Sleep-wake Behavior Research Articles

Electrophysiological properties of melanin-concentrating hormone neuron subpopulations defined by anatomical localization and CART expression

IntroductionMelanin-concentrating hormone (MCH) neurons are essential regulators of energy and glucose homeostasis, sleep–wake behaviors, motivation, learning and memory. These neurons are anatomically distributed across the medial (MH) and lateral hypothalamus (LH), and the adjacent zona incerta (ZI), which may represent functional subgroups with distinct connectivity with different brain regions. Furthermore, MCH neurons can be classified according to co-expression of neuropeptides, such as cocaine and amphetamine- regulated transcript (CART).MethodsTo identify functional similarities and differences of MCH subpopulations, we characterized their intrinsic electrophysiological properties using whole cell current clamp recording on acute brain slices from male and female mice.ResultsMCH neurons were classified into subgroups according to their anatomical localization in three MCH-rich brain areas: MH, LH and ZI. Among the three brain regions, ZI MCH neurons were the least excitable while LH MCH neurons were the most excitable. Furthermore, grouping MCH neurons according to CART co-expression revealed that MCH/CART− cells are uniquely depolarized and excitable, and display H-currents. These MCH/CART− cells were mainly found in the LH, which may in part explain why LH MCH neurons are more excitable. While some sex differences were found, the majority of parameters investigated were not different.DiscussionOur results suggest that MCH/CART− cells are electrophysiologically distinct, whereas MCH/CART+ cells are largely similar despite their diffuse distribution in the hypothalamus. It is therefore a combination of intrinsic electrophysiological properties and neurochemical identities, in addition to anatomy and connectivity that are likely to be critical in defining functional subpopulations of MCH neurons.

Diurnal fluctuations of subthalamic nucleus local field potentials follow naturalistic sleep-wake behavior in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) may improve sleep dysfunction, a common non-motor symptom of Parkinson disease (PD). Improvement in motor symptoms correlates with DBS-suppressed local field potential (LFP) activity, particularly in the beta frequency (13 - 30 Hz). Although well-characterized in the short term, little is known about the innate progression of these oscillations across the sleep-wake cycle. We sought to characterize LFP fluctuations over several days and nights in the home setting in patients chronically treated with DBS. LFPs in the beta and alpha frequency range were recorded from the STN in 13 PD subjects (18 hemispheres) over 14.6 (interquartile range 4) days. Sleep and wake were determined by validated actigraphy. We calculated the mean difference between sleep and wakefulness in LFP power (µVp), probability density functions of normalized LFP, and the fraction of overlap between probability density histograms. STN LFPs showed a consistent fluctuation based on behavioral state. LFP power was higher during wakefulness than during sleep, with little overlap in the magnitude of LFP power between these two states. Delineation of subject activity patterns revealed that LFP variance by time of day was more strongly correlated at night. STN LFP fluctuations represent a useful measure to distinguish between sleep and wakefulness in PD. These fluctuations can be detected in the home setting using commercially available devices, including in patients who have been treated with DBS for years. This technology may lead to opportunities for closed-loop DBS therapy.

Phasic dopamine release in the nucleus accumbens influences REM sleep timing.

Based on the activity of dopamine (DA) neurons during behavioral states, the DA system has long been thought to be foundational in regulating sleep-wake behavior; over the past decade advances in circuit manipulation and recording techniques have strengthened this perspective. Recently, several studies have demonstrated that DA release in regions of the limbic system is important in the promotion of REM sleep. Yet how DA dynamics change within bouts of sleep, how these changes are regulated, and whether they influence future state changes remains unclear. To address these questions, in mice of both sexes we used in vivo fiber photometry and inhibitory optogenetics to identify a specific role of DA transients in the nucleus accumbens (NAcc) in state transitions from NREM sleep. We found that DA transients increase their frequency and amplitude over the duration of NREM sleep and that this increase is more pronounced during NREM bouts that transition into REM sleep. Next, we found that DA transients in NREM sleep are influenced by changes in REM sleep pressure. Finally, we show that transient DA release in the NAcc plays a functional role in regulating the timing of REM sleep entrances, as inhibition of midbrain DA neuron terminals in the NAcc prolonged bouts of NREM sleep and decreased the frequency of bouts of REM sleep. These findings demonstrate that DA release in the NAcc is dynamically regulated by sleep pressure and has a functional role in transitions from NREM sleep, particularly those into REM sleep.Significance Statement Sleep is a central component of daily life and is heavily influenced by midbrain dopamine neurons. Dopamine release in limbic regions, such as the nucleus accumbens, has been implicated in the promotion of REM sleep. However, dopamine release dynamics during sleep and how these influence future changes in state remain unclear. We used a fluorescence-based dopamine biosensor to elucidate the pattern of dopamine release during sleep and inhibitory optogenetics to disrupt dopamine release. Dopamine release increases across the duration of NREM sleep bouts and is sensitive to REM sleep need. Inhibition of dopamine terminals in the nucleus accumbens decreases the frequency of REM sleep. This suggests that phasic dopamine release during NREM sleep functionally influences REM sleep timing.

