Altered sleep regulation in leptin-deficient mice

Recent epidemiological, clinical, and experimental studies have demonstrated important links between sleep duration and architecture, circadian rhythms, and metabolism, although the genetic pathways that interconnect these processes are not well understood. Leptin is a circulating hormone and major adiposity signal involved in long-term energy homeostasis. In this study, we tested the hypothesis that leptin deficiency leads to impairments in sleep-wake regulation. Male ob/ob mice, a genetic model of leptin deficiency, had significantly disrupted sleep architecture with an elevated number of arousals from sleep [wild-type (WT) mice, 108.2 ± 7.2 vs. ob/ob mice, 148.4 ± 4.5, P < 0.001] and increased stage shifts (WT, 519.1 ± 25.2 vs. ob/ob, 748.0 ± 38.8, P < 0.001) compared with WT mice. Ob/ob mice also had more frequent, but shorter-lasting sleep bouts compared with WT mice, indicating impaired sleep consolidation. Interestingly, ob/ob mice showed changes in sleep time, with increased amounts of 24-h non-rapid eye movement (NREM) sleep (WT, 601.5 ± 10.8 vs. ob/ob, 669.2 ± 13.4 min, P < 0.001). Ob/ob mice had overall lower body temperature (WT, 35.1 ± 0.2 vs. ob/ob, 33.4 ± 0.2°C, P < 0.001) and locomotor activity counts (WT, 25125 ± 2137 vs. ob/ob, 5219 ± 1759, P < 0.001). Ob/ob mice displayed an attenuated diurnal rhythm of sleep-wake stages, NREM delta power, and locomotor activity. Following sleep deprivation, ob/ob mice had smaller amounts of NREM and REM recovery sleep, both in terms of the magnitude and the duration of the recovery response. In combination, these results indicate that leptin deficiency disrupts the regulation of sleep architecture and diurnal rhythmicity.

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Sleep-wake regulation is altered in leptin-resistant (db/db) genetically obese and diabetic mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00026.2008 ◽

2008 ◽

Vol 295 (6) ◽

pp. R2059-R2066 ◽

Cited By ~ 79

Author(s):

A. D. Laposky ◽

M. A. Bradley ◽

D. L. Williams ◽

J. Bass ◽

F. W. Turek

Keyword(s):

Energy Metabolism ◽

Eye Movement ◽

Energy Homeostasis ◽

Leptin Receptor ◽

Sleep Time ◽

Rapid Eye Movement ◽

Sleep Regulation ◽

Compensatory Response ◽

Leptin Signaling ◽

Obesity And Diabetes

Recent epidemiological and clinical studies indicate that the control of sleep-wake states may be an important factor in the regulation of energy metabolism. Leptin is a peripherally synthesized hormone that has critical signaling properties in the brain for the control of long-term energy homeostasis. In this study, we examined the hypothesis that leptin signaling exerts a role in sleep-wake regulation and that leptin may represent an important mechanistic link in the coordination of sleep-wake states and metabolism. Sleep-wake patterns were recorded in a genetic mouse model of obesity and diabetes, the db/db mouse, which harbors a mutation in a particular isoform of the leptin receptor (long form, LRb). We found that db/db mice exhibit a variety of alterations in sleep regulation, including an increase in overall sleep time, a dramatic increase in sleep fragmentation, attenuated diurnal rhythmicity in rapid eye movement sleep and non-rapid eye movement EEG delta power (a measure of sleep homeostatic drive), and a decrease in the compensatory response to acute (i.e., 6 h) sleep deprivation. The db/db mice also generated low amounts of locomotor activity and a reduction in the diurnal rhythm of activity. These results indicate that impaired leptin signaling has deleterious effects on the regulation of sleep amount, sleep architecture, and temporal consolidation of these arousal states. In summary, leptin may represent an important molecular component in the integration of sleep, circadian rhythms, and energy metabolism.

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Time course of EEG power density during long sleep in humans

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1990.258.3.r650 ◽

1990 ◽

Vol 258 (3) ◽

pp. R650-R661 ◽

Cited By ~ 10

Author(s):

D. J. Dijk ◽

D. P. Brunner ◽

A. A. Borbely

Keyword(s):

Slow Wave ◽

Process Model ◽

Time Course ◽

Slow Wave Sleep ◽

Nrem Sleep ◽

Sleep Stages ◽

Base Line ◽

Sleep Regulation ◽

Recovery Sleep ◽

Electroencephalogram Eeg

In nine subjects sleep was recorded under base-line conditions with a habitual bedtime (prior wakefulness 16 h; lights off at 2300 h) and during recovery from sleep deprivation with a phase-advanced bedtime (prior wakefulness 36 h; lights off at 1900 h). The duration of phase-advanced recovery sleep was greater than 12 h in all subjects. Spectral analysis of the sleep electroencephalogram (EEG) revealed that slow-wave activity (SWA; 0.75-4.5 Hz) in non-rapid-eye-movement (NREM) sleep was significantly enhanced during the first two NREM-REM sleep cycles of displaced recovery sleep. The sleep stages 3 and 4 (slow-wave sleep) and SWA decreased monotonically over the first three and four NREM-REM cycles of, respectively, base-line and recovery sleep. The time course of SWA in base-line and recovery sleep could be adequately described by an exponentially declining function with a horizontal asymptote. The results are in accordance with the two-process model of sleep regulation in which it is assumed that SWA rises as a function of the duration of prior wakefulness and decreases exponentially as a function of prior sleep. We conclude that the present data do not provide evidence for a 12.5-h sleep-dependent rhythm of deep NREM sleep.

