Acetylcholine-gated current translates wake neuronal firing rate information into a spike timing-based code in Non-REM sleep,stabilizing neural network dynamics during memory consolidation

Sleep is critical for memory consolidation, although the exact mechanisms mediating this process are unknown. Combining reduced network models and analysis of in vivo recordings, we tested the hypothesis that neuromodulatory changes in acetylcholine (ACh) levels during non-rapid eye movement (NREM) sleep mediate stabilization of network-wide firing patterns, with temporal order of neurons’ firing dependent on their mean firing rate during wake. In both reduced models and in vivo recordings from mouse hippocampus, we find that the relative order of firing among neurons during NREM sleep reflects their relative firing rates during prior wake. Our modeling results show that this remapping of wake-associated, firing frequency-based representations is based on NREM-associated changes in neuronal excitability mediated by ACh-gated potassium current. We also show that learning-dependent reordering of sequential firing during NREM sleep, together with spike timing-dependent plasticity (STDP), reconfigures neuronal firing rates across the network. This rescaling of firing rates has been reported in multiple brain circuits across periods of sleep. Our model and experimental data both suggest that this effect is amplified in neural circuits following learning. Together our data suggest that sleep may bias neural networks from firing rate-based towards phase-based information encoding to consolidate memories.     

Promotion of non-rapid eye movement sleep in mice after oral administration of ornithine

We examined the effects of ornithine on the sleep-wake cycle by monitoring the electroencephalo-gram, electromyogram, and locomotor activity of freely moving mice after oral administration of it at lights-off time (18:00). Ornithine (1.0 and 3.0 g/kg of body weight) increased the amount of non-rapid eye movement (non-REM, NREM) sleep for 2 h after its administration, with a peak at 60 min post administration, to 164% and 198%, respectively, of that of the vehicle-administered mice, without changing the amount of REM sleep. The administration of ornithine at a lower dose (0.3 g/kg of body weight) did not increase the amount of NREM sleep compared with the vehicle administration. Ornithine did not affect the power spectrum density of NREM sleep but increased the number of episodes of wakefulness and NREM sleep and that of transitions between wakefulness and NREM sleep, and decreased the mean duration of wake episodes in a dose-dependent manner for 2 h after the oral administration. These results indicate that ornithine increased the amount of NREM sleep without reducing the power spectrum density of NREM sleep.

     

Endoplasmic reticulum stress in wake-active neurons progresses with aging

Fragmentation of wakefulness and sleep are expected outcomes of advanced aging. We hypothesize that wake neurons develop endoplasmic reticulum dyshomeostasis with aging, in parallel with impaired wakefulness. In this series of experiments, we sought to more fully characterize age-related changes in wakefulness and then, in relevant wake neuronal populations, explore functionality and endoplasmic reticulum homeostasis. We report that old mice show greater sleep/wake transitions in the active period with markedly shortened wake periods, shortened latencies to sleep, and less wake time in the subjective day in response to a novel social encounter. Consistent with sleep/wake instability and reduced social encounter wakefulness, orexinergic and noradrenergic wake neurons in aged mice show reduced c-fos response to wakefulness and endoplasmic reticulum dyshomeostasis with increased nuclear translocation of CHOP and GADD34. We have identified an age-related unfolded protein response injury to and dysfunction of wake neurons. It is anticipated that these changes contribute to sleep/wake fragmentation and cognitive impairment in aging.     