Compound 38, a novel potent and selective antagonist of adenosine A2A receptor, enhances arousal in mice.

Adenosine A2A receptor (A2AR) plays a pivotal role in the regulation of sleep-wake behaviors. We previously reported an A2AR selective antagonist compound 38 with an IC50 value of 29.0 nM. In this study, we investigated its effect on sleep-wake regulation in mice. Wild-type (WT) mice were administered compound 38 (3.3, 5.0, 7.5, 15, 30 mg/kg, i.p.) at 9:00, and electroencephalography and electromyography were simultaneously recorded. We showed that administration of compound 38 exhibited a dose-dependent effect on wakefulness promotion. To investigate the impact of compound 38 on sleeprebound, we conducted a 6 h (13:00-19:00) sleep deprivation experiment. We found that administration of compound 38 (30 mg/kg) produced a wakefulness-promoting effect lasting for 1 h. Subsequently, we explored the critical role of A2AR in the wakefulness-promoting effect of compound 38 using A2AR knockout (KO) mice and their WT littermates. We found that compound 38 enhanced wakefulness in WT mice, but did not have an arousal-promoting effect in A2AR KO mice, suggesting that the arousal-promoting effect of compound 38 was mediated by A2AR. We conducted immunohistochemistry and selectively ablated A2AR-positive neurons using cell type-specific caspase-3 expression, which revealed an essential role of A2AR-positive neurons in the nucleus accumbens shell for the arousal-promoting effect of compound 38. In conclusion, as a novel A2AR antagonist, compound 38 promotes wakefulness in mice via the A2AR and exhibits promising applications for further advancements in the field of sleep-wake disorders.

Involvement of the parabrachial nucleus in emergence from general anesthesia.

The parabrachial nucleus (PBN), located in the dorsolateral pons, is involved in many important biological functions, such as sensory signaling, feeding, defensive behaviors, fear, anxiety, and sleep-wake cycles. General anesthesia shares the classical feature of reversible loss of consciousness with natural sleep, and accumulating evidence has indicated that general anesthesia and sleep-wake behaviors share some common underlying neural mechanism. In recent years, emerging studies have investigated the involvement of PBN in emergence from general anesthesia, but divergence exists in terms of different types of general anesthetics or different durations of treatment with the same group of general anesthetics. Here, we reviewed the current literature and summarized the evidence about the contribution of PBN to general anesthesia.

Adenosine-Dependent Arousal Induced by Astrocytes in a Brainstem Circuit.

Astrocytes play a crucial role in regulating sleep-wake behavior. However, how astrocytes govern a specific sleep-arousal circuit remains unknown. Here, the authors show that parafacial zone (PZ) astrocytes responded to sleep-wake cycles with state-differential Ca2+ activity, peaking during transitions from sleep to wakefulness. Using chemogenetic and optogenetic approaches, they find that activating PZ astrocytes elicited and sustained wakefulness by prolonging arousal episodes while impeding transitions from wakefulness to non-rapid eye movement (NREM) sleep. Activation of PZ astrocytes specially induced the elevation of extracellular adenosine through the ATP hydrolysis pathway but not equilibrative nucleoside transporter (ENT) mediated transportation. Strikingly, the rise in adenosine levels induced arousal by activating A1 receptors, suggesting a distinct role for adenosine in the PZ beyond its conventional sleep homeostasis modulation observed in the basal forebrain (BF) and cortex. Moreover, at the circuit level, PZ astrocyte activation induced arousal by suppressing the GABA release from the PZGABA neurons, which promote NREM sleep and project to the parabrachial nucleus (PB). Thus, their study unveils a distinctive arousal-promoting effect of astrocytes within the PZ through extracellular adenosine and elucidates the underlying mechanism at the neural circuit level.

