Sleep Bouts Research Articles

The importance of including both sexes in preclinical sleep studies and analyses

A significant effort in biomedical sciences has been made to examine relationships between sex and the mechanisms underlying various disease states and behaviors, including sleep. Here, we investigated biological sex differences in sleep using male and female C57BL/6J mice (n = 267). Physiological parameters were recorded for 48-h using non-invasive piezoelectric cages to determine total sleep, non-rapid eye movement (NREM) sleep, rapid eye movement (REM)-like sleep, and wakefulness (WAKE). We fit hierarchical generalized linear mixed models with nonlinear time effects and found substantial sex differences in sleep. Female mice slept less overall, with less NREM sleep compared to males. Females also exhibited more REM-like sleep and WAKE and had shorter NREM sleep bout lengths. We also conducted a simulation exercise where we simulated a hypothetical treatment that altered the sleep of female mice, but not male mice. In models that included an appropriate sex by treatment interaction, a female-specific treatment response was accurately estimated when sample sizes were equal but was not detected when sample sizes were unequal, and females were underrepresented. Failure to include both sexes in experimental designs or appropriately account for sex during analysis could lead to inaccurate translational recommendations in pre-clinical sleep studies.

Intra-species quantification reveals differences in activity and sleep levels in the yellow fever mosquito, Aedes aegypti.

Aedes aegypti is an important mosquito vector of human disease with a wide distribution across the globe. Climatic conditions and ecological pressure drive differences in the biology of several populations of this mosquito species, including blood-feeding behaviour and vector competence. However, no study has compared activity and/or sleep among different populations/lineages of Ae. aegypti. Having recently established sleep-like states in three mosquito species with observable differences in timing and amount of sleep among species, we investigated differences in activity and sleep levels among 17 Ae. aegypti lines drawn from both its native range in Africa and its invasive range across the global tropics. Activity monitoring indicates that all the lines show consistent diurnal activity, but significant differences in activity level, sleep amount, number of sleep bouts and bout duration were observed among the lines. The variation in day activity was associated with differences in host preference and ancestry for the lineages collected in Africa. This study provides evidence that the diurnal sleep and activity profiles for Ae. aegypti are consistent, but there are significant population differences for Ae. aegypti sleep and activity levels and interactions with host species may significantly impact mosquito activity.

Maternal immune activation exerts long-term effects on activity and sleep in male offspring mice.

Exposure to infectious or non-infectious immune activation during early development is a serious risk factor for long-term behavioural dysfunctions. Mouse models of maternal immune activation (MIA) have increasingly been used to address neuronal and behavioural dysfunctions in response to prenatal infections. One commonly employed MIA model involves administering poly(I:C) (polyriboinosinic-polyribocytdilic acid), a synthetic analogue of double-stranded RNA, during gestation, which robustly induces an acute viral-like inflammatory response. Using electroencephalography (EEG) and infrared (IR) activity recordings, we explored alterations in sleep/wake, circadian and locomotor activity patterns on the adult male offspring of poly(I:C)-treated mothers. Our findings demonstrate that these offspring displayed reduced home cage activity during the (subjective) night under both light/dark or constant darkness conditions. In line with this finding, these mice exhibited an increase in non-rapid eye movement (NREM) sleep duration as well as an increase in sleep spindles density. Following sleep deprivation, poly(I:C)-exposed offspring extended NREM sleep duration and prolonged NREM sleep bouts during the dark phase as compared with non-exposed mice. Additionally, these mice exhibited a significant alteration in NREM sleep EEG spectral powerunder heightened sleep pressure. Together, our study highlights the lasting effects of infection and/or immune activation during pregnancy on circadian activity and sleep/wake patterns in the offspring.

Inflammatory pain in mice induces light cycle-dependent effects on sleep architecture.

As a syndrome, chronic pain comprises physical, emotional, and cognitive symptoms such as disability, negative affect, feelings of stress, and fatigue. A rodent model of long-term inflammatory pain, induced by complete Freund's adjuvant (CFA) injection, has previously been shown to cause anhedonia and dysregulated naturalistic behaviors, in a manner similar to animal models of stress. We examined whether this extended to alterations in circadian rhythms and sleep, such as those induced by chronic social defeat stress, using actigraphy and wireless EEG. CFA-induced inflammatory pain profoundly altered sleep architecture in male and female mice. Injection of the hind paw, whether with CFA or saline, reduced some measures of circadian rhythmicity such as variance, period, and amplitude. CFA increased sleep duration primarily in the dark phase, while sleep bout length was decreased in the light and increased in the dark phase. Additionally, CFA reduced wake bout length, especially during the dark phase. Increases in REM and SWS duration and bouts were most significant in the dark phase, regardless of whether CFA had been injected at its onset or 12 hours prior. Taken together, these results indicate that inflammatory pain acutely promotes but also fragments sleep.

Sleep and circadian rhythm activity alterations during adolescence in a mouse model of neonatal fentanyl withdrawal syndrome.

Fentanyl, a highly potent synthetic opioid, is a major contributor to the ongoing opioid epidemic. During adulthood, fentanyl is known to induce pronounced sleep and circadian disturbances during use and withdrawal. Children exposed to opioids in utero are likely to develop neonatal opioid withdrawal syndrome, and display sleep disturbances after birth. However, it is currently unknown how neonatal opioid withdrawal from fentanyl impacts sleep and circadian rhythms in mice later in life. To model neonatal opioid withdrawal syndrome, mice were treated with fentanyl from postnatal days 1 through 14, analogous to the third trimester of human gestation. After weaning, fentanyl and saline treated mice underwent non-invasive sleep and circadian rhythm monitoring during adolescence postnatal days 23 through 30. Neonatal fentanyl exposure led to reduced duration of wake and a decrease in the number of bouts of non-rapid eye movement sleep. Further, neonatally exposed mice displayed an increase in the average duration of rapid eye movement sleep bouts, reflecting an overall increase in the percent time spent in rapid eye movement sleep across days. Neonatal fentanyl exposure leads to altered sleep-wake states during adolescence in mice.

Neuronal PAS domain 1 identifies a major subpopulation of wakefulness-promoting GABAergic neurons in the basal forebrain

Here, we describe a group of basal forebrain (BF) neurons expressing neuronal Per-Arnt-Sim (PAS) domain 1 (Npas1), a developmental transcription factor linked to neuropsychiatric disorders. Immunohistochemical staining in Npas1-cre-2A-TdTomato mice revealed BF Npas1+ neurons are distinct from well-studied parvalbumin or cholinergic neurons. Npas1 staining in GAD67-GFP knock-in mice confirmed that the vast majority of Npas1+ neurons are GABAergic, with minimal colocalization with glutamatergic neurons in vGlut1-cre-tdTomato or vGlut2-cre-tdTomato mice. The density of Npas1+ neurons was high, five to six times that of neighboring cholinergic, parvalbumin, or glutamatergic neurons. Anterograde tracing identified prominent projections of BF Npas1+ neurons to brain regions involved in sleep-wake control, motivated behaviors, and olfaction such as the lateral hypothalamus, lateral habenula, nucleus accumbens shell, ventral tegmental area, and olfactory bulb. Chemogenetic activation of BF Npas1+ neurons in the light period increased the amount of wakefulness and the latency to sleep for 2 to 3 h, due to an increase in long wake bouts and short NREM sleep bouts. NREM slow-wave and sigma power, as well as sleep spindle density, amplitude, and duration, were reduced, reminiscent of findings in several neuropsychiatric disorders. Together with previous findings implicating BF Npas1+ neurons in stress responsiveness, the anatomical projections of BF Npas1+ neurons and the effect of activating them suggest a possible role for BF Npas1+ neurons in motivationally driven wakefulness and stress-induced insomnia. Identification of this major subpopulation of BF GABAergic neurons will facilitate studies of their role in sleep disorders, dementia, and other neuropsychiatric conditions involving BF.

Sleep fragmentation after traumatic brain injury impairs behavior and conveys long-lasting impacts on neuroinflammation

Traumatic brain injury (TBI) causes a prolonged inflammatory response in the central nervous system (CNS) driven by microglia. Microglial reactivity is exacerbated by stress, which often provokes sleep disturbances. We have previously shown that sleep fragmentation (SF) stress after experimental TBI increases microglial reactivity and impairs hippocampal function 30 days post-injury (DPI). The neuroimmune response is highly dynamic the first few weeks after TBI, which is also when injury induced sleep-wake deficits are detected. Therefore, we hypothesized that even a few weeks of TBI SF stress would synergize with injury induced sleep-wake deficits to promote neuroinflammation and impair outcome. Here, we investigated the effects of environmental SF in a lateral fluid percussion model of mouse TBI. Half of the mice were undisturbed, and half were exposed to 5 h of SF around the onset of the light cycle, daily, for 14 days. All mice were then undisturbed 15–30 DPI, providing a period for SF stress recovery (SF-R). Mice exposed to SF stress slept more than those in control housing 7–14 DPI and engaged in more total daily sleep bouts during the dark period. However, SF stress did not exacerbate post-TBI sleep deficits. Testing in the Morris water maze revealed sex dependent differences in spatial reference memory 9–14 DPI with males performing worse than females. Post-TBI SF stress suppressed neurogenesis-related gene expression and increased inflammatory signaling in the cortex at 14 DPI. No differences in sleep behavior were detected between groups during the SF stress recovery period 15–30 DPI. Microscopy revealed cortical and hippocampal IBA1 and CD68 percent-area increased in TBI SF-R mice 30 DPI. Additionally, neuroinflammatory gene expression was increased, and synaptogenesis-related gene expression was suppressed in TBI-SF mice 30 DPI. Finally, IPA canonical pathway analysis showed post-TBI SF impaired and delayed activation of synapse-related pathways between 14 and 30 DPI. These data show that transient SF stress after TBI impairs recovery and conveys long-lasting impacts on neuroimmune function independent of continuous sleep deficits. Together, these finding support that even limited exposure to post-TBI SF stress can have lasting impacts on cognitive recovery and regulation of the immune response to trauma.

Differential effects of the stress peptides PACAP and CRF on sleep architecture in mice

Stress produces profound effects on behavior, including persistent alterations in sleep patterns. Here we examined the effects of two prototypical stress peptides, pituitary adenylate cyclase-activating polypeptide (PACAP) and corticotropin-releasing factor (CRF), on sleep architecture and other translationally-relevant endpoints. Male and female mice were implanted with subcutaneous transmitters enabling continuous measurement of electroencephalography (EEG) and electromyography (EMG), as well as body temperature and locomotor activity, without tethering that restricts free movement, body posture, or head orientation during sleep. At baseline, females spent more time awake (AW) and less time in slow wave sleep (SWS) than males. Mice then received intracerebral infusions of PACAP or CRF at doses producing equivalent increases in anxiety-like behavior. The effects of PACAP on sleep architecture were similar in both sexes and resembled those reported in male mice after chronic stress exposure. Compared to vehicle infusions, PACAP infusions decreased time in AW, increased time in SWS, and increased rapid eye movement sleep (REM) time and bouts on the day following treatment. In addition, PACAP effects on REM time remained detectable a week after treatment. PACAP infusions also reduced body temperature and locomotor activity. Under the same experimental conditions, CRF infusions had minimal effects on sleep architecture in either sex, causing only transient increases in SWS during the dark phase, with no effects on temperature or activity. These findings suggest that PACAP and CRF have fundamentally different effects on sleep-related metrics and provide new insights into the mechanisms by which stress disrupts sleep.

Multivariate classification of multichannel long-term electrophysiology data identifies different sleep stages in fruit flies.

Identifying different sleep stages in humans and other mammals has traditionally relied on electroencephalograms. Such an approach is not feasible in certain animals such as invertebrates, although these animals could also be sleeping in stages. Here, we perform long-term multichannel local field potential recordings in the brains of behaving flies undergoing spontaneous sleep bouts. We acquired consistent spatial recordings of local field potentials across multiple flies, allowing us to compare brain activity across awake and sleep periods. Using machine learning, we uncover distinct temporal stages of sleep and explore the associated spatial and spectral features across the fly brain. Further, we analyze the electrophysiological correlates of microbehaviors associated with certain sleep stages. We confirm the existence of a distinct sleep stage associated with rhythmic proboscis extensions and show that spectral features of this sleep-related behavior differ significantly from those associated with the same behavior during wakefulness, indicating a dissociation between behavior and the brain states wherein these behaviors reside.

Transcranial Direct Current Stimulation (tDCS) Ameliorates Stress-Induced Sleep Disruption via Activating Infralimbic-Ventrolateral Preoptic Projections.

Transcranial direct current stimulation (tDCS) is acknowledged for its non-invasive modulation of neuronal activity in psychiatric disorders. However, its application in insomnia research yields varied outcomes depending on different tDCS types and patient conditions. Our primary objective is to elucidate its efficiency and uncover the underlying mechanisms in insomnia treatment. We hypothesized that anodal prefrontal cortex stimulation activates glutamatergic projections from the infralimbic cortex (IL) to the ventrolateral preoptic area (VLPO) to promote sleep. After administering 0.06 mA of electrical currents for 8 min, our results indicate significant non-rapid eye movement (NREM) enhancement in naïve mice within the initial 3 h post-stimulation, persisting up to 16-24 h. In the insomnia group, tDCS enhanced NREM sleep bout numbers during acute stress response and improved NREM and REM sleep duration in subsequent acute insomnia. Sleep quality, assessed through NREM delta powers, remains unaffected. Interference of the IL-VLPO pathway, utilizing designer receptors exclusively activated by designer drugs (DREADDs) with the cre-DIO system, partially blocked tDCS's sleep improvement in stress-induced insomnia. This study elucidated that the activation of the IL-VLPO pathway mediates tDCS's effect on stress-induced insomnia. These findings support the understanding of tDCS effects on sleep disturbances, providing valuable insights for future research and clinical applications in sleep therapy.

Development of the sleep-wake switch in rats during the P2-P21 early infancy period.

In early infancy, rats randomly alternate between the sleeping and waking states-from postnatal day 2-10 (P2-P10), sleep and wake bouts are both exponentially distributed with increasing means, while from P10-P21 sleep and wake bout means continue to increase, though there is a striking qualitative shift in the distribution of wake bouts from exponential to power law. The behavioral states of sleep and wakefulness correspond to the activity of sleep-active and wake-active neuronal brainstem populations, with reciprocal inhibition between the two ensuring that only one population is active at a time. The locus coeruleus (LC) forms a third component of this circuit that rises in prominence during the P10-P21 period, as experimental evidence shows that an as-of-yet undeciphered interaction of the LC with sleep-active and wake-active populations is responsible for the transformation of the wake bout distribution from exponential to power law. Interestingly, the LC undergoes remarkable physiological changes during the P10-P21 period-gap junctions within the LC are pruned and network-wide oscillatory synchrony declines and vanishes. In this work, we discuss a series of models of sleep-active, wake-active, and the LC populations, and we use these models to postulate the nature of the interaction between these three populations and how these interactions explain empirical observations of sleep and wake bout dynamics. We hypothesize a circuit in which there is reciprocal excitation between the LC and wake-active population with inhibition from the sleep-active population to the LC that suppresses the LC during sleep bouts. During the P2-P10 period, we argue that a noise-based switching mechanism between the sleep-active and wake-active populations provides a simple and natural way to account for exponential bout distributions, and that the locked oscillatory state of the LC prevents it from impacting bout distributions. From P10-P21, we use our models to postulate that, as the LC gradually shifts from a state of synchronized oscillations to a state of continuous firing, reciprocal excitation between the LC and the wake-active population is able to gradually transform the wake bout distribution from exponential to power law.

An integrate-and-fire mathematical model of sleep-wake neuronal networks in the developing mammal.

Sleep behavior is present in nearly all animals, and is a vital part of growth, development, and overall health. Infant mammals cycle randomly between short bouts of sleep and wake, and the lengths of these bouts both follow an exponential distribution. As mammals mature into adulthood, the mean sleep and wake bout lengths increase, and we also observe a change in the distribution of wake bout lengths from exponential to power law. Focusing on three regions of the brainstem that are involved in sleep-wake regulation, we develop a novel integrate-and-fire neuronal network model to expand upon previous mathematical models of sleep-wake regulation in mammals, focusing on rats. This model allows fine control over neuronal connectivity while simultaneously increasing the size and complexity of the modeled system to make it more representative of reality. We establish a relationship between neuronal network structure and function that could explain the different sleep-wake behaviors observed in rats as they progress through development. We explore the relationship between three different neuronal populations as well as the overall network behavior of the system. We find that increasing synaptic connectivity strength between the wake-promoting region and the wake-active region accounts for the observed changes in mammalian sleep-wake patterns. This dynamic neuronal connectivity is a possible mechanism that accurately accounts for sleep-wake pattern changes observed during mammalian development.

State of the science and recommendations for using wearable technology in sleep and circadian research.

Wearable sleep-tracking technology is of growing use in the sleep and circadian fields, including for applications across other disciplines, inclusive of a variety of disease states. Patients increasingly present sleep data derived from their wearable devices to their providers and the ever-increasing availability of commercial devices and new-generation research/clinical tools has led to the wide adoption of wearables in research, which has become even more relevant given the discontinuation of the Philips Respironics Actiwatch. Standards for evaluating the performance of wearable sleep-tracking devices have been introduced and the available evidence suggests that consumer-grade devices exceed the performance of traditional actigraphy in assessing sleep as defined by polysomnogram. However, clear limitations exist, for example, the misclassification of wakefulness during the sleep period, problems with sleep tracking outside of the main sleep bout or nighttime period, artifacts, and unclear translation of performance to individuals with certain characteristics or comorbidities. This is of particular relevance when person-specific factors (like skin color or obesity) negatively impact sensor performance with the potential downstream impact of augmenting already existing healthcare disparities. However, wearable sleep-tracking technology holds great promise for our field, given features distinct from traditional actigraphy such as measurement of autonomic parameters, estimation of circadian features, and the potential to integrate other self-reported, objective, and passively recorded health indicators. Scientists face numerous decision points and barriers when incorporating traditional actigraphy, consumer-grade multi-sensor devices, or contemporary research/clinical-grade sleep trackers into their research. Considerations include wearable device capabilities and performance, target population and goals of the study, wearable device outputs and availability of raw and aggregate data, and data extraction, processing, and analysis. Given the difficulties in the implementation and utilization of wearable sleep-tracking technology in real-world research and clinical settings, the following State of the Science review requested by the Sleep Research Society aims to address the following questions. What data can wearable sleep-tracking devices provide? How accurate are these data? What should be taken into account when incorporating wearable sleep-tracking devices into research? These outstanding questions and surrounding considerations motivated this work, outlining practical recommendations for using wearable technology in sleep and circadian research.

A two-process model of Drosophila sleep reveals an inter-dependence between circadian clock speed and the rate of sleep pressure decay.

Sleep is controlled by two processes-a circadian clock that regulates its timing and a homeostat that regulates the drive to sleep. Drosophila has been an insightful model for understanding both processes. For four decades, Borbély and Daan's two-process model has provided a powerful framework for understanding sleep regulation. However, the field of fly sleep has not employed such a model as a framework for the investigation of sleep. To this end, we have adapted the two-process model to the fly and established its utility by showing that it can provide empirically testable predictions regarding the circadian and homeostatic control of fly sleep. We show that the ultradian rhythms previously reported for loss-of-function clock mutants in the fly are robustly detectable and a predictable consequence of a functional sleep homeostat in the absence of a functioning circadian system. We find that a model in which the circadian clock speed and homeostatic rates act without influencing each other provides imprecise predictions regarding how clock speed influences the strength of sleep rhythms and the amount of daily sleep. We also find that quantitatively good fits between empirical values and model predictions were achieved only when clock speeds were positively correlated with rates of decay of sleep pressure. Our results indicate that longer sleep bouts better reflect the homeostatic process than the current definition of sleep as any inactivity lasting 5 minutes or more. This two-process model represents a powerful framework for work on the molecular and physiological regulation of fly sleep.

Effects of Dendropanax morbiferus Leaf Extract on Sleep Parameters in Invertebrate and Vertebrate Models.

Dendropanax morbiferus is highly valued in traditional medicine and has been used to alleviate the symptoms of numerous diseases owing to its excellent antioxidant activity. This study aimed to evaluate the sleep promotion and related signaling pathways of D. morbiferus extract (DE) via behavioral analysis, molecular biological techniques, and electrophysiological measurements in invertebrate and vertebrate models. In Drosophila, the group treated with 4% DE experienced decreased subjective nighttime movement and sleep bout and increased total sleeping time. Moreover, substantial changes in locomotor activity, including distance moved, velocity, and movement, were confirmed in the 4% DE-treated group. Compared to Drosophila in which insomnia and oxidative stress were induced by exposure to 0.1% caffeine, the DE-treated group improved sleep-related parameters to the level of the normal group. In the Drosophila model, exposure to 4% DE upregulated the expression of gamma-aminobutyric acid (GABA)-related receptors and serotonin receptor (5-HT1A), along with the expression of antioxidant-related factors, glutathione, and catalase. In the pentobarbital-induced sleep test using ICR mice, the duration of sleep was markedly increased by high concentration of DE. In addition, through the electroencephalography analysis of SD-rats, a significant increase in non-rapid-eye-movement sleep and delta waves was confirmed with high concentrations of DE administration. The increase in sleep time and improvement in sleep quality were confirmed to be related to the expression of altered GABA receptors and the enhancement of the contents of the neurotransmitters GABA and serotonin (5-HT) because of high DE administration. High-dose administration of DE also increased the expression of antioxidant-related factors in the brain and significantly decreased malondialdehyde content. Taken together, DE induced improvements in sleep quantity and quality by regulating neurotransmitter content and related receptor expression, along with high antioxidant activity, and may have a therapeutic effect on sleep disorders.

Ketogenic Diet Affects Sleep Architecture in C57BL/6J Wild Type and Fragile X Mice.

Nearly half of children with fragile X syndrome experience sleep problems including trouble falling asleep and frequent nighttime awakenings. The goals here were to assess sleep-wake cycles in mice in response to Fmr1 genotype and a dietary intervention that reduces hyperactivity. Electroencephalography (EEG) results were compared with published rest-activity patterns to determine if actigraphy is a viable surrogate for sleep EEG. Specifically, sleep-wake patterns in adult wild type and Fmr1KO littermate mice were recorded after EEG electrode implantation and the recordings manually scored for vigilance states. The data indicated that Fmr1KO mice exhibited sleep-wake patterns similar to wild type littermates when maintained on a control purified ingredient diet. Treatment with a high-fat, low-carbohydrate ketogenic diet increased the percentage of non-rapid eye movement (NREM) sleep in both wild type and Fmr1KO mice during the dark cycle, which corresponded to decreased activity levels. Treatment with a ketogenic diet flattened diurnal sleep periodicity in both wild type and Fmr1KO mice. Differences in several sleep microstructure outcomes (number and length of sleep and wake bouts) supported the altered sleep states in response to a ketogenic diet and were correlated with altered rest-activity cycles. While actigraphy may be a less expensive, reduced labor surrogate for sleep EEG during the dark cycle, daytime resting in mice did not correlate with EEG sleep states.

Examining sleep modulation by Drosophila ellipsoid body neurons.

Recent work in Drosophila has uncovered several neighboring classes of sleep-regulatory neurons within the central complex. However, the logic of connectivity and network motifs remains limited by the incomplete examination of relevant cell types. Using a recent genetic-anatomical classification of ellipsoid body ring neurons, we conducted a thermogenetic screen in female flies to assess sleep/wake behavior and identified two wake-promoting drivers that label ER3d neurons and two sleep-promoting drivers that express in ER3m cells. We then used intersectional genetics to refine driver expression patterns. Activation of ER3d cells shortened sleep bouts, suggesting a key role in sleep maintenance. While sleep-promoting drivers from our miniscreen label overlapping ER3m neurons, intersectional strategies cannot rule out sleep regulatory roles for additional neurons in their expression patterns. Suppressing GABA synthesis in ER3m neurons prevents post-injury sleep, and GABAergic ER3d cells are required for thermogenetically induced wakefulness. Finally, we use an activity-dependent fluorescent reporter for putative synaptic contacts to embed these neurons within the known sleep-regulatory network. ER3m and ER3d neurons may receive connections from wake-active Helicon/ExR1 cells, and ER3m neurons likely inhibit ER3d neurons. Together, these data suggest a neural mechanism by which previously uncharacterized circuit elements stabilize sleep-wake states.Significance StatementNeural circuits that control sleep must be stable to ensure therapeutic rest but readily adaptable to a variety of experiences. The Drosophila ellipsoid body (EB) regulates many cognitive processes, and recent studies show that certain EB neurons can intensify sleepiness, but the contributions of other EB neuron subclasses in sleep regulation remain unclear. Thus, we searched for sleep-regulatory neurons across the EB to better understand sleep control. Our studies indicate that ER3d neurons promote wakefulness by reducing the persistence of sleep episodes and suggest that ER3m neuron activity may increase sleep. Understanding the stability and flexibility of sleep, then, may emerge from investigating the connectivity and conductivity of sleep-regulatory neurons in the EB.

Continuous home cage monitoring of activity and sleep in mice during repeated paroxetine treatment and discontinuation.

Non-invasive home cage monitoring is emerging as a valuable tool to assess the effects of experimental interventions on mouse behaviour. A field in which these techniques may prove useful is the study of repeated selective serotonin reuptake inhibitor (SSRI) treatment and discontinuation. SSRI discontinuation syndrome is an under-researched condition that includes the emergence of sleep disturbances following treatment cessation. We used passive infrared (PIR) monitoring to investigate changes in activity, sleep, and circadian rhythms during repeated treatment with the SSRI paroxetine and its discontinuation in mice. Male mice received paroxetine (10mg/kg/day, s.c.) for 12days, then were swapped to saline injections for a 13day discontinuation period and compared to mice that received saline injections throughout. Mice were continuously tracked using the Continuous Open Mouse Phenotyping of Activity and Sleep Status (COMPASS) system. Repeated paroxetine treatment reduced activity and increased behaviourally-defined sleep in the dark phase. These effects recovered to saline-control levels within 24h of paroxetine cessation, yet there was also evidence of a lengthening of sleep bouts in the dark phase for up to a week following discontinuation. This study provides the first example of how continuous non-invasive home cage monitoring can be used to detect objective behavioural changes in activity and sleep during and after drug treatment in mice. These data suggest that effects of paroxetine administration reversed soon after its discontinuation but identified an emergent change in sleep bout duration, which could be used as a biomarker in future preclinical studies to prevent or minimise SSRI discontinuation symptoms.

High-fat diet-induced dopaminergic dysregulation induces REM sleep fragmentation and ADHD-like behaviors

Consumption of a high-fat diet (HFD) has been associated with reduced wakefulness and various behavioral deficits, including anxiety, depression, and anhedonia. The dopaminergic system, which plays a crucial role in sleep and ADHD, is known to be vulnerable to chronic HFD. However, the association between HFD-induced behavioral and molecular changes remains unclear. Therefore, we investigated the effects of a HFD on the dopaminergic system and its association with behavioral deficits in male mice. The mice were divided into normal diet and HFD groups and were analyzed for sleep patterns, behavior tests, and transcription levels of dopamine-related genes in the brain. The HFD group showed decreased wakefulness, increased REM sleep with fragmented patterns, decreased time spent in the center zone of the open field test, shorter immobile time in the tail suspension test, impaired visuospatial memory, and reduced sucrose preference. Additionally, the HFD group had decreased mRNA levels of D1R, COMT, and DAT in the nucleus accumbens, which negatively correlated with REM sleep proportion and REM sleep bout count. The results suggest that HFD-induced behavioral deficits were resemblance to ADHD-like behavioral phenotypes and disturbs REM sleep by dysregulating the dopaminergic system.

Actigraphy sleep patterns in presymptomatic Alzheimer’s Disease: the potential role of neuroinflammation

AbstractBackgroundBoth short and long sleep duration have been associated with increased risk of developing Alzheimer’s Disease (AD). While short sleep has been hypothesized to be a risk factor promoting neurodegenerative processes. Long sleep has been viewed as a marker of ongoing neurodegeneration, potentially as a result of neuroinflammation. The objective of the study is to evaluate sleep patterns measured with actigraphy close to expected symptom onset in association with neuroinflammatory biomarkers. We leveraged the PREVENT‐AD cohort in which participants with a parental history of sporadic AD are studied before clinical onset.Method203 participants (age: 68.5±5.4 years, 151 women) free of dementia were tested with a week of actigraphy. Nighttime sleep duration, time in bed, sleep latency, sleep efficiency, and number of sleep bouts were calculated using the Actiware scoring algorithm (medium threshold). The standard deviation of these characteristics was calculated across actigraphy days to assess day‐to‐day variability. Years to expected onset was calculated by the number of years remaining before the age of clinical onset of a parent, or the earliest age of clinical onset if both parents developed AD. A subset of 100 participants underwent a lumbar puncture, and IL‐6 and MCP‐1 levels were assessed using OLINK technology in cerebrospinal fluid (CSF). The association between sleep characteristics, years to expected onset and inflammatory markers was assessed using linear regressions adjusted for age, sex, and time interval between measurements.ResultBeing closer to expected onset was associated with longer nighttime sleep duration (b = ‐0.19, p = 0.015) and lower sleep bouts day‐to‐day variability (b = 0.17, p = 0.027). Higher CSF IL‐6 was associated with longer sleep duration and time in bed (b = 0.30, p = 0.006; b = 0.24, p = 0.028), whereas higher MCP‐1 was associated with longer nighttime sleep duration (b = 0.25, p = 0.019). Higher CSF MCP‐1 levels were associated with lower sleep bouts day‐to‐day variability and shorter sleep onset latency only in those within 10 years of expected onset (interaction p = 0.012 and 0.061; b = ‐0.31, p = 0.043; b = ‐0.31, p = 0.047).ConclusionProximity to parental onset of sporadic AD onset was associated with a longer sleep profile that is more consolidated and stable, which may be due to proinflammatory processes.