The Temporal Structure of Behaviour and Sleep Homeostasis

The amount and architecture of vigilance states are governed by two distinct processes, which occur at different time scales. The first, a slow one, is related to a wake/sleep dependent homeostatic Process S, which occurs on a time scale of hours, and is reflected in the dynamics of NREM sleep EEG slow-wave activity. The second, a fast one, is manifested in a regular alternation of two sleep states – NREM and REM sleep, which occur, in rodents, on a time scale of ∼5–10 minutes. Neither the mechanisms underlying the time constants of these two processes – the slow one and the fast one, nor their functional significance are understood. Notably, both processes are primarily apparent during sleep, while their potential manifestation during wakefulness is obscured by ongoing behaviour. Here, we find, in mice provided with running wheels, that the two sleep processes become clearly apparent also during waking at the level of behavior and brain activity. Specifically, the slow process was manifested in the total duration of waking periods starting from dark onset, while the fast process was apparent in a regular occurrence of running bouts during the waking periods. The dynamics of both processes were stable within individual animals, but showed large interindividual variability. Importantly, the two processes were not independent: the periodic structure of waking behaviour (fast process) appeared to be a strong predictor of the capacity to sustain continuous wakefulness (slow process). The data indicate that the temporal organization of vigilance states on both the fast and the slow time scales may arise from a common neurophysiologic mechanism.     

Essential Roles of GABA Transporter-1 in Controlling Rapid Eye Movement Sleep and in Increased Slow Wave Activity after Sleep Deprivation

GABA is the major inhibitory neurotransmitter in the mammalian central nervous system that has been strongly implicated in the regulation of sleep. GABA transporter subtype 1 (GAT1) constructs high affinity reuptake sites for GABA and regulates GABAergic transmission in the brain. However, the role of GAT1 in sleep-wake regulation remains elusive. In the current study, we characterized the spontaneous sleep-wake cycle and responses to sleep deprivation in GAT1 knock-out (KO) mice. GAT1 KO mice exhibited dominant theta-activity and a remarkable reduction of EEG power in low frequencies across all vigilance stages. Under baseline conditions, spontaneous rapid eye movement (REM) sleep of KO mice was elevated both during the light and dark periods, and non-REM (NREM) sleep was reduced during the light period only. KO mice also showed more state transitions from NREM to REM sleep and from REM sleep to wakefulness, as well as more number of REM and NREM sleep bouts than WT mice. During the dark period, KO mice exhibited more REM sleep bouts only. Six hours of sleep deprivation induced rebound increases in NREM and REM sleep in both genotypes. However, slow wave activity, the intensity component of NREM sleep was briefly elevated in WT mice but remained completely unchanged in KO mice, compared with their respective baselines. These results indicate that GAT1 plays a critical role in the regulation of REM sleep and homeostasis of NREM sleep.     

Effect of REM sleep on retroglossal cross-sectional area and compliance in normal subjects.

It has been proposed that the upper airway compliance should be highest during rapid eye movement (REM) sleep. Evidence suggests that the increased compliance is secondary to an increased retroglossal compliance. To test this hypothesis, we examined the effect of sleep stage on the relationship of retroglossal cross-sectional area (CSA; visualized with a fiber-optic scope) to pharyngeal pressure measured at the level of the oropharynx during eupneic breathing in subjects without significant sleep-disordered breathing. Breaths during REM sleep were divided into phasic (associated with eye movement, PREM) and tonic (not associated with eye movements, TREM). Retroglossal CSA decreased with non-REM (NREM) sleep and decreased further in PREM [wake 156.8 +/- 48.6 mm(2), NREM 104.6 +/- 65.0 mm(2) (P < 0.05 wake vs. NREM), TREM 83.1 +/- 46.4 mm(2) (P = not significant NREM vs. TREM), PREM 73.9 + 39.2 mm(2) (P < 0.05 TREM vs. PREM)]. Retroglossal compliance, defined as the slope of the regression CSA vs. pharyngeal pressure, was the same between all four conditions (wake -0.7 + 2.1 mm(2)/cmH(2)O, NREM 0.6 +/- 3.0 mm(2)/cmH(2)O, TREM -0.2 +/- 3.3 mm(2)/cmH(2)O, PREM -0.6 +/- 5.1 mm(2)/cmH(2)O, P = not significant). We conclude that the intrinsic properties of the airway wall determine retroglossal compliance independent of changes in the neuromuscular activity associated with changes in sleep state.     