Regulation of wakefulness by neurotensin neurons in the lateral hypothalamus

The lateral hypothalamic region (LH) has been identified as a key region for arousal regulation, yet the specific cell types and underlying mechanisms are not fully understood. While neurons expressing orexins (OX) are considered the primary wake-promoting population in the LH, their loss does not reduce daily wake levels, suggesting the presence of additional wake-promoting populations. In this regard, we recently discovered that a non-OX cell group in the LH, marked by the expression of neurotensin (Nts), could powerfully drive wakefulness. Activation of these NtsLH neurons elicits rapid arousal from non-rapid eye movement (NREM) sleep and produces uninterrupted wakefulness for several hours in mice. However, it remains unknown if these neurons are necessary for spontaneous wakefulness and what their precise role is in the initiation and maintenance of this state. To address these questions, we first examined the activity dynamics of the NtsLH population across sleep-wake behavior using fiber photometry. We find that NtsLH neurons are more active during wakefulness, and their activity increases concurrently with, but does not precede, wake-onset. We then selectively destroyed the NtsLH neurons using a diphtheria-toxin-based conditional ablation method, which significantly reduced wake amounts and mean duration of wake bouts and increased the EEG delta power during wakefulness. These findings demonstrate a crucial role for NtsLH neurons in maintaining normal arousal levels, and their loss may be associated with chronic sleepiness in mice.

GABAergic neurons in the central amygdala promote emergence from isoflurane anesthesia in mice.

Recent evidence indicates that general anesthesia and sleep-wake behavior share some overlapping neural substrates. GABAergic neurons in the central amygdala (CeA) have a high firing rate during wakefulness and play a role in regulating arousal-related behaviors. The objective of this study is to investigate whether CeA GABAergic neurons participate in the regulation of isoflurane general anesthesia and uncover the underlying neural circuitry. Fiber photometry recording was used to determine the changes in calcium signals of CeA GABAergic neurons during isoflurane anesthesia in Vgat-Cre mice. Chemogenetic and optogenetic approaches were used to manipulate the activity of CeA GABAergic neurons, and a righting reflex test was used to determine the induction and emergence from isoflurane anesthesia. Cortical electroencephalogram (EEG) recording was used to assess the changes in EEG spectral power and burst-suppression ratio during 0.8% and 1.4% isoflurane anesthesia, respectively. Both male and female mice were used in this study. The calcium signals of CeA GABAergic neurons decreased during the induction of isoflurane anesthesia and was restored during the emergence. Chemogenetic activation of CeA GABAergic neurons delayed induction time (mean ± SD, vehicle vs. clozapine-N-oxide: 58.75±5.42 s vs. 67.63±5.01 s; n=8, P=0.0017) and shortened emergence time (385.50±66.26 s vs. 214.60±40.21 s; n=8, P=0.0017) from isoflurane anesthesia. Optogenetic activation of CeA GABAergic neurons produced a similar effect. Furthermore, optogenetic activation decreased EEG delta power (Pre-stim vs. Stim: 46.63%±4.40% vs. 34.16%±6.47%; n=8, P=0.0195) and burst-suppression ratio (83.39%±5.15% vs. 52.60%±12.98%; n=8, P=0.0002). Moreover, optogenetic stimulation of terminals of CeA GABAergic neurons in the basal forebrain (BF) also promoted cortical activation and accelerated behavioral emergence from isoflurane anesthesia. Our results suggest that CeA GABAergic neurons play a role in general anesthesia regulation, which facilitates behavioral and cortical emergence from isoflurane anesthesia through the GABAergic CeA-BF pathway.

A Longitudinal Examination between Chronotype and Insomnia in Youths: A Cross-Lagged Panel Analysis.

Adolescence and young adulthood are transitional periods associated with significant changes and challenges, leading to a heightened vulnerability to sleep disturbances and mental health difficulties. This stage is often associated with an increased preference for eveningness, manifested as a later chronotype. The current study aimed to investigate the directionality of the association between chronotype, based on an individual's sleep-wake behaviour, and insomnia in young people using a two-wave panel design with a 12-month interval. A total of 370 participants aged 15-24 (mean age: 21.0 ± 2.0, 72.7% female) were recruited from local secondary schools and universities. Insomnia symptoms were assessed using the Insomnia Severity Index, while chronotype was measured using the Munich Chronotype Questionnaire. Temporal associations were analysed using a series of cross-lagged panel models. The best fitting and most parsimonious model indicated that a later chronotype at baseline predicts more severe insomnia symptoms at the 12-month follow-up after accounting for autoregressive effects. However, the opposite causal model, where baseline insomnia symptoms predicted the chronotype at the 12-month follow-up, was not supported. These findings suggest that a late chronotype may be a potential risk factor for the development of insomnia in young people, emphasising the importance of considering circadian factors in the prevention and treatment of sleep disturbances among this population.

Cognitive correlates of circadian rhythm and sleep-wake behaviour in chronic obstructive pulmonary disease patients

ABSTRACT Chronic obstructive pulmonary disease (COPD) patients often experience reduced physical activity, sleep disturbances, and cognitive impairment. However, reports on measurement of rest-activity rhythm and sleep-wake behavior and their impact on cognitive functions in COPD patients are limited. This study aimed to objectively measure circadian rhythms (rest-activity and ambient illuminance) and sleep behaviors in clinically stable COPD patients and their relationship with cognitive functions. The study involved 65 male COPD patients and 50 age-matched controls, monitored over 3–7 days using actigraphy. Cognitive status was assessed using the Montreal Cognitive Assessment (MoCA) followed by short interbal time estimation via time production and reproduction with reaction time measurement using TimeProd software. Findings indicated significant disruptions in circadian rhythms in COPD patients, characterized by lower mesor, amplitude, and autocorrelation coefficients compared to controls. Patients also reported poorer sleep quality and higher sleep fragmentation, with 85.7% displaying cognitive impairment. Notably, longer time estimations, increased variability in task performance, and slower reaction times suggested cognitive deterioration. Positive correlations emerged between rhythm parameters (amplitude and circadian quotient) and cognitive performance metrics. This highlights the relevance of circadian and sleep disturbances in COPD, suggesting that addressing these rhythms could help mitigate cognitive decline, potentially through chronotherapeutic strategies.

Enhanced homeostatic sleep response and decreased neurodegenerative proteins in cereblon knock-out mice

Energy homeostasis and sleep have a bidirectional relationship. Cereblon (CRBN) regulates energy levels by ubiquitinating the AMP-activated protein kinase(AMPK), an energy sensor. However, whether CRBN participates in sleep is unclear. Here, we examine sleep–wake patterns in Crbn+/+ and Crbn−/− mice during 24-h baseline, 6-h sleep deprivation (SD), and following 6-h recovery sleep (RS). At baseline, overall sleep patterns are similar between genotypes. However, SD decreases CRBN expression in Crbn+/+ mice and increases phospho-Tau, phospho-α-synuclein, DNAJA1 (DJ2), and DNAJB1 (DJ1) in both genotypes, with Crbn−/− mice showing a lesser extent of increase in p-Tau and p-α-synuclein and a higher level of heat shock protein 70 (HSP70), DJ2, and DJ1. During RS, Crbn−/− mice show increased slow-wave activity in the low-delta range (0.5–2.5 Hz), suggesting higher homeostatic sleep propensity associated with AMPK hyperactivation. By illuminating the role of CRBN in regulating sleep–wake behaviors through AMPK, we suggest CRBN as a potential therapeutic target for managing sleep disorders and preventing neurodegeneration.

Melatonin Ameliorates Abnormal Sleep-Wake Behavior via Facilitating Lipid Metabolism in a Zebrafish Model of Parkinson's Disease.

Sleep-wake disorder is one of the most common nonmotor symptoms of Parkinson's disease (PD). Melatonin has the potential to improve sleep-wake disorder, but its mechanism of action is still unclear. Our data showed that melatonin only improved the motor and sleep-wake behavior of a zebrafish PD model when melatonin receptor 1 was present. Thus, we explored the underlying mechanisms by applying a rotenone model. After the PD zebrafish model was induced by 10 nmol/L rotenone, the motor and sleep-wake behavior were assessed. In situ hybridization and real-time quantitative PCR were used to detect the expression of melatonin receptors and lipid-metabolism-related genes. In the PD model, we found abnormal lipid metabolism, which was reversed by melatonin. This may be one of the main pathways for improving PD sleep-wake disorder.

Associations between real-life light exposure patterns and sleep behaviour in adolescents.

One of the most striking changes in the regulation of sleep-wake behaviour during adolescence is circadian phase delay. Light exposure synchronises circadian rhythms, impacting sleep regulation, however, the influence of real-life light exposure on sleep variations remains less clear. We aimed to describe the sleep and light exposure patterns of high school students with comparable schedules and socio-economic backgrounds, and to evaluate whether there was any association between them, considering chronotype. We analysed five school days and two free days of actigraphy records, from 35 adolescents (24 female, mean age: 16.23 ± 0.60). The sample was described using the Sleep Regularity Index (SRI), chronotype (actigraphy MSFsc), and self-reported diurnal preference (Morning/Evening Scale). Regression models were constructed to assess the impact of light exposure (daytime and nighttime) on subsequent sleep episodes; and to confirm whether the associations could be an indirect consequence of chronotype. Despite following similar routines, the SRI varied considerably (48.25 to 88.28). There was compatibility between the actigraphy proxy for chronotype and the self-reported diurnal preference, extracted using the circadian rhythm scale for adolescents. Less light exposure during the day was associated with later sleep onset and shorter sleep duration. An increase of 100 lux in average daytime light exposure advance of 8.08 minutes in sleep onset and 7.16 min in sleep offset. When the regressions were controlled for chronotype, these associations persisted. These findings facilitate discussions regarding the behavioural aspect of the impact of real-life light exposure on sleep and its potential as a target for interventions aiming to enhance adolescents' sleep quality.

Characterization of Chronotypes Using the Symbolic Aggregate apprXimation (SAX) on Actigraphy Data.

In this study, we discuss an efficient approach to characterizing chronotypes using Symbolic Aggregate approXimation (SAX) on actigraphy data. Actigraphy, a non-invasive monitoring of human rest/activity cycles, provides valuable insights into sleep-wake behaviors and circadian rhythms. However, the high dimensionality of actigraphy data poses significant challenges in storage, processing, and analysis. To address these challenges, we applied the SAX algorithm to transform continuous time-series actigraphy data into a symbolic representation, enabling dimensionality reduction while preserving essential patterns. We analyzed actigraphy data from the National Health and Nutrition Examination Survey (NHANES) database, covering over 10,000 individuals, and used unsupervised clustering to identify distinct chronotype patterns. The SAX transformation facilitated the application of machine learning techniques, revealing five chronotype clusters characterized by differences in activity onset, resolution, and intensity. Age distribution analysis showed biases towards specific age groups within the clusters, highlighting the relationship between age and chronotype. Key findings include age-related Chronotype variations with younger individuals exhibiting delayed chronotypes with significant differences in sleep onset (SOT) and wake time (WT) compared to older adults, suggesting a phase delay in sleep patterns as age decreases and activity transition dynamics where clusters showed distinct patterns in winding up and winding down periods, providing insights into the dynamics of activity transitions. This study demonstrates the efficiency and effectiveness of SAX in processing large-scale actigraphy data, enabling robust chronotype characterization that can inform personalized healthcare and public health initiatives. Further exploration of SAX integration with other biometric measures could deepen our understanding of human circadian biology and its impact on health and behavior.

Sleep deprivation and recovery: Endurance racing as a novel model.

The aim of this study was to investigate sleep-wake behavior and gain insights into perceived impairment (sleep, fatigue, and cognitive function) of athletes competing in two international multi-day adventure races. Twenty-four athletes took part across two independent adventure races: Queensland, Australia and Alaska, USA. Individual sleep periods were determined via actigraphy, and racers self-reported their perceived sleep disturbances, sleep impairment, fatigue and cognitive function. Each of these indices was calculated for pre-, during- and post-race periods. Sleep was severely restricted during the race period compared to pre-race (Queensland, 7:46 [0:29] vs. 2:50 [1:01]; Alaska, 7:39 [0:58] vs. 2:45 [2:05]; mean [SD], hh:mm). As a result, there was a large cumulative sleep debt at race completion, which was not 'reversed' in the post-race period (up to 1week). The deterioration in all four self-reported scales of perceived impairment during the race period was largely restored in the post-race period. This is the first study to document objective sleep-wake behaviors and subjective impairment of adventure racers, in the context of two geographically diverse, multi-day, international adventure races. Measures of sleep deprivation indicate that sleep debt was extreme and did not recover to pre-race levels within 1week following each race. Despite this objective debt continuing, perceived impairment returned to pre-race levels quickly post-race. Therefore, further examination of actual and perceived sleep recovery is warranted. Adventure racing presents a unique scenario to examine sleep, performance and recovery.

Sleep-wake behavior and responses to sleep deprivation and immune challenge of protein kinase RNA-activated knockout mice

Protein Kinase RNA-activated (PKR) is an enzyme that plays a role in many systemic processes, including modulation of inflammation, and is implicated in neurodegenerative diseases, such as Alzheimer’s disease (AD). PKR phosphorylation results in the production of several cytokines involved in the regulation / modulation of sleep, including interleukin-1β, tumor necrosis factor-α and interferon-γ. We hypothesized targeting PKR would alter spontaneous sleep of mice, attenuate responses to sleep deprivation, and inhibit responses to immune challenge. To test these hypotheses, we determined the sleep-wake phenotype of mice lacking PKR (knockout; PKR-/-) during undisturbed baseline conditions; in responses to six hours of sleep deprivation; and after immune challenge with lipopolysaccharide (LPS). Adult male mice (C57BL/6J, n = 7; PKR-/-, n = 7) were surgically instrumented with EEG recording electrodes and an intraperitoneal microchip to record core body temperature. During undisturbed baseline conditions, PKR -/- mice spent more time in non-rapid eye movement sleep (NREMS) and rapid-eye movement sleep (REMS), and less time awake at the beginning of the dark period of the light:dark cycle. Delta power during NREMS, a measure of sleep depth, was less in PKR-/- mice during the dark period, and core body temperatures were lower during the light period. Both mouse strains responded to sleep deprivation with increased NREMS and REMS, although these changes did not differ substantively between strains. The initial increase in delta power during NREMS after sleep deprivation was greater in PKR-/- mice, suggesting a faster buildup of sleep pressure with prolonged waking. Immune challenge with LPS increased NREMS and inhibited REMS to the same extent in both mouse strains, whereas the initial LPS-induced suppression of delta power during NREMS was greater in PKR-/- mice. Because sleep regulatory and immune responsive systems in brain are redundant and overlapping, other mediators and signaling pathways in addition to PKR are involved in the responses to acute sleep deprivation and LPS immune challenge.

Clinical and functional studies of MTOR variants in Smith-Kingsmore syndrome reveal deficits of circadian rhythm and sleep-wake behavior

Heterozygous de novo or inherited gain-of-function mutations in the MTOR gene cause Smith-Kingsmore syndrome (SKS). SKS is a rare autosomal dominant condition, and individuals with SKS display macrocephaly/megalencephaly, developmental delay, intellectual disability, and seizures. A few dozen individuals are reported in the literature. Here, we report a cohort of 28 individuals with SKS that represent nine MTOR pathogenic variants. We conducted a detailed natural history study and found pathophysiological deficits among individuals with SKS in addition to the common neurodevelopmental symptoms. These symptoms include sleep-wake disturbance, hyperphagia, and hyperactivity, indicative of homeostatic imbalance. To characterize these variants, we developed cell models and characterized their functional consequences. We showed that these SKS variants display a range of mechanistic target of rapamycin (mTOR) activities and respond to the mTOR inhibitor, rapamycin, differently. For example, the R1480_C1483del variant we identified here and the previously known C1483F are more active than wild-type controls and less responsive to rapamycin. Further, we showed that SKS mutations dampened circadian rhythms and low-dose rapamycin improved the rhythm amplitude, suggesting that optimal mTOR activity is required for normal circadian function. As SKS is caused by gain-of-function mutations in MTOR, rapamycin was used to treat several patients. While higher doses of rapamycin caused delayed sleep-wake phase disorder in a subset of patients, optimized lower doses improved sleep. Our study expands the clinical and molecular spectrum of SKS and supports further studies for mechanism-guided treatment options to improve sleep-wake behavior and overall health.

Restoration of sleep-wake behavior following short photoperiod exposure in ventral subicular lesioned male Wistar rats: A 24-h sleep-wake electroencephalographical study.

The ventral subiculum regulates emotion, stress responses, and spatial and social cognition. In our previous studies, we have demonstrated anxiety- and depression-like symptoms, deficits in spatial and social cognition in ventral subicular lesioned (VSL) rats, and restoration of affective and cognitive behaviors following photoperiod manipulation (short photoperiod regime, SPR; 6:18 LD cycle). In the present study, we have studied the impact of VSL on sleep-wake behavioral patterns and the effect of SPR on sleep-wakefulness behavior. Adult male Wistar rats subjected to VSL demonstrated decreased wake duration and enhanced total sleep time due to increased non-rapid eye movement sleep (NREMS) and rapid eye movement sleep (REMS). Power spectral analysis indicated increased delta activity during NREMS and decreased sigma band power during all vigilance states. Light is one of the strongest entrainers of the circadian rhythm, and its manipulation may have various physiological and functional consequences. We investigated the effect of 21-day exposure to SPR on sleep-wakefulness (S-W) behavior in VSL rats. We observed that SPR exposure restored S-W behavior in VSL rats, resulting in an increase in wake duration and a significant increase in theta power during wake and REMS. This study highlights the crucial role of the ventral subiculum in maintaining normal sleep-wakefulness patterns and highlights the effectiveness of photoperiod manipulation as a non-pharmacological treatment for reversing sleep disturbances reported in mood and neuropsychiatric disorders like Alzheimer's disease, bipolar disorder, and major depressive disorder, which also involve alterations in circadian rhythm.

Endocannabinoid agonist 2-arachidonoylglycerol differentially alters diurnal activity and sleep during fentanyl withdrawal in male and female mice

Fentanyl has become the leading driver of opioid overdoses in the United States. Cessation of opioid use represents a challenge as the experience of withdrawal drives subsequent relapse. One of the most prominent withdrawal symptoms that can contribute to opioid craving and vulnerability to relapse is sleep disruption. The endocannabinoid agonist, 2-Arachidonoylglycerol (2-AG), may promote sleep and reduce withdrawal severity; however, the effects of 2-AG on sleep disruption during opioid withdrawal have yet to be assessed. Here, we investigated the effects of 2-AG administration on sleep-wake behavior and diurnal activity in mice during withdrawal from fentanyl. Sleep-wake activity measured via actigraphy was continuously recorded before and after chronic fentanyl administration in both male and female C57BL/6J mice. Immediately following cessation of fentanyl administration, 2-AG was administered intraperitoneally to investigate the impact of endocannabinoid agonism on opioid-induced sleep disruption. We found that female mice maintained higher activity levels in response to chronic fentanyl than male mice. Furthermore, fentanyl administration increased wake and decreased sleep during the light period and inversely increased sleep and decreased wake in the dark period in both sexes. 2-AG treatment increased arousal and decreased sleep in both sexes during first 24-h of withdrawal. On withdrawal day 2, only females showed increased wakefulness with no changes in males, but by withdrawal day 3 male mice displayed decreased rapid-eye movement sleep during the dark period with no changes in female mice. Overall, repeated administration of fentanyl altered sleep and diurnal activity and administration of the endocannabinoid agonist, 2-AG, had sex-specific effects on fentanyl-induced sleep and diurnal changes.

Sleep-wake behaviors associated with cognitive performance in middle-aged participants of the Hispanic Community Health Study/Study of Latinos

ObjectivesMany sleep-wake behaviors have been associated with cognition. We examined a panel of sleep-wake/activity characteristics to determine which are most robustly related to having low cognitive performance in midlife. Secondarily, we evaluate the predictive utility of sleep-wake measures to screen for low cognitive performance. MethodsThe outcome was low cognitive performance defined as being >1 standard deviation below average age/sex/education internally normalized composite cognitive performance levels assessed in the Hispanic Community Health Study/Study of Latinos. Analyses included 1006 individuals who had sufficient sleep-wake measurements about 2years later (mean age=54.9, standard deviation= 5.1; 68.82% female). We evaluated associations of 31 sleep-wake variables with low cognitive performance using separate logistic regressions. ResultsIn individual models, the strongest sleep-wake correlates of low cognitive performance were measures of weaker and unstable 24-hour rhythms; greater 24-hour fragmentation; longer time-in-bed; and lower rhythm amplitude. One standard deviation worse on these sleep-wake factors was associated with ∼20%-30% greater odds of having low cognitive performance. In an internally cross-validated prediction model, the independent correlates of low cognitive performance were: lower Sleep Regularity Index scores; lower pseudo-F statistics (modellability of 24-hour rhythms); lower activity rhythm amplitude; and greater time in bed. Area under the curve was low/moderate (64%) indicating poor predictive utility. ConclusionThe strongest sleep-wake behavioral correlates of low cognitive performance were measures of longer time-in-bed and irregular/weak rhythms. These sleep-wake assessments were not useful to identify previous low cognitive performance. Given their potential modifiability, experimental trials could test if targeting midlife time-in-bed and/or irregular rhythms influences cognition.