with monoamine neurotransmitters. Depressive-behavior tests (body weight, sucrose preference test, tail-suspension test, forced-swimming test) were carried in the CUMS model. After behavior tests and killing, rat brains were separated into the hippocampus, frontier cortex and dorsal raphe nucleus. The main monoamine neurotransmitters and their metabolite concentrations in these three brain regions were measured by rapid resolution liquid chromatography coupled with triple quadrupole tandem mass spectrometry. ResultsForty-one compounds were identified in S4, including fatty acids, terpenoids, amino acids, plant sterols and flavonoids. S4 could increase the total rest time and decrease the waking activity of zebrafish. S4 showed high correlation with adrenaline agonists, 5-hydroxytryptamine (5-HT) reuptake inhibitors and dopamine agonists. CUMS-group rats, compared with controls, had significantly decreased body weight and preference for sucrose water, whereas the immobility time in the tail-suspension test and forced-swimming test was increased. S4 could significantly rescue the increased levels of 5-HT, noradrenaline and dopamine in the prefrontal cortex and dorsal raphe nucleus. ConclusionsWe demonstrated that S4 was a potential inhibitor of MAO reuptake that could rescue depression in a CUMS-model rats by restoring monoamine neurotransmitters in different encephalic regions.

Earlier bedtimes and more sleep displace sedentary behavior but not moderate-to-vigorous physical activity in adolescents

ObjectivesCorrelational models suggest increased cardiometabolic risk when sleep replaces moderate-to-vigorous (but not sedentary or light) physical activity. This study tested which activity ranges are impacted by experimentally altering adolescents’ bedtime. MethodAdolescents completed a 3-week within-subjects crossover experiment with 5 nights of late bedtimes and 5 nights early bedtimes (6.5- and 9.5-hours sleep opportunity, respectively). Experimental condition order was randomized. Waketimes were held constant throughout to mimic school start times. Sleep and physical activity occurred in the natural environments, with lab appointments following each 5-day condition. Waist-worn accelerometers measured physical activity and sedentary behavior. Wrist-worn actigraphs confirmed sleep condition adherence. Wilcoxon tests and linear mixed effects models compared waking activity levels between conditions and across time. ResultsNinety healthy adolescents (14-17 years) completed the study. When in the early (vs. late) bedtime condition, adolescents fell asleep 1.96 hours earlier (SD = 1.08, d = 1.82, p < .0001) and slept 1.49 hours more (SD = 1.01, d = 1.74, p < .0001). They spent 1.68 and 0.32 fewer hours in sedentary behavior (SD = 1.67, d = 1.0, p < .0001) and light physical activity (SD = 0.87, d = 0.37, p = .0005), respectively. This pattern was reflected in increased proportion of waking hours spent in sedentary and light activity. Absolute and proportion of moderate-to-vigorous physical activity did not differ between conditions (d = 0.02, p = .89; d = 0.14, p = .05, respectively). ConclusionsInducing earlier bedtimes (allowing for healthy sleep opportunity) did not affect moderate-to-vigorous physical activity. Alternatively, later bedtimes (allowing for ≤ 6.5 hours of sleep opportunity, mimicking common adolescent school night sleep) increased sedentary behavior. Results are reassuring for the benefits of earlier bedtimes.

Brain temperature affects quantitative features of hippocampal sharp wave ripples.

Biochemical mechanisms are temperature dependent. Brain temperature shows wide variations across brain states, and such changes may explain quantitative changes in network oscillations. Here, we report on the relationship between various hippocampal sharp wave ripple features to brain temperature. Ripple frequency, occurrence rate, and duration correlated with temperature dynamics. By focal manipulation of the brain temperature in the hippocampal CA1 region, we show that ripple frequency can be increased and decreased by local heating and cooling, respectively. Changes of other parameters, such as the rate of sharp wave-ripple complex (SPW-R) and ripple duration were not consistently affected. Our findings suggest that brain temperature in the CA1 region plays a leading role in affecting ripple frequency, whereas other parameters of SPW-Rs may be determined by mechanisms upstream from the CA1 region. These findings illustrate that physiological variations of brain temperature exert important effects on hippocampal circuit operations.NEW & NOTEWORTHY During physiological conditions, brain temperature fluctuates approximately 3°C between sleep and active waking. Here, we show that features of hippocampal ripples, including the rate of occurrence, peak frequency, and duration are correlated with brain temperature variations. Focal bidirectional manipulation of temperature in the hippocampal CA1 region in awake rodents show that ripple frequency can be altered in the direction expected from the correlational observations, implying that temperature plays a significant role.

Neuroinflammation, Sleep, and Circadian Rhythms.

Molecules involved in innate immunity affect sleep and circadian oscillators and vice versa. Sleep-inducing inflammatory molecules are activated by increased waking activity and pathogens. Pathologies that alter inflammatory molecules, such as traumatic brain injury, cancer, cardiovascular disease, and stroke often are associated with disturbed sleep and electroencephalogram power spectra. Moreover, sleep disorders, such as insomnia and sleep disordered breathing, are associated with increased dysregulation of inflammatory processes. Inflammatory molecules in both the central nervous system and periphery can alter sleep. Inflammation can also modulate cerebral vascular hemodynamics which is associated with alterations in electroencephalogram power spectra. However, further research is needed to determine the interactions of sleep regulatory inflammatory molecules and circadian clocks. The purpose of this review is to: 1) describe the role of the inflammatory cytokines interleukin-1 beta and tumor necrosis factor-alpha and nucleotide-binding domain and leucine-rich repeat protein-3 inflammasomes in sleep regulation, 2) to discuss the relationship between the vagus nerve in translating inflammatory signals between the periphery and central nervous system to alter sleep, and 3) to present information about the relationship between cerebral vascular hemodynamics and the electroencephalogram during sleep.

Effects of renal denervation on sleep apnea and arrhythmia in rats with myocardial infarction

BackgroundSympathetic hyperactivity and poor sleep quality have been reported in patients with myocardial infarction (MI). Sleep is an important modulator of cardiovascular function. We aimed to evaluate the effects of renal denervation (RDN) on cardiac autonomic activity and disordered sleep patterns in rats with MI. MethodsWireless transmission of polysomnographic recordings was performed in sham and left coronary artery (LCA) ligation male rats during normal daytime sleep before and after RDN. Spectral analyses of electroencephalogram and electromyogram (EMG) recordings were performed to define active waking, quiet sleep, and paradoxical sleep. Cardiac autonomic activity was measured by analyzing the power spectrum of heart rate variability. Central sleep apnea events were measured by analyzing the EMG recordings of the diaphragm. ResultsIn the LCA ligation group, there was a higher low-frequency (LF)/high-frequency (HF) power ratio during sleep; the LF/HF ratio decreased significantly in the rats that underwent RDN in all sleep stages when compared with that in the rats that did not. The frequency of sleep interruptions increased without RDN in the LCA ligation group when compared with that in the sham group. This change was ameliorated and prevented with RDN in the LCA ligation group. ConclusionsOur results demonstrate significant sleep fragmentation with sympathetic hyperactivity after MI and that RDN prevents autonomic dysfunction and disordered sleep. RDN may then reduce sleep apnea and sleep-related sudden cardiac death after MI by restoring autonomic homeostasis.