High Resolution Topography of Age-Related Changes in Non-Rapid Eye Movement Sleep Electroencephalography

Sleeping brain activity reflects brain anatomy and physiology. The aim of this study was to use high density (256 channel) electroencephalography (EEG) during sleep to characterize topographic changes in sleep EEG power across normal aging, with high spatial resolution. Sleep was evaluated in 92 healthy adults aged 18–65 years old using full polysomnography and high density EEG. After artifact removal, spectral power density was calculated for standard frequency bands for all channels, averaged across the NREM periods of the first 3 sleep cycles. To quantify topographic changes with age, maps were generated of the Pearson’s coefficient of the correlation between power and age at each electrode. Significant correlations were determined by statistical non-parametric mapping. Absolute slow wave power declined significantly with increasing age across the entire scalp, whereas declines in theta and sigma power were significant only in frontal regions. Power in fast spindle frequencies declined significantly with increasing age frontally, whereas absolute power of slow spindle frequencies showed no significant change with age. When EEG power was normalized across the scalp, a left centro-parietal region showed significantly less age-related decline in power than the rest of the scalp. This partial preservation was particularly significant in the slow wave and sigma bands. The effect of age on sleep EEG varies substantially by region and frequency band. This non-uniformity should inform the design of future investigations of aging and sleep. This study provides normative data on the effect of age on sleep EEG topography, and provides a basis from which to explore the mechanisms of normal aging as well as neurodegenerative disorders for which age is a risk factor.     

A probabilistic model for the ultradian timing of REM sleep in mice

A salient feature of mammalian sleep is the alternation between rapid eye movement (REM) and non-REM (NREM) sleep. However, how these two sleep stages influence each other and thereby regulate the timing of REM sleep episodes is still largely unresolved. Here, we developed a statistical model that specifies the relationship between REM and subsequent NREM sleep to quantify how REM sleep affects the following NREM sleep duration and its electrophysiological features in mice. We show that a lognormal mixture model well describes how the preceding REM sleep duration influences the amount of NREM sleep till the next REM sleep episode. The model supports the existence of two different types of sleep cycles: Short cycles form closely interspaced sequences of REM sleep episodes, whereas during long cycles, REM sleep is first followed by an interval of NREM sleep during which transitions to REM sleep are extremely unlikely. This refractory period is characterized by low power in the theta and sigma range of the electroencephalogram (EEG), low spindle rate and frequent microarousals, and its duration proportionally increases with the preceding REM sleep duration. Using our model, we estimated the propensity for REM sleep at the transition from NREM to REM sleep and found that entering REM sleep with higher propensity resulted in longer REM sleep episodes with reduced EEG power. Compared with the light phase, the buildup of REM sleep propensity was slower during the dark phase. Our data-driven modeling approach uncovered basic principles underlying the timing and duration of REM sleep episodes in mice and provides a flexible framework to describe the ultradian regulation of REM sleep in health and disease.     

Acid Reflux Directly Causes Sleep Disturbances in Rat with Chronic Esophagitis

Background & Aims

Gastroesophageal reflux disease (GERD) is strongly associated with sleep disturbances. Proton pump inhibitor (PPI) therapy improves subjective but not objective sleep parameters in patients with GERD. This study aimed to investigate the association between GERD and sleep, and the effect of PPI on sleep by using a rat model of chronic acid reflux esophagitis.

Methods

Acid reflux esophagitis was induced by ligating the transitional region between the forestomach and the glandular portion and then wrapping the duodenum near the pylorus. Rats underwent surgery for implantation of electrodes for electroencephalogram and electromyogram recordings, and they were transferred to a soundproof recording chamber. Polygraphic recordings were scored by using 10-s epochs for wake, rapid eye movement sleep, and non-rapid eye movement (NREM) sleep. To examine the role of acid reflux, rats were subcutaneously administered a PPI, omeprazole, at a dose of 20 mg/kg once daily.

Results

Rats with reflux esophagitis presented with several erosions, ulcers, and mucosal thickening with basal hyperplasia and marked inflammatory infiltration. The reflux esophagitis group showed a 34.0% increase in wake (232.2±11.4 min and 173.3±7.4 min in the reflux esophagitis and control groups, respectively; p<0.01) accompanied by a reduction in NREM sleep during light period, an increase in sleep fragmentation, and more frequent stage transitions. The use of omeprazole significantly improved sleep disturbances caused by reflux esophagitis, and this effect was not observed when the PPI was withdrawn.

Conclusions

Acid reflux directly causes sleep disturbances in rats with chronic esophagitis.     

Age- and Gender-Related Changes in Contractile Properties of Non-Atrophied EDL Muscle

Background

In humans, ageing causes skeletal muscles to become atrophied, weak, and easily fatigued. In rodent studies, ageing has been associated with significant muscle atrophy and changes in the contractile properties of the muscles. However, it is not entirely clear whether these changes in contractile properties can occur before there is significant atrophy, and whether males and females are affected differently.

Methods and Results

We investigated various contractile properties of whole isolated fast-twitch EDL muscles from adult (2–6 months-old) and aged (12–22 months-old) male and female mice. Atrophy was not present in the aged mice. Compared with adult mice, EDL muscles of aged mice had significantly lower specific force, longer tetanus relaxation times, and lower fatiguability. In the properties of absolute force and muscle relaxation times, females were affected by ageing to a greater extent than males. Additionally, EDL muscles from a separate group of male mice were subjected to eccentric contractions of 15% strain, and larger force deficits were found in aged than in adult mice.

Conclusion

Our findings provide further insight into the muscle atrophy, weakness and fatiguability experienced by the elderly. We have shown that even in the absence of muscle atrophy, there are definite alterations in the physiological properties of whole fast-twitch muscle from ageing mice, and for some of these properties the alterations are more pronounced in female mice than in male mice.     

Altered sleep and behavioral activity phenotypes in PER3-deficient mice

Sleep homeostasis and circadian rhythmicity interact to determine the timing of behavioral activity. Circadian clock genes contribute to circadian rhythmicity centrally and in the periphery, but some also have roles within sleep regulation. The clock gene Period3 (Per3) has a redundant function within the circadian system and is associated with sleep homeostasis in humans. This study investigated the role of PER3 in sleep/wake activity and sleep homeostasis in mice by recording wheel-running activity under baseline conditions in wild-type (WT; n = 54) and in PER3-deficient (Per3(-/-); n = 53) mice, as well as EEG-assessed sleep before and after 6 h of sleep deprivation in WT (n = 7) and Per3(-/-) (n = 8) mice. Whereas total activity and vigilance states did not differ between the genotypes, the temporal distribution of wheel-running activity, vigilance states, and EEG delta activity was affected by genotype. In Per3(-/-) mice, running wheel activity was increased, and REM sleep and NREM sleep were reduced in the middle of the dark phase, and delta activity was enhanced at the end of the dark phase. At the beginning of the baseline light period, there was less wakefulness and more REM and NREM sleep in Per3(-/-) mice. Per3(-/-) mice spent less time in wakefulness and more time in NREM sleep in the light period immediately after sleep deprivation, and REM sleep accumulated more slowly during the recovery dark phase. These data confirm a role for PER3 in sleep-wake timing and sleep homeostasis.     

Mild Transient Hypercapnia as a Novel Fear Conditioning Stimulus Allowing Re-Exposure during Sleep

Introduction

Studies suggest that sleep plays a role in traumatic memories and that treatment of sleep disorders may help alleviate symptoms of posttraumatic stress disorder. Fear-conditioning paradigms in rodents are used to investigate causal mechanisms of fear acquisition and the relationship between sleep and posttraumatic behaviors. We developed a novel conditioning stimulus (CS) that evoked fear and was subsequently used to study re-exposure to the CS during sleep.

Methods

Experiment 1 assessed physiological responses to a conditioned stimulus (mild transient hypercapnia, mtHC; 3.0% CO₂; n = 17)+footshock for the purpose of establishing a novel CS in male FVB/J mice. Responses to the novel CS were compared to tone+footshock (n = 18) and control groups of tone alone (n = 17) and mild transient hypercapnia alone (n = 10). A second proof of principle experiment re-exposed animals during sleep to mild transient hypercapnia or air (control) to study sleep processes related to the CS.

Results

Footshock elicited a response of acute tachycardia (30–40 bpm) and increased plasma epinephrine. When tone predicted footshock it elicited mild hypertension (1–2 mmHg) and a three-fold increase in plasma epinephrine. When mtHC predicted footshock it also induced mild hypertension, but additionally elicited a conditioned bradycardia and a smaller increase in plasma epinephrine. The overall mean 24 hour sleep–wake profile was unaffected immediately after fear conditioning.

Discussion

Our study demonstrates the efficacy of mtHC as a conditioning stimulus that is perceptible but innocuous (relative to tone) and applicable during sleep. This novel model will allow future studies to explore sleep-dependent mechanisms underlying maladaptive fear responses, as well as elucidate the moderators of the relationship between fear responses and sleep.     

Adolescent Sleep Patterns and Night-Time Technology Use: Results of the Australian Broadcasting Corporation's Big Sleep Survey

Introduction

Electronic devices in the bedroom are broadly linked with poor sleep in adolescents. This study investigated whether there is a dose-response relationship between use of electronic devices (computers, cellphones, televisions and radios) in bed prior to sleep and adolescent sleep patterns.

Methods

Adolescents aged 11–17 yrs (n = 1,184; 67.6% female) completed an Australia-wide internet survey that examined sleep patterns, sleepiness, sleep disorders, the presence of electronic devices in the bedroom and frequency of use in bed at night.

Results

Over 70% of adolescents reported 2 or more electronic devices in their bedroom at night. Use of devices in bed a few nights per week or more was 46.8% cellphone, 38.5% computer, 23.2% TV, and 15.8% radio. Device use had dose-dependent associations with later sleep onset on weekdays (highest-dose computer adjOR  = 3.75: 99% CI  = 2.17–6.46; cellphone 2.29: 1.22–4.30) and weekends (computer 3.68: 2.14–6.32; cellphone 3.24: 1.70–6.19; TV 2.32: 1.30–4.14), and later waking on weekdays (computer 2.08: 1.25–3.44; TV 2.31: 1.33–4.02) and weekends (computer 1.99: 1.21–3.26; cellphone 2.33: 1.33–4.08; TV 2.04: 1.18–3.55). Only ‘almost every night’ computer use (: 2.43: 1.45–4.08) was associated with short weekday sleep duration, and only ‘almost every night’ cellphone use (2.23: 1.26–3.94) was associated with wake lag (waking later on weekends).

Conclusions

Use of computers, cell-phones and televisions at higher doses was associated with delayed sleep/wake schedules and wake lag, potentially impairing health and educational outcomes.     

Sleep-Wake Cycle Dysfunction in the TgCRND8 Mouse Model of Alzheimer’s Disease: From Early to Advanced Pathological Stages

In addition to cognitive decline, individuals affected by Alzheimer’s disease (AD) can experience important neuropsychiatric symptoms including sleep disturbances. We characterized the sleep-wake cycle in the TgCRND8 mouse model of AD, which overexpresses a mutant human form of amyloid precursor protein resulting in high levels of β-amyloid and plaque formation by 3 months of age. Polysomnographic recordings in freely-moving mice were conducted to study sleep-wake cycle architecture at 3, 7 and 11 months of age and corresponding levels of β-amyloid in brain regions regulating sleep-wake states were measured. At all ages, TgCRND8 mice showed increased wakefulness and reduced non-rapid eye movement (NREM) sleep during the resting and active phases. Increased wakefulness in TgCRND8 mice was accompanied by a shift in the waking power spectrum towards fast frequency oscillations in the beta (14-20 Hz) and low gamma range (20-50 Hz). Given the phenotype of hyperarousal observed in TgCRND8 mice, the role of noradrenergic transmission in the promotion of arousal, and previous work reporting an early disruption of the noradrenergic system in TgCRND8, we tested the effects of the alpha-1-adrenoreceptor antagonist, prazosin, on sleep-wake patterns in TgCRND8 and non-transgenic (NTg) mice. We found that a lower dose (2 mg/kg) of prazosin increased NREM sleep in NTg but not in TgCRND8 mice, whereas a higher dose (5 mg/kg) increased NREM sleep in both genotypes, suggesting altered sensitivity to noradrenergic blockade in TgCRND8 mice. Collectively our results demonstrate that amyloidosis in TgCRND8 mice is associated with sleep-wake cycle dysfunction, characterized by hyperarousal, validating this model as a tool towards understanding the relationship between β-amyloid overproduction and disrupted sleep-wake patterns in AD.     

Sleep and cortical temperature in the Djungarian hamster under baseline conditions and after sleep deprivation

The Djungarian hamster (Phodopus sungorus) is a markedly photoperiodic rodent which exhibits daily torpor under short photoperiod. Normative data were obtained on vigilance states, electroencephalogram (EEG) power spectra (0.25–25.0 Hz), and cortical temperature (T_CRT) under a 168 h light-dark schedule, in 7 Djungarian hamsters for 2 baseline days, 4 h sleep deprivation (SD) and 20 h recovery.During the baseline days total sleep time amounted to 59% of recording time, 67% in the light period and 43% in the dark period. The 4 h SD induced a small increase in the amount of non-rapid eye movement (NREM) sleep and a marked increase in EEG slow-wave activity (SWA; mean power density 0.75–4.0 Hz) within NREM sleep in the first hours of recovery. T_CRT was lower in the light period than in the dark period. It decreased at transitions from either waking or rapid eye movement (REM) sleep to NREM sleep, and increased at the transition from NREM sleep to waking or REM sleep. After SD, T_CRT was lower in all vigilance states.In conclusion, the sleep-wake pattern, EEG spectrum, and time course of T_CRT in the Djungarian hamster are similar to other nocturnal rodents. Also in the Djungarian hamster the time course of SWA seems to reflect a homeostatically regulated process as was formulated in the two-process model of sleep regulation.Abbreviations EEG electroencephalogram - EMG electromyogram - N NREM sleep - NREM non-rapid eye movement - R REM sleep - REM rapid eye movement - SD sleep deprivation - SWA slow-wave activity - T_CRT cortical temperature - TST total sleep time - VS vigilance state - W waking     

Behavioral and sleep/wake characteristics of mice lacking norepinephrine and hypocretin

We investigated the interaction between norepinephrine (NE) and orexin/hypocretin (Hcrt) in the control of sleep behavior and narcoleptic symptoms by creating mice that were deficient in both neurotransmitters. Mice with a targeted disruption of the dopamine beta-hydroxylase (Dbh) gene (deficient in NE and epinephrine) or the Hcrt gene were bred to generate double knockouts (DKOs), each single KO (Dbh-KO and Hcrt-KO), and control mice. The duration of wake, non-rapid eye movement (NREM) and REM sleep were monitored by electroencephalogram (EEG)/electromyogram (EMG) recording over a 24-h period, and the occurrence of behavioral arrests was monitored by video/EEG recording for 4 h. Overall, there was very little interaction between the two genes; for most parameters that were measured, the DKO mice resembled either Dbh-KO or Hcrt-KO mice. REM sleep was increased in both DKO and Hcrt-KO mice at night relative to the other groups, but DKO mice had significantly more REM sleep during the day than the other three groups. Sleep latency in response to saline or amphetamine injections was reduced in Dbh-KO and DKO mice relative to other groups. Behavioral arrests, that are frequent in Hcrt-KO mice, were not exacerbated in DKO mice.     