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The role of adenosine in the maturation of sleep homeostasis in rats

Journal of Neurophysiology ◽

10.1152/jn.00675.2016 ◽

2017 ◽

Vol 117 (1) ◽

pp. 327-335 ◽

Cited By ~ 5

Author(s):

Irma Gvilia ◽

Natalia Suntsova ◽

Andrey Kostin ◽

Anna Kalinchuk ◽

Dennis McGinty ◽

...

Keyword(s):

Sleep Deprivation ◽

Sleep Time ◽

Saline Control ◽

Central Administration ◽

Sleep Regulation ◽

Recovery Sleep ◽

Discharge Rates ◽

Sleep Homeostasis ◽

Underlying Mechanisms ◽

The Brain

Sleep homeostasis in rats undergoes significant maturational changes during postweaning development, but the underlying mechanisms of this process are unknown. In the present study we tested the hypothesis that the maturation of sleep is related to the functional emergence of adenosine (AD) signaling in the brain. We assessed postweaning changes in 1) wake-related elevation of extracellular AD in the basal forebrain (BF) and adjacent lateral preoptic area (LPO), and 2) the responsiveness of median preoptic nucleus (MnPO) sleep-active cells to increasing homeostatic sleep drive. We tested the ability of exogenous AD to augment homeostatic responses to sleep deprivation (SD) in newly weaned rats. In groups of postnatal day (P)22 and P30 rats, we collected dialysate from the BF/LPO during baseline (BSL) wake-sleep, SD, and recovery sleep (RS). HPLC analysis of microdialysis samples revealed that SD in P30 rats results in significant increases in AD levels compared with BSL. P22 rats do not exhibit changes in AD levels in response to SD. We recorded neuronal activity in the MnPO during BSL, SD, and RS at P22/P30. MnPO neurons exhibited adult-like increases in waking neuronal discharge across SD on both P22 and P30, but discharge rates during enforced wake were higher on P30 vs. P22. Central administration of AD (1 nmol) during SD on P22 resulted in increased sleep time and EEG slow-wave activity during RS compared with saline control. Collectively, these findings support the hypothesis that functional reorganization of an adenosinergic mechanism of sleep regulation contributes to the maturation of sleep homeostasis. NEW & NOTEWORTHY Brain mechanisms that regulate the maturation of sleep are understudied. The present study generated first evidence about a potential mechanistic role for adenosine in the maturation of sleep homeostasis. Specifically, we demonstrate that early postweaning development in rats, when homeostatic response to sleep loss become adult like, is characterized by maturational changes in wake-related production/release of adenosine in the brain. Pharmacologically increased adenosine signaling in developing brain facilitates homeostatic responses to sleep deprivation.

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Maturation of sleep homeostasis in developing rats: a role for preoptic area neurons

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00727.2010 ◽

2011 ◽

Vol 300 (4) ◽

pp. R885-R894 ◽

Cited By ~ 14

Author(s):

Irma Gvilia ◽

Natalia Suntsova ◽

Bryan Angara ◽

Dennis McGinty ◽

Ronald Szymusiak

Keyword(s):

Preoptic Area ◽

Nrem Sleep ◽

Sleep Time ◽

Acid Decarboxylase ◽

Dark Phase ◽

Experimental Conditions ◽

Recovery Sleep ◽

Cell Counts ◽

State Dependent ◽

Sleep Homeostasis

The present study evaluated the hypothesis that developmental changes in hypothalamic sleep-regulatory neuronal circuits contribute to the maturation of sleep homeostasis in rats during the fourth postnatal week. In a longitudinal study, we quantified electrographic measures of sleep during baseline and in response to sleep deprivation (SD) on postnatal days 21/29 (P21/29) and P22/30 ( experiment 1). During 24-h baseline recordings on P21, total sleep time (TST) during the light and dark phases did not differ significantly. On P29, TST during the light phase was significantly higher than during the dark phase. Mean duration of non-rapid-eye-movement (NREM) sleep bouts was significantly longer on P29 vs. P21, indicating improved sleep consolidation. On both P22 and P30, rats exhibited increased NREM sleep amounts and NREM electroencephalogram delta power during recovery sleep (RS) compared with baseline. Increased NREM sleep bout length during RS was observed only on P30. In experiment 2, we quantified activity of GABAergic neurons in median preoptic nucleus (MnPN) and ventrolateral preoptic area (VLPO) during SD and RS in separate groups of P22 and P30 rats using c-Fos and glutamic acid decarboxylase (GAD) immunohistochemistry. In P22 rats, numbers of Fos+GAD+ neurons in VLPO did not differ among experimental conditions. In P30 rats, Fos+GAD+ counts in VLPO were elevated during RS. MnPN neuronal activity was state-dependent in P22 rats, but Fos+GAD+ cell counts were higher in P30 rats. These findings support the hypothesis that functional emergence of preoptic sleep-regulatory neurons contributes to the maturation of sleep homeostasis in the developing rat brain.

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Sleep maturation influences cognitive development of preterm toddlers

Scientific Reports ◽

10.1038/s41598-021-95495-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Akiko Ando ◽

Hidenobu Ohta ◽

Yuko Yoshimura ◽

Machiko Nakagawa ◽

Yoko Asaka ◽

...

Keyword(s):

Cognitive Development ◽

Sleep Duration ◽

Sleep Time ◽

Brain Maturation ◽

Sleep Diary ◽

Sleep Regulation ◽

Wake Time ◽

Daytime Nap ◽

Nighttime Sleep ◽

The Relationship

AbstractOur recent study on full-term toddlers demonstrated that daytime nap properties affect the distribution ratio between nap and nighttime sleep duration in total sleep time but does not affect the overall total amount of daily sleep time. However, there is still no clear scientific consensus as to whether the ratio between naps and nighttime sleep or just daily total sleep duration itself is more important for healthy child development. In the current study, to gain an answer to this question, we examined the relationship between the sleep properties and the cognitive development of toddlers born prematurely using actigraphy and the Kyoto scale of psychological development (KSPD) test. 101 premature toddlers of approximately 1.5 years of age were recruited for the study. Actigraphy units were attached to their waist with an adjustable elastic belt for 7 consecutive days and a child sleep diary was completed by their parents. In the study, we found no significant correlation between either nap or nighttime sleep duration and cognitive development of the preterm toddlers. In contrast, we found that stable daily wake time was significantly associated with better cognitive development, suggesting that sleep regulation may contribute to the brain maturation of preterm toddlers.

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072 Sleep Spindle Harmonics in Insomnia

SLEEP ◽

10.1093/sleep/zsab072.071 ◽

2021 ◽

Vol 44 (Supplement_2) ◽

pp. A29-A30

Author(s):

Michael Goldstein ◽

Monika Haack ◽

Janet Mullington

Keyword(s):

Spectral Power ◽

Nrem Sleep ◽

Sleep Time ◽

Sleep Spindle ◽

Time Frequency ◽

Insomnia Disorder ◽

Spectral Peaks ◽

Limited Application ◽

Thalamic Relay Nuclei ◽

Restorative Sleep

Abstract Introduction Prior research has reported NREM spectral EEG differences between individuals with insomnia and good-sleeper controls, including elevated high-frequency EEG power (beta/gamma bands, ~16-50Hz) and, to a lesser extent, elevations in sleep spindle parameters. However, the mechanisms driving these differences remain unclear. Harmonics have been observed in EEG data as spectral peaks at multiples of a fundamental frequency associated with an event (e.g., for a 14Hz spindle, the 2nd harmonic is expected to be a peak at 28Hz). Thus far, there has been very limited application of this idea of spectral harmonics to sleep spindles, even though these patterns can indeed be seen in some existing literature. We sought to build on this literature to apply spectral harmonic analysis to better understand differences between insomnia and good sleepers. Methods 15 individuals with insomnia disorder (DSM-5 criteria, 13 female, age 18–32 years) and 15 good-sleeper controls (matched for sex, age, and BMI) completed an overnight polysomnography recording in the laboratory and subsequent daytime testing. Insomnia diagnosis was determined by a board-certified sleep specialist, and exclusion criteria included psychiatric history within past 6 months, other sleep disorders, significant medical conditions, and medications with significant effects on inflammation, autonomic function, or other psychotropic effects. Results Consistent with prior studies, we found elevated sleep spindle density and fast sigma power (14-16Hz). Despite no difference in beta or gamma band power when averaged across NREM sleep, time-frequency analysis centered on the peaks of detected spindles revealed a phasic elevation in spectral power surrounding the 28Hz harmonic peak in the insomnia group, especially for spindles coupled with slow waves. We also observed an overall pattern of time-locked delay in the 28Hz harmonic peak, occurring approximately 40 msec after spindle peaks. Furthermore, we observed a 42Hz ‘3rd harmonic’ peak, not yet predicted by the existing modeling work, which was also elevated for insomnia. Conclusion In conjunction with existing mathematical modeling work that has linked sleep spindle harmonic peaks with thalamic relay nuclei as the primary generators of this EEG signature, these findings may enable novel insights into specific thalamocortical mechanisms of insomnia and non-restorative sleep. Support (if any) NIH 5T32HL007901-22

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Cellular Effects of Rhynchophylline and Relevance to Sleep Regulation

Clocks & Sleep ◽

10.3390/clockssleep3020020 ◽

2021 ◽

Vol 3 (2) ◽

pp. 312-341

Author(s):

Maria Neus Ballester Roig ◽

Tanya Leduc ◽

Cassandra C. Areal ◽

Valérie Mongrain

Keyword(s):

Sleep Time ◽

Sleep Regulation ◽

Neuronal Communication ◽

Cellular Effects ◽

Pathological Conditions ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Cellular Pathways ