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The mechanisms leading to the alternation between active (UP) and silent (DOWN) states during sleep slow waves (SWs) remain poorly understood. Previous models have explained the transition to the DOWN state by a progressive failure of excitation because of the build-up of adaptation currents or synaptic depression. However, these models are at odds with recent studies suggesting a role for presynaptic inhibition by Martinotti cells (MaCs) in generating SWs. Here, we update a classical large-scale model of sleep SWs to include MaCs and propose a different mechanism for the generation of SWs. In the wake mode, the network exhibits irregular and selective activity with low firing rates (FRs). Following an increase in the strength of background inputs and a modulation of synaptic strength and potassium leak potential mimicking the reduced effect of acetylcholine during sleep, the network enters a sleep-like regime in which local increases of network activity trigger bursts of MaC activity, resulting in strong disfacilitation of the local network via presynaptic GABA B1a -type inhibition. This model replicates findings on slow wave activity (SWA) during sleep that challenge previous models, including low and skewed FRs that are comparable between the wake and sleep modes, higher synchrony of transitions to DOWN states than to UP states, the possibility of triggering SWs by optogenetic stimulation of MaCs, and the local dependence of SWA on synaptic strength. Overall, this work points to a role for presynaptic inhibition by MaCs in the generation of DOWN states during sleep., (© 2022 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Memory consolidation is promoted by sleep. However, there is also evidence for consolidation into long-term memory during wakefulness via processes that preferentially affect nonhippocampal representations. We compared, in rats, the effects of 2-h postencoding periods of sleep and wakefulness on the formation of long-term memory for objects and their associated environmental contexts. We employed a novel-object recognition (NOR) task, using object exploration and exploratory rearing as behavioral indicators of these memories. Remote recall testing (after 1 wk) confirmed significant long-term NOR memory under both conditions, with NOR memory after sleep predicted by the occurrence of EEG spindle-slow oscillation coupling. Rats in the sleep group decreased their exploratory rearing at recall testing, revealing successful recall of the environmental context. By contrast, rats that stayed awake after encoding showed equally high levels of rearing upon remote testing as during encoding, indicating that context memory was lost. Disruption of hippocampal function during the postencoding interval (by muscimol administration) suppressed long-term NOR memory together with context memory formation when animals slept, but enhanced NOR memory when they were awake during this interval. Testing remote recall in a context different from that during encoding impaired NOR memory in the sleep condition, while exploratory rearing was increased. By contrast, NOR memory in the wake rats was preserved and actually superior to that after sleep. Our findings indicate two distinct modes of long-term memory formation: Sleep consolidation is hippocampus dependent and implicates event-context binding, whereas wake consolidation is impaired by hippocampal activation and strengthens context-independent representations.

Sleep is a necessity for our survival, but its regulation remains incompletely understood. Here, we used a human sleep duration gene to identify a population of cells in the peri-tegmental reticular nucleus (pTRN ADRB1 ) that regulate sleep-wake, uncovering a role for a poorly understood brain area. Although initial ablation in mice led to increased wakefulness, further validation revealed that pTRN ADRB1 neuron stimulation strongly promotes wakefulness, even after stimulation offset. Using combinatorial genetics, we found that excitatory pTRN ADRB1 neurons promote wakefulness. pTRN neurons can be characterized as anterior- or posterior-projecting neurons based on multiplexed analysis of projections by sequencing (MAPseq) analysis. Finally, we found that pTRN ADRB1 neurons promote wakefulness, in part, through projections to the lateral hypothalamus. Thus, human genetic information from a human sleep trait allowed us to identify a role for the pTRN in sleep-wake regulation.

Previous studies have shown that the synchronization of electroencephalogram (EEG) signals is found during propofol-induced general anesthesia, which is similar to that of slow-wave sleep (SWS). However, a complete understanding is lacking in terms of the characteristics of EEG changes in rats after propofol administration and whether propofol acts through natural sleep circuits. Here, we examined the characteristics of EEG patterns induced by intraperitoneal injection of propofol in rats. We found that high (10 mg/kg) and medium (5 mg/kg) doses of propofol induced a cortical EEG of low-frequency, high-amplitude activity with rare electromyographic activity and markedly shortened sleep latency. The high dose of propofol increased deep slow-wave sleep (SWS2) to 4 h, as well as the number of large SWS2 bouts (>480 s), their mean duration and the peak of the power density curve in the delta range of 0.75-3.25 Hz. After the medium dose of propofol, the total number of wakefulness, light slow-wave sleep (SWS1) and SWS2 episodes increased, whereas the mean duration of wakefulness decreased. The high dose of propofol significantly increased c-fos expression in the ventrolateral preoptic nucleus (VLPO) sleep center and decreased the number of c-fos-immunoreactive neurons in wake-related systems including the tuberomammillary nucleus (TMN), perifornical nucleus (PeF), lateral hypothalamic nucleus (LH), ventrolateral periaqueductal gray (vPAG) and supramammillary region (SuM). These results indicated that the high dose of propofol produced high-quality sleep by increasing SWS2, whereas the medium dose produced fragmented and low-quality sleep by disrupting the continuity of wakefulness. Furthermore, sleep-promoting effects of propofol are correlated with activation of the VLPO cluster and inhibition of the TMN, PeF, LH, vPAG and SuM., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The midbrain dopamine system via the dorsal and ventral striatum regulates a wide range of behaviors. To dissect the role of dopaminergic projections to the dorsal striatum (nigrostriatal projection) and ventral striatum (mesolimbic projection) in sleep-wake behavior, we selectively chemogenetically stimulated nigrostriatal or mesolimbic projections and examined the resulting effects on sleep in rats. Stimulation of nigrostriatal pathways increased sleep and EEG delta power, while stimulation of mesolimbic pathways decreased sleep and reduced cortical EEG power. These results indicate that midbrain dopamine signaling in the dorsal or ventral striatum promotes sleep or wake, respectively.

Introduction: The activating role of non-rapid eye movement (NREM) sleep on epileptic cortex and conversely, the seizure remission brought about by antiepileptic medications, has been attributed to their effects on neuronal synchrony. This study aims to understand the role of neural synchrony of NREM sleep in promoting interictal epileptiform discharges (IEDs) in patients with epilepsy (PWE) by assessing the peri-IED phase synchrony during awake and sleep states. It also studies the role played by antiepileptic drugs (AEDs) on EEG desynchronization in the above cohort., Methods: A total of 120 PWE divided into 3 groups (each n = 40; juvenile myoclonic epilepsy [JME], temporal lobe epilepsy [TLE]. and extratemporal lobe epilepsy [Ex-TLE]) were subjected to overnight polysomnography. Each patient group was subdivided into drug-naive and on treatment (Each n = 20). EEG phase synchronization analysis was performed to compare peri-IED phase synchronization indices (SI) during awake and sleep stages and between drug naïve and on treatment groups in 4 frequency bands, namely delta, theta, alpha, and beta. The mean ± SD of peri-IED SI among various subgroups was compared employing a multilevel mixed effects modeling approach., Results: Patients with JME had increased peri-IED cortical synchrony in N3 sleep stage, whereas patients with partial epilepsy had increased IED cortical synchrony in N1 sleep stage. On the other hand, peri-IED synchrony was lower during wake and REM sleep. We also found that peri-IED synchronization in patients with JME was higher in drug-naive patients compared with those on sodium valproate monotherapy in theta, alpha, and beta bands., Conclusion: The findings of this study suggest that sleep stages can alter cortical synchrony in patients with JME and focal epilepsy, with NREM IEDs being more synchronized and wake/REM IEDs being less synchronized. Furthermore, it also suggests that AEDs alleviate seizures in PWE by inhibiting cortical synchrony.

Circadian clocks modulate timing of sleep/wake cycles in animals; however, the underlying mechanisms remain poorly understood. In Drosophila melanogaster , large ventral lateral neurons (l-LN v ) are known to promote wakefulness through the action of the neuropeptide pigment dispersing factor (PDF), but the downstream targets of PDF signalling remain elusive. In a screen using downregulation or overexpression (OEX) of the gene encoding PDF receptor ( pdfr ), we found that a subset of dopaminergic neurons responds to PDF to promote wakefulness during the day. Moreover, we found that small LN v (s-LN v ) and dopaminergic neurons form synaptic contacts, and PDFR signalling inhibited dopaminergic neurons specifically during day time. We propose that these dopaminergic neurons that respond to PDFR signalling are sleep-promoting and that during the day when PDF levels are high, they are inhibited, thereby promoting wakefulness. Thus, we identify a novel circadian clock pathway that mediates wake promotion specifically during day time.

Introduction: Excessive cortical synchrony within neural ensembles has been implicated as an important mechanism driving epileptiform activity. The current study measures and compares background electroencephalographic (EEG) phase synchronization in patients having various types of epilepsies and healthy controls during awake and sleep stages., Methods: A total of 120 patients with epilepsy (PWE) subdivided into 3 groups (juvenile myoclonic epilepsy [JME], temporal lobe epilepsy [TLE], and extra-temporal lobe epilepsy [Ex-TLE]; n = 40 in each group) and 40 healthy controls were subjected to overnight polysomnography. EEG phase synchronization (SI) between the 8 EEG channels was assessed for delta, theta, alpha, sigma, and high beta frequency bands using ensemble measure on 10-second representative time windows and compared between patients and controls and also between awake and sleep stages. Mean ± SD of SI was compared using 2-way analysis of variance followed by pairwise comparison ( P ≤ .05)., Results: In both delta and theta bands, the SI was significantly higher in patients with JME, TLE, and Ex-TLE compared with controls, whereas in alpha, sigma, and high beta bands, SI was comparable between the groups. On comparison of SI between sleep stages, delta band: progressive increase in SI from wake ⇒ N1 ⇒ N2 ⇒ N3, whereas REM (rapid eye movement) was comparable to wake; theta band: decreased SI during N2 and increase during N3; alpha band: SI was highest in wake and lower in N1, N2, N3, and REM; and sigma and high beta bands: progressive increase in SI from wake ⇒ N1 ⇒ N2 ⇒ N3; however, sigma band showed lower SI during REM., Conclusion: This study found an increased background cortical synchronization in PWE compared with healthy controls in delta and theta bands during wake and sleep. This background hypersynchrony may be an important property of epileptogenic brain circuitry in PWE, which enables them to effortlessly generate a paroxysmal EEG depolarization shift.

Orexin (OX)/hypocretin-containing neurons are main regulators of wakefulness stability, arousal, and energy homeostasis. Their activity varies in relation to the animal's behavioral state. We here tested whether such variation is subserved by synaptic plasticity phenomena in basal conditions. Mice were sacrificed during day or night, at times when sleep or wake, respectively, predominates, as assessed by electroencephalography in matched mice. Triple immunofluorescence was used to visualize OX-A perikarya and varicosities containing the vesicular glutamate transporter (VGluT)2 or the vesicular GABA transporter (VGAT) combined with synaptophysin (Syn) as a presynaptic marker. Appositions on OX-A + somata were quantitatively analyzed in pairs of sections in epifluorescence and confocal microscopy. The combined total number of glutamatergic (Syn + /VGluT2 + ) and GABAergic (Syn + /VGAT + ) varicosities apposed to OX-A somata was similar during day and night. However, glutamatergic varicosities were significantly more numerous at night, whereas GABAergic varicosities prevailed in the day. Triple immunofluorescence in confocal microscopy was employed to visualize synapse scaffold proteins as postsynaptic markers and confirmed the nighttime prevalence of VGluT2 + together with postsynaptic density protein 95 + excitatory contacts, and daytime prevalence of VGAT + together with gephyrin + inhibitory contacts, while also showing that they formed synapses on OX-A + cell bodies. The findings reveal a daily reorganization of axosomatic synapses in orexinergic neurons, with a switch from a prevalence of excitatory innervation at a time corresponding to wakefulness to a prevalence of inhibitory innervations in the antiphase, at a time corresponding to sleep. This reorganization could represent a key mechanism of plasticity of the orexinergic network in basal conditions.

In the developing visual system before eye opening, spontaneous retinal waves trigger bursts of neural activity in downstream structures, including visual cortex. At the same ages when retinal waves provide the predominant input to the visual system, sleep is the predominant behavioral state. However, the interactions between behavioral state and retinal wave-driven activity have never been explicitly examined. Here we characterized unit activity in visual cortex during spontaneous sleep-wake cycles in 9- and 12-day-old rats. At both ages, cortical activity occurred in discrete rhythmic bursts, ~30-60 s apart, mirroring the timing of retinal waves. Interestingly, when pups spontaneously woke up and moved their limbs in the midst of a cortical burst, the activity was suppressed. Finally, experimentally evoked arousals also suppressed intraburst cortical activity. All together, these results indicate that active wake interferes with the activation of the developing visual cortex by retinal waves. They also suggest that sleep-wake processes can modulate visual cortical plasticity at earlier ages than has been previously considered. NEW & NOTEWORTHY By recording in visual cortex in unanesthetized infant rats, we show that neural activity attributable to retinal waves is specifically suppressed when pups spontaneously awaken or are experimentally aroused. These findings suggest that the relatively abundant sleep of early development plays a permissive functional role for the visual system. It follows, then, that biological or environmental factors that disrupt sleep may interfere with the development of these neural networks., (Copyright © 2017 the American Physiological Society.)

Pharmacological studies in mammals and zebrafish suggest that histamine plays an important role in promoting arousal. However, genetic studies using rodents with disrupted histamine synthesis or signaling have revealed only subtle or no sleep/wake phenotypes. Studies of histamine function in mammalian arousal are complicated by its production in cells of the immune system and its roles in humoral and cellular immunity, which can have profound effects on sleep/wake states. To avoid this potential confound, we used genetics to explore the role of histamine in regulating sleep in zebrafish, a diurnal vertebrate in which histamine production is restricted to neurons in the brain. Similar to rodent genetic studies, we found that zebrafish that lack histamine due to mutation of histidine decarboxylase ( hdc ) exhibit largely normal sleep/wake behaviors. Zebrafish containing predicted null mutations in several histamine receptors also lack robust sleep/wake phenotypes, although we are unable to verify that these mutants are completely nonfunctional. Consistent with some rodent studies, we found that arousal induced by overexpression of the neuropeptide hypocretin (Hcrt) or by stimulation of hcrt -expressing neurons is not blocked in hdc or hrh1 mutants. We also found that the number of hcrt -expressing or histaminergic neurons is unaffected in animals that lack histamine or Hcrt signaling, respectively. Thus, while acute pharmacological manipulation of histamine signaling has been shown to have profound effects on zebrafish and mammalian sleep, our results suggest that chronic loss of histamine signaling due to genetic mutations has only subtle effects on sleep in zebrafish, similar to rodents.

Sleep remains one of the most mysterious yet ubiquitous animal behaviors. We review current perspectives on the neural systems that regulate sleep/wake states in mammals and the circadian mechanisms that control their timing. We also outline key models for the regulation of rapid eye movement (REM) sleep and non-REM sleep, how mutual inhibition between specific pathways gives rise to these distinct states, and how dysfunction in these circuits can give rise to sleep disorders., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The aim of the study was to evaluate the EEG modifications in patients with Huntington disease (HD) compared with controls, by means of the exact LOw REsolution Tomography (eLORETA) software. We evaluated EEG changes during wake, non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Moreover, we reviewed the literature concerning EEG modifications in HD. Twenty-three consecutive adult patients affected by HD were enrolled, 14 women and 9 men, mean age was 57.0 ± 12.4 years. Control subjects were healthy volunteers (mean age 58.2 ± 14.6 years). EEG and polygraphic recordings were performed during wake (before sleep) and during sleep. Sources of EEG activities were determined using the eLORETA software. In wake EEG, significant differences between patients and controls were detected in the delta frequency band (threshold T = ±4.606; P < .01) in the Brodmann areas (BAs) 3, 4, and 6 bilaterally. In NREM sleep, HD patients showed increased alpha power (T = ±4.516; P < .01) in BAs 4 and 6 bilaterally; decreased theta power (T = ±4.516; P < .01) in the BAs 23, 29, and 30; and decreased beta power (T = ±4.516; P < .01) in the left BA 30. During REM, HD patients presented decreased theta and alpha power (threshold T = ±4.640; P < .01) in the BAs 23, 29, 30, and 31 bilaterally. In conclusion, EEG data suggest a motor cortex dysfunction during wake and sleep in HD patients, which correlates with the clinical and polysomnographic evidence of increased motor activity during wake and NREM, and nearly absent motor abnormalities in REM., (© EEG and Clinical Neuroscience Society (ECNS) 2016.)

The role of specific cortical regions in sleep-regulating circuits is unclear. The anterior insula (AI) has strong reciprocal connectivity with wake and sleep-promoting hypothalamic and brainstem regions, and we hypothesized that the AI regulates patterns of sleep and wakefulness. To test this hypothesis, we lesioned the AI in rats (n = 8) and compared sleep, wake, and activity regulation in these animals with nonlesioned controls (n = 8) with 24-h sleep recordings and chronic infrared activity monitoring. Compared to controls, animals with AI lesions had decreased wakefulness and increased rapid eye movement (REM) sleep and non-REM (NREM) sleep. AI-lesioned animals had shorter wake bouts, especially during the active dark phase. AI-lesioned animals also had more transitions from NREM to REM sleep, especially during the inactive light phase. Chronic infrared monitoring revealed that AI-lesioned animals also had a disturbed temporal organization of locomotor activity at multiple time scales with more random activity fluctuations from 4 to 12 h despite intact circadian rhythms. These results suggest that the AI regulates sleep and activity and contributes to the regulation of sleep and motor behavior rhythmicity across multiple time scales. Dysfunction of the AI may underlie changes in sleep-wake patterns in neurological diseases., (© 2016 The Author(s).)

Aim: To determine whether respiratory support via heated humidified high flow nasal cannulae (HHHFNC) results in infants <32weeks gestation spending a greater proportion of time in sleep compared to those receiving nasal continuous positive airway pressure (NCPAP)., Methods: A subgroup of infants enrolled in a randomized controlled trial to compare HHHFNC or NCPAP post-extubation had sleep and wake activity measured by actigraphy for 72hours post-extubation. Activity diaries were completed contemporaneously to record episodes of infant handling. Actigraphy data were downloaded with known periods of handling excluded from the analysis., Results: 28 infants with mean gestation of 28.3weeks (SD 2) and birth weight 1074g (SD 371) were studied. Infants receiving HHHFNC spent a lesser proportion of time in sleep 59.8% (SD 18.5) than those on NCPAP 82.2% (SD 23.8) p=0.004. Infants receiving HHHFNC had a lower sleep efficiency and higher mean activity score than those on NCPAP (p=0.003, p=0.002, respectively)., Conclusion: Infants receiving HHHFNC had a higher mean activity score and spent less time in sleep than those allocated NCPAP. Further study of sleep wake activity in preterm infants receiving respiratory support is required as this may impact on neurodevelopmental outcomes., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Our lives are structured by the daily alternation of activity and rest, of wake and sleep. Despite significant advances in circadian and sleep research, we still lack answers to many of the most fundamental questions about this conspicuous behavioral pattern. We strongly believe that investigating this pattern in entrained conditions, real-life and daily contexts-in situ-will help the field to elucidate some of these central questions. Here, we present two common approaches for in situ investigation of human activity and rest: the Munich ChronoType Questionnaire (MCTQ) and actimetry. In the first half of this chapter, we provide detailed instructions on how to use and interpret the MCTQ. In addition, we give an overview of the main insights gained with this instrument over the past 10 years, including some new findings on the interaction of light and age on sleep timing. In the second half of this chapter, we introduce the reader to the method of actimetry and share our experience in basic analysis techniques, including visualization, smoothing, and cosine model fitting of in situ recorded data. Additionally, we describe our new approach to automatically detect sleep from activity recordings. Our vision is that the broad use of such easy techniques in real-life settings combined with automated analyses will lead to the creation of large databases. The resulting power of big numbers will promote our understanding of such fundamental biological phenomena as sleep., (© 2015 Elsevier Inc. All rights reserved.)

Objectives: Premature newborns are exposed to a great deal of over-stimulation, which can affect their cerebral development. For better sleep, certain practices should be recommended. The aim of this study was to evaluate the effect of a professional training program on the improvement of practices promoting respect for the newborn's sleep-wake cycle. Materials and Methods: This was an interventional study with a longitudinal, single-group, and before-and-after design. The experimental design followed a three-stage time series: Eight months before, three months after, then eight months after intervention. It targeted a comprehensive sample of 66 professionals. It took place between October 2020 and March 2022 at the Neonatal Intensive Care Unit of the Hassan II University Hospital in Fez, Morocco. It was based on an observation grid and a self-administered questionnaire, validated and tested with a Cronbach's alpha reliability of 0.91. Results: The light environment showed significant differences between the 1st and 3rd step (3.3% vs. 45.0%; P = 0.02; confidence interval [CI] = 13.644-10.456) for knowledge and (13.3% vs. 78.3%; P = 0.01; CI = 14.412-10.888) for practices; the noise environment showed a positive improvement between the 2nd and 3rd intervention (31.7% vs. 41.7%; P < 0.001; CI = 5.954-2.913) for knowledge and (65.0% vs. 73.3%; P < 0.001; CI = 3.597-1.236) for practices, with an average of (8.98 ± 0.30-28.15 ± 0.48; CI = 3.806-1.094) between the 1st and 3rd step. Practices surrounding sleep and wakefulness reported significant improvement between the three periods (14.35 ± 0.22 vs. 18.10 ± 0.35 vs. 19.90 ± 0.35; P P < 0.001; CI = 4.647-2.853) for sleep and (13.25 ± 0.48 vs. 22.27 ± 0.59; P < 0.001; CI = 10.563-7.471) for wakefulness with statistically significant correlations between knowledge and practices (0.426**) for sleep and (0.606**) for wakefulness. Conclusion: The study demonstrated the positive impact of this sleep management and assessment program on the development of professional skills. Its implementation requires rigorous application of developmental support strategies for individualized care in neonatology. [ABSTRACT FROM AUTHOR]

Sleep during the midday, commonly referred to as siesta, is a common trait of animals that mainly sleep during the night. Work using Drosophila led to the identification of the daywake (dyw) gene, found to have anti‐siesta activity. Herein, we show that the DYW protein undergoes signal peptide‐dependent secretion, is present in the circulatory system, and accumulates in multiple organs, but, surprisingly, it is not detected in the brain where wake–sleep centers are located. The abundance of DYW in adult flies is regulated by age, sex, temperature, and the splicing efficiency of a nearby thermosensitive intron. We suggest that DYW regulates daytime wake–sleep balance in an indirect, extracerebral manner, via a multi‐organ network that interfaces with the circulatory system. [ABSTRACT FROM AUTHOR]

Summary The circuitry underlying the initiation, maintenance, and coordination of wakefulness, rapid eye movement sleep, and non‐rapid eye movement sleep is not thoroughly understood. Sleep is thought to arise due to decreased activity in the ascending reticular arousal system, which originates in the brainstem and awakens the thalamus and cortex during wakefulness. Despite the conventional association of sleep–wake states with hippocampal rhythms, the mutual influence of the hippocampal formation in regulating vigilance states has been largely neglected. Here, we focus on the subiculum, the main output region of the hippocampal formation. The subiculum, particulary the ventral part, sends extensive monosynaptic projections to crucial regions implicated in sleep–wake regulation, including the thalamus, lateral hypothalamus, tuberomammillary nucleus, basal forebrain, ventrolateral preoptic nucleus, ventrolateral tegmental area, and suprachiasmatic nucleus. Additionally, second‐order projections from the subiculum are received by the laterodorsal tegmental nucleus, locus coeruleus, and median raphe nucleus, suggesting the potential involvement of the subiculum in the regulation of the sleep–wake cycle. We also discuss alterations in the subiculum observed in individuals with sleep disorders and in sleep‐deprived mice, underscoring the significance of investigating neuronal communication between the subiculum and pathways promoting both sleep and wakefulness. [ABSTRACT FROM AUTHOR]

Sleep-wake and fasting-feeding are tightly coupled behavioral states that require coordination between several brain regions. The mammalian lateral hypothalamus (LH) is a functionally and anatomically complex brain region harboring heterogeneous cell populations that regulate sleep, feeding, and energy metabolism. Significant attempts were made to understand the cellular and circuit bases of LH actions. Rapid advancements in genetic and electrophysiological manipulation help to understand the role of discrete LH cell populations. The opposing action of LH orexin/hypocretin and melanin-concentrating hormone (MCH) neurons on metabolic sensing and sleep-wake regulation make them the candidate to explore in detail. This review surveys the molecular, genetic, and neuronal components of orexin and MCH signaling in the regulation of sleep and metabolism. [ABSTRACT FROM AUTHOR]

Summary: The sleep disorder narcolepsy, a hypocretin deficiency disorder thought to be due to degeneration of hypothalamic hypocretin/orexin neurons, is currently treated symptomatically. We evaluated the efficacy of two small molecule hypocretin/orexin receptor‐2 (HCRTR2) agonists in narcoleptic male orexin/tTA; TetO‐DTA mice. TAK‐925 (1–10 mg/kg, s.c.) and ARN‐776 (1–10 mg/kg, i.p.) were injected 15 min before dark onset in a repeated measures design. EEG, EMG, subcutaneous temperature (Tsc) and activity were recorded by telemetry; recordings for the first 6 h of the dark period were scored for sleep/wake and cataplexy. At all doses tested, TAK‐925 and ARN‐776 caused continuous wakefulness and eliminated sleep for the first hour. Both TAK‐925 and ARN‐776 caused dose‐related delays in NREM sleep onset. All doses of TAK‐925 and all but the lowest dose of ARN‐776 eliminated cataplexy during the first hour after treatment; the anti‐cataplectic effect of TAK‐925 persisted into the second hour for the highest dose. TAK‐925 and ARN‐776 also reduced the cumulative amount of cataplexy during the 6 h post‐dosing period. The acute increase in wakefulness produced by both HCRTR2 agonists was characterised by increased spectral power in the gamma EEG band. Although neither compound provoked a NREM sleep rebound, both compounds affected NREM EEG during the second hour post‐dosing. TAK‐925 and ARN‐776 also increased gross motor activity, running wheel activity, and Tsc, suggesting that the wake‐promoting and sleep‐suppressing activities of these compounds could be a consequence of hyperactivity. Nonetheless, the anti‐cataplectic activity of TAK‐925 and ARN‐776 is encouraging for the development of HCRTR2 agonists. [ABSTRACT FROM AUTHOR]

Sleep-wake and fasting-feeding are tightly coupled behavioral states that require coordination between several brain regions. The mammalian lateral hypothalamus (LH) is a functionally and anatomically complex brain region harboring heterogeneous cell populations that regulate sleep, feeding, and energy metabolism. Significant attempts were made to understand the cellular and circuit bases of LH actions. Rapid advancements in genetic and electrophysiological manipulation help to understand the role of discrete LH cell populations. The opposing action of LH orexin/hypocretin and melanin-concentrating hormone (MCH) neurons on metabolic sensing and sleep-wake regulation make them the candidate to explore in detail. This review surveys the molecular, genetic, and neuronal components of orexin and MCH signaling in the regulation of sleep and metabolism.

High physical activity levels during wake are beneficial for health, while high movement levels during sleep are detrimental to health. Our aim was to compare the associations of accelerometer-assessed physical activity and sleep disruption with adiposity and fitness using standardized and individualized wake and sleep windows. People (N = 609) with type 2 diabetes wore an accelerometer for up to 8 days. Waist circumference, body fat percentage, Short Physical Performance Battery (SPPB) test score, sit-to-stands, and resting heart rate were assessed. Physical activity was assessed via the average acceleration and intensity distribution (intensity gradient) over standardized (most active 16 continuous hours (M16h)) and individualized wake windows. Sleep disruption was assessed via the average acceleration over standardized (least active 8 continuous hours (L8h)) and individualized sleep windows. Average acceleration and intensity distribution during the wake window were beneficially associated with adiposity and fitness, while average acceleration during the sleep window was detrimentally associated with adiposity and fitness. Point estimates for the associations were slightly stronger for the standardized than for individualized wake/sleep windows. In conclusion, standardized wake and sleep windows may have stronger associations with health due to capturing variations in sleep durations across individuals, while individualized windows represent a purer measure of wake/sleep behaviors. [ABSTRACT FROM AUTHOR]

Astrocytes mediate many important aspects of neural homeostasis, but until recently, their role in sleep was largely unknown. The situation has dramatically changed in the last decade. The use of transgenic animals, optogenetics, chemogenetics, brain imaging and sophisticated molecular assays has led to exciting discoveries. Astrocytes dynamically change their activity across the sleep–wake cycle and may encode sleep need via changes in intracellular signalling pathways. Astrocytes also exocytose/secrete sleep‐inducing molecules which modulate brain activity, sleep architecture and sleep regulation. Many of these observations have been made in mice and Drosophila melanogaster, indicating that astroglial sleep mechanisms are evolutionarily conserved. We review recent findings and discuss future directions. [ABSTRACT FROM AUTHOR]

The histaminergic neurons of the tuberomammillary nucleus (TMNHDC) of the posterior hypothalamus have long been implicated in promoting arousal. More recently, a role for GABAergic signaling by the TMNHDC neurons in arousal control has been proposed. Here, we investigated the effects of selective chronic disruption of GABA synthesis (via genetic deletion of the GABA synthesis enzyme, glutamic acid decarboxylase 67) or GABAergic transmission (via genetic deletion of the vesicular GABA transporter (VGAT)) in the TMNHDC neurons on sleep-wake in male mice. We also examined the effects of acute chemogenetic activation and optogenetic inhibition of TMNHDC neurons upon arousal in male mice. Unexpectedly, we found that neither disruption of GABA synthesis nor GABAergic transmission altered hourly sleep-wake quantities, perhaps because very few TMNHDC neurons coexpressed VGAT. Acute chemogenetic activation of TMNHDC neurons did not increase arousal levels above baseline but did enhance vigilance when the mice were exposed to a behavioral cage change challenge. Similarly, acute optogenetic inhibition had little effect upon baseline levels of arousal. In conclusion, we could not identify a role for GABA release by TMNHDC neurons in arousal control. Further, if TMNHDC neurons do release GABA, the mechanism by which they do so remains unclear. Our findings support the view that TMNHDC neurons may be important for enhancing arousal under certain conditions, such as exposure to a novel environment, but play only a minor role in behavioral and EEG arousal under baseline conditions.SIGNIFICANCE STATEMENT The histaminergic neurons of the tuberomammillary nucleus of the hypothalamus (TMNHDC) have long been thought to promote arousal. Additionally, TMNHDC neurons may counter-regulate the wake-promoting effects of histamine through co-release of the inhibitory neurotransmitter, GABA. Here, we show that impairing GABA signaling from TMNHDC neurons does not impact sleep-wake amounts and that few TMNHDC neurons contain the vesicular GABA transporter, which is presumably required to release GABA. We further show that acute activation or inhibition of TMNHDC neurons has limited effects upon baseline arousal levels and that activation enhances vigilance during a behavioral challenge. Counter to general belief, our findings support the view that TMNHDC neurons are neither necessary nor sufficient for the initiation and maintenance of arousal under baseline conditions.

Sleep and wakefulness are basic behavioral states that require coordination between several brain regions, and they involve multiple neurochemical systems, including neuropeptides. Neuropeptides are a group of peptides produced by neurons and neuroendocrine cells of the central nervous system. Like traditional neurotransmitters, neuropeptides can bind to specific surface receptors and subsequently regulate neuronal activities. For example, orexin is a crucial component for the maintenance of wakefulness and the suppression of rapid eye movement (REM) sleep. In addition to orexin, melanin-concentrating hormone, and galanin may promote REM sleep. These results suggest that neuropeptides play an important role in sleep–wake regulation. These neuropeptides can be divided into three categories according to their effects on sleep–wake behaviors in rodents and humans. (i) Galanin, melanin-concentrating hormone, and vasoactive intestinal polypeptide are sleep-promoting peptides. It is also noticeable that vasoactive intestinal polypeptide particularly increases REM sleep. (ii) Orexin and neuropeptide S have been shown to induce wakefulness. (iii) Neuropeptide Y and substance P may have a bidirectional function as they can produce both arousal and sleep-inducing effects. This review will introduce the distribution of various neuropeptides in the brain and summarize the roles of different neuropeptides in sleep–wake regulation. We aim to lay the foundation for future studies to uncover the mechanisms that underlie the initiation, maintenance, and end of sleep–wake states. [ABSTRACT FROM AUTHOR]

• Oxytocin (OXT) interventions can influence sleep-wake behaviour and neurobiology. • Preclinically, OXT system activation exerts wake-promoting effects at higher doses. • Clinically, OXT seems to exert no or minor sleep-promoting effects at doses tested. The oxytocin (OXT) system has garnered considerable interest due to its influence on diverse behaviours. However, scant research has considered the influence of oxytocin on sleep-wake and sleep-related behaviour and neurobiology. Consequently, the objective of this systematic review was to assess the extant preclinical and clinical evidence for the influence of oxytocin-based interventions on sleep-wake outcomes. The primary search was conducted on 22/7/2020 using six electronic databases; 30 studies (19 preclinical, 11 clinical) were included based on inclusion criteria. Studies were evaluated for risk of bias using the SYRCLE tool and the Cochrane risk of bias tools for preclinical and clinical studies, respectively. Results indicated manipulation of the OXT system can influence sleep-wake outcomes. Preclinical evidence suggests a wake-promoting influence of OXT system activation whereas the clinical evidence suggests little or no sleep-promoting influence of OXT. OXT dose was identified as a likely modulatory factor of OXT-induced effects on sleep-wake behaviour. Future studies are necessary to validate and strengthen these tentative conclusions about the influence of OXT on sleep-wake behaviour. [ABSTRACT FROM AUTHOR]

• Emergent electrophysiology develops faster in vitro in absence of TNF or TNFRs. • Soluble TNFR1 treatment in vitro induces wake-like states in TNFKO and TNFRKO cells. • TNF forward/reverse signals to sleep/wake concur with other opposing TNF actions. Tumor necrosis factor alpha (TNF) has sleep regulatory and brain development roles. TNF promotes sleep in vivo and in vitro while TNF inhibition diminishes sleep. Transmembrane (tm) TNF and the tmTNF receptors (Rs), are cleaved by tumor necrosis factor alpha convertase to produce soluble (s) TNF and sTNFRs. Reverse signaling occurs in cells expressing tmTNF upon sTNFR binding. sTNFR administration in vivo inhibits sleep, thus we hypothesized that a wake-like state in vitro would be induced by sTNFR-tmTNF reverse signaling. Somatosensory cortical neuron/glia co-cultures derived from male and female mice lacking both TNFRs (TNFRKO), or lacking TNF (TNFKO) and wildtype (WT) mice were plated onto six-well multi-electrode arrays. Daily one-hour electrophysiological recordings were taken on culture days 4 through 14. sTNFR1 (0.0, 0.3, 3, 30, 60, and 120 ng/µL) was administered on day 14. A final one-hour recording was taken on day 15. Four measures were characterized that are also used to define sleep in vivo : action potentials (APs), burstiness index (BI), synchronization of electrical activity (SYN), and slow wave power (SWP; 0.25–3.75 Hz). Development rates of these emergent electrophysiological properties increased in cells from mice lacking TNF or both TNFRs compared to cells from WT mice. Decreased SWP, after the three lowest doses (0.3, 3 and 30 ng/µL) of the sTNFR1, indicate a wake-like state in cells from TNFRKO mice. A wake-like state was also induced after 3 ng/µl sTNFR1 treatment in cells from TNFKO mice, which express the TNFR1 ligand, lymphotoxin alpha. Cells from WT mice showed no treatment effects. Results are consistent with prior studies demonstrating involvement of TNF in brain development, TNF reverse signaling, and sleep regulation in vivo. Further, the current demonstration of sTNFR1 induction of a wake-like state in vitro is consistent with the idea that small neuronal/glial circuits manifest sleep- and wake-like states analogous to those occurring in vivo. Finally, that sTNF forward signaling enhances sleep while sTNFR1 reverse signaling enhances a wake-like state is consistent with other sTNF/tmTNF/sTNFR1 brain actions having opposing activities. [ABSTRACT FROM AUTHOR]

Sleep and wakefulness are basic behavioral states that require coordination between several brain regions, and they involve multiple neurochemical systems, including neuropeptides. Neuropeptides are a group of peptides produced by neurons and neuroendocrine cells of the central nervous system. Like traditional neurotransmitters, neuropeptides can bind to specific surface receptors and subsequently regulate neuronal activities. For example, orexin is a crucial component for the maintenance of wakefulness and the suppression of rapid eye movement (REM) sleep. In addition to orexin, melanin-concentrating hormone, and galanin may promote REM sleep. These results suggest that neuropeptides play an important role in sleep–wake regulation. These neuropeptides can be divided into three categories according to their effects on sleep–wake behaviors in rodents and humans. (i) Galanin, melanin-concentrating hormone, and vasoactive intestinal polypeptide are sleep-promoting peptides. It is also noticeable that vasoactive intestinal polypeptide particularly increases REM sleep. (ii) Orexin and neuropeptide S have been shown to induce wakefulness. (iii) Neuropeptide Y and substance P may have a bidirectional function as they can produce both arousal and sleep-inducing effects. This review will introduce the distribution of various neuropeptides in the brain and summarize the roles of different neuropeptides in sleep–wake regulation. We aim to lay the foundation for future studies to uncover the mechanisms that underlie the initiation, maintenance, and end of sleep–wake states.

• Glutamatergic neurons of the paraventricular nucleus could regulate wakefulness. • The calcium activities of PVN glutamatergic neurons increased before NREM to wake. • The calcium activities of PVN glutamatergic neurons decreased before wake to NREM. • Chemogenetic activation of the PVN glutamatergic neurons increased wakefulness. • Chemogenetic inhibition of the PVN glutamatergic neurons decreased wakefulness. Normal sleep–wake behavior is extremely important for humans to maintain basic physiological and cognitive activities. However, the neural mechanisms underlying sleep–wake regulation are not fully understood. The paraventricular nucleus (PVN) of the hypothalamus has been classically defined as a region for the regulation of the hypothalamoneurohypophysial system and autonomic nervous system. Here, we identify the glutamatergic neurons in the PVN that play a unique role in sleep–wake regulation. Firstly using in vivo fiber photometry, we found altered calcium activities of PVN glutamatergic neurons during three sleep state transitions in freely behaving mice. The calcium activities of PVN glutamatergic neurons began to increase before non-rapid-eye movement (NREM) sleep to wake transitions and NREM sleep to rapid-eye-movement (REM) sleep transitions and began to decrease before wake to NREM sleep transitions. Then we used chemogenetic manipulations together with polysomnographic recordings, activation of PVN neurons increased wakefulness and decreased NREM sleep, while inhibition of PVN neurons caused a reduction in wakefulness and an increase in NREM sleep. Altogether, our findings revealed an important role for PVN glutamatergic neurons in the regulation of wake state. [ABSTRACT FROM AUTHOR]

Relational memory is the ability to flexibly organize and integrate multiple sources of information to produce emergent outcomes. In tests for one type of relational memory—stimulus equivalence—arbitrary stimuli become related in ways not explicitly trained. Little is known, however, about whether stimulus equivalence-based relational memory ability differentially emerges during offline periods of either sleep or wake. In this study, 51 healthy young adults learned a series of interconnected conditional relations involving arbitrary visual images (A-B, A-C, and A-D), and were immediately tested for maintenance of these relations. Following a 12-hour offline period consisting of either sleep or wake, both groups were tested for novel inferences—symmetry (B-A, C-A, and D-A) and equivalence relations (B-C, C-B, C-D, and D-C)—as well as retention of the trained relations. Results from delayed testing, supported by Bayesian statistics, showed that accuracy did not differ between the sleep and wake groups. Potential limitations of this preliminary investigation and directions for future research are discussed. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a major cause of disability worldwide. Post-TBI sleep and wake disturbances are extremely common and difficult for patients to manage. Sleep and wake disturbances contribute to poor functional and emotional outcomes from TBI, yet effective therapies remain elusive. A more comprehensive understanding of mechanisms underlying post-TBI sleep and wake disturbance will facilitate development of effective pharmacotherapies. Previous research in human patients and animal models indicates that altered hypocretinergic function may be a major contributor to sleep–wake disturbance after TBI. In this study, we further elucidate the role of hypocretin by determining the impact of TBI on sleep–wake behavior of hypocretin knockout (HCRT KO) mice. Adult male C57BL/6J and HCRT KO mice were implanted with electroencephalography recording electrodes, and pre-injury baseline recordings were obtained. Mice were then subjected to either moderate TBI or sham surgery. Additional recordings were obtained and sleep–wake behavior determined at 3, 7, 15, and 30 days after TBI or sham procedures. At baseline, HCRT KO mice had a significantly different sleep–wake phenotype than control C57BL/6J mice. Post-TBI sleep–wake behavior was altered in a genotype-dependent manner: sleep of HCRT KO mice was not altered by TBI, whereas C57BL/6J mice had more non–rapid eye movement sleep, less wakefulness, and more short wake bouts and fewer long wake bouts. Numbers of hypocretin-positive cells were reduced in C57BL/6J mice by TBI. Collectively, these data indicate that the hypocretinergic system is involved in the alterations in sleep–wake behavior that develop after TBI in this model, and suggest potential therapeutic interventions. [ABSTRACT FROM AUTHOR]

The hypocretins (Hcrts) are two alternatively spliced neuropeptides (Hcrt1/Ox-A and Hcrt2/Ox-B) that are synthesized exclusively in the hypothalamus. Data collected in the 20 years since their discovery have supported the view that the Hcrts play a broad role in the control of arousal with a particularly important role in the maintenance of wakefulness and sleep-to-wake transitions. While this latter point has received an overwhelming amount of research attention, a growing literature has begun to broaden our understanding of the many diverse roles that the Hcrts play in physiology and behavior. Here, we review recent advances in the neurobiology of Hcrt in three sections. We begin by surveying findings on Hcrt function within normal sleep/wake states as well as situations of aberrant sleep (that is, narcolepsy). In the second section, we discuss research establishing a role for Hcrt in mood and affect (that is, anxiety, stress, and motivation). Finally, in the third section, we briefly discuss future directions for the field and place an emphasis on analytical modeling of Hcrt neural activity. We hope that the data discussed here provide a broad overview of recent progress in the field and make clear the diversity of roles played by these neuromodulators.

Background: Premature birth is a major cause of infant mortality in developed countries. Newborns confined to neonatal intensive care units (NICUs) are in a rapid stage of brain development. As such, sleep plays a pivotal role in the proper brain development of newborns. However, this developmental aspect is often disregarded due to the lack of information. Aim: This study aimed to evaluate the effect of nest posture on the sleep-wake state of premature infants. Method: This cross-over clinical trial was conducted on 60 premature infants admitted in the NICU of Ghaem Hospital in Mashhad, Iran in 2015. Infants were divided into two groups of experimental and control. Data were collected using the Assessment of Premature Infants' Behavior (APIB). Neonates in the control group were placed in an incubator, and neonates in the experimental group were positioned in a nest. Between-group comparison was performed using paired-samples T-test for normal variables and Wilcoxon test for non-normal variables. Results: In this study, no statistically significant differences were observed between the two groups in terms of the scores of deep sleep state before (P=0.50) and after the intervention (P=0.59). However, during the intervention, mean score of deep sleep was higher in the experimental group (P=0.08). Moreover, mean score of slow wake state had no significant difference between the study groups before (P=0.67), after (P=0.86), and during the intervention (P=0.81). Implications for Practice: According to the results of this study, nest posture increased the deep sleep hours of premature infants as the most imperative state of brain development. Therefore, it is recommended that nest posture be used to improve the deep sleep state of premature infants.

Transcriptomic studies revealed that hundreds of mRNAs show differential expression in the brains of sleeping relative to awake rats, mice, flies, and sparrows. Although these results have offered clues regarding the molecular consequences of sleep and sleep loss, their functional significance thus far has been limited. This is probably because the previous studies pooled transcripts from all brain cells, including neurons and glia. In Bellesi et al. (2015) [1], we used the translating ribosome affinity purification technology (TRAP) and microarray analysis to obtain a genome-wide mRNA profiling of astrocytes as a function of sleep and wake. We used bacterial artificial chromosome (BAC) transgenic mice expressing eGFP tagged ribosomal protein L10a under the promoter of the Aldh1L1 gene, a highly expressed astrocytic gene. Using this approach, we could extract only the astrocytic mRNAs, and only those already committed to be translated into proteins (L10a is part of the translational machinery). Here, we report a detailed description of the protocol used in the study (Bellesi et al., 2015 [1]). Array data have been submitted to NCBI GEO under accession number (GSE69079).

In the heterogeneous hub represented by the lateral hypothalamus, neurons containing the orexin/hypocretin peptides play a key role in vigilance state transitions and wakefulness stability, energy homeostasis, and other functions relevant for motivated behaviors. Orexin neurons, which project widely to the neuraxis, are innervated by multiple extra- and intra-hypothalamic sources. A key property of the adaptive capacity of orexin neurons is represented by daily variations of activity, which is highest in the period of the animal’s activity and wakefulness. These sets of data are here reviewed. They concern the discharge profile during the sleep/wake cycle, spontaneous Fos induction, peptide synthesis and release reflected by immunostaining intensity and peptide levels in the cerebrospinal fluid as well as postsynaptic effects. At the synaptic level, adaptive capacity of orexin neurons subserved by remodeling of excitatory and inhibitory inputs has been shown in response to changes in the nutritional status and prolonged wakefulness. The present review wishes to highlight that synaptic plasticity in the wiring of orexin neurons also occurs in unperturbed conditions and could account for diurnal variations of orexin neuron activity. Data in zebrafish larvae have shown rhythmic changes in the density of inhibitory innervation of orexin dendrites in relation to vigilance states. Recent findings in mice have indicated a diurnal reorganization of the excitatory/inhibitory balance in the perisomatic innervation of orexin neurons. Taken together these sets of data point to “chronoconnectivity,” i.e., a synaptic rearrangement of inputs to orexin neurons over the course of the day in relation to sleep and wake states. This opens questions on the underlying circadian and homeostatic regulation and on the involved players at synaptic level, which could implicate dual transmitters, cytoskeletal rearrangements, hormonal regulation, as well as surrounding glial cells and extracellular matrix. Furthermore, the question arises of a “chronoconnectivity” in the wiring of other neuronal cell groups of the sleep-wake-regulatory network, many of which are characterized by variations of their firing rate during vigilance states.

In the heterogeneous hub represented by the lateral hypothalamus, neurons containing the orexin/hypocretin peptides play a key role in vigilance state transitions and wakefulness stability, energy homeostasis, and other functions relevant for motivated behaviors. Orexin neurons, which project widely to the neuraxis, are innervated by multiple extra- and intra-hypothalamic sources. A key property of the adaptive capacity of orexin neurons is represented by daily variations of activity, which is highest in the period of the animal's activity and wakefulness. These sets of data are here reviewed. They concern the discharge profile during the sleep/wake cycle, spontaneous Fos induction, peptide synthesis and release reflected by immunostaining intensity and peptide levels in the cerebrospinal fluid as well as postsynaptic effects. At the synaptic level, adaptive capacity of orexin neurons subserved by remodeling of excitatory and inhibitory inputs has been shown in response to changes in the nutritional status and prolonged wakefulness. The present review wishes to highlight that synaptic plasticity in the wiring of orexin neurons also occurs in unperturbed conditions and could account for diurnal variations of orexin neuron activity. Data in zebrafish larvae have shown rhythmic changes in the density of inhibitory innervation of orexin dendrites in relation to vigilance states. Recent findings in mice have indicated a diurnal reorganization of the excitatory/inhibitory balance in the perisomatic innervation of orexin neurons. Taken together these sets of data point to "chronoconnectivity," i.e., a synaptic rearrangement of inputs to orexin neurons over the course of the day in relation to sleep and wake states. This opens questions on the underlying circadian and homeostatic regulation and on the involved players at synaptic level, which could implicate dual transmitters, cytoskeletal rearrangements, hormonal regulation, as well as surrounding glial cells and extracellular matrix. Furthermore, the question arises of a "chronoconnectivity" in the wiring of other neuronal cell groups of the sleep-wake-regulatory network, many of which are characterized by variations of their firing rate during vigilance states. [ABSTRACT FROM AUTHOR]

Neuron populations of the lateral hypothalamus which synthesize the orexin (OX)/hypocretin or melanin-concentrating hormone (MCH) peptides play crucial, reciprocal roles in regulating wake stability and sleep. The disease human African trypanosomiasis (HAT), also called sleeping sickness, caused by extracellular Trypanosoma brucei (T. b.) parasites, leads to characteristic sleep-wake cycle disruption and narcoleptic-like alterations of the sleep structure. Previous studies have revealed damage of OX and MCH neurons during systemic infection of laboratory rodents with the non-human pathogenic T. b. brucei subspecies. No information is available, however, on these peptidergic neurons after systemic infection with T. b. gambiense, the etiological agent of 97% of HAT cases. The present study was aimed at the investigation of immunohistochemically characterized OX and MCH neurons after T. b. gambiense or T. b. brucei infection of a susceptible rodent, the multimammate mouse, Mastomys natalensis. Cell counts and evaluation of OX fiber density were performed at 4 and 8 weeks post-infection, when parasites had entered the brain parenchyma from the periphery. A significant decrease of OX neurons (about 44% reduction) and MCH neurons (about 54% reduction) was found in the lateral hypothalamus and perifornical area at 8 weeks in T. b. gambiense-infected M. natalensis. A moderate decrease (21% and 24% reduction, respectively), which did not reach statistical significance, was found after T. b. brucei infection. In two key targets of diencephalic orexinergic innervation, the peri-suprachiasmatic nucleus (SCN) region and the thalamic paraventricular nucleus (PVT), densitometric analyses showed a significant progressive decrease in the density of orexinergic fibers in both infection paradigms, and especially during T. b. gambiense infection. Altogether the findings provide novel information showing that OX and MCH neurons are highly vulnerable to chronic neuroinflammatory signaling caused by the infection of human-pathogenic African trypanosomes. [ABSTRACT FROM AUTHOR]

Bio-mathematical models that predict fatigue and/or sleepiness have proved a useful adjunct in the management of what has been typically referred to as fatigue-related risk. Codifying what constitutes appropriate use of these models will be increasingly important over the next decade. Current guidelines for determining a safe working time arrangement based on model outputs generally use a single upper threshold and are, arguably, over-simplistic. These guidelines fail to incorporate explicitly essential aspects of the risk assessment process – namely, the inherent uncertainty and variability in human sleep–wake behavior; the non-linear relationship between fatigue, task performance and safety outcomes; the consequence of a fatigue-related error and its influence on overall risk; and the impact of risk mitigation or controls in reducing the likelihood or consequence of a fatigue-related error. As industry and regulatory bodies increasingly move toward performance-based approaches to safety management, any fatigue risk management system that includes a bio-mathematical model should specify what exactly is measured by the model, and how the model can be used in the context of a safety management system approach. This will require significant dialog between the various parties with an interest in bio-mathematical models, i.e. developers, vendors, end-users, and regulators. [ABSTRACT FROM AUTHOR]