Hypaphorine, an indole alkaloid from Erythrina velutina, induced sleep on normal mice

An indole alkaloid (hypaphorine (1)) was isolated from Brazilian medicinal plant, Erythrina velutina (Leguminosae). This compound was investigated for sleep promoting effects in mice, and the results showed that it significantly increased non-rapid eye movement (NREM) sleep time during the first hour after its administration. The NREM sleep time was enhanced by 33% in the experimental mice when compared to that of the controls. This study therefore confirmed its sleep promoting property.     

Coupling of Thalamocortical Sleep Oscillations Are Important for Memory Consolidation in Humans

Sleep, specifically non-rapid eye movement (NREM) sleep, is thought to play a critical role in the consolidation of recent memories. Two main oscillatory activities observed during NREM, cortical slow oscillations (SO, 0.5–1.0Hz) and thalamic spindles (12–15Hz), have been shown to independently correlate with memory improvement. Yet, it is not known how these thalamocortical events interact, or the significance of this interaction, during the consolidation process. Here, we found that systemic administration of the GABAergic drug (zolpidem) increased both the phase-amplitude coupling between SO and spindles, and verbal memory improvement in humans. These results suggest that thalamic spindles that occur during transitions to the cortical SO Up state are optimal for memory consolidation. Our study predicts that the timely interactions between cortical and thalamic events during consolidation, contribute to memory improvement and is mediated by the level of inhibitory neurotransmission.     

miR-155 deletion modulates lipopolysaccharide-induced sleep in female mice

Immune signaling is known to regulate sleep. miR-155 is a microRNA that regulates immune responses. We hypothesized that miR-155 would alter sleep regulation. Thus, we investigated the potential effects of miR-155 deletion on sleep-wake behavior in adult female homozygous miR-155 knockout (miR-155^KO) mice and littermate controls (WT). Mice were implanted with biotelemetry units and EEG/EMG biopotentials were recorded continuously for three baseline days. miR-155^KO mice had decreased bouts of NREM and REM sleep compared with WT mice, but no differences were observed in the length of sleep bouts or total time spent in sleep-wake states. Locomotor activity and subcutaneous temperature did not differ between WT and miR-155^KO mice. Following baseline recordings, mice were sleep-deprived during the first six hours of the rest phase (light phase; ZT 0–6) followed by an 18 h recovery period. There were no differences between groups in sleep rebound (% sleep and NREM δ power) after sleep deprivation. Following recovery from sleep deprivation, mice were challenged with a somnogen (viz., lipopolysaccharide (LPS)) one hour prior to the initiation of the dark (active) phase. Biopotentials were continuously recorded for the following 24 h, and miR-155^KO mice displayed increased wakefulness and decreased NREM sleep during the dark phase following LPS injection. Additionally, miR-155^KO mice had reduced EEG slow-wave responses (0.5–4 Hz) compared to WT mice. Together, our findings indicate that miR-155 deletion attenuates the somnogenic and EEG delta-enhancing effects of LPS.

Abbreviations: ANOVA: analysis of variance; EEG: electroencephalogram; EMG: electromyogram; h: hour; IL-1: interleukin-1; IL-6: interleukin-6; IP: intra-peritoneal; LPS: lipopolysaccharide; miR/miRNA: microRNA; miR-155^KO: miR-155 knockout; NREM: non-rapid eye movement; REM: rapid eye movement; TNF: tumor necrosis factor; SWS: slow-wave sleep; WT: wild-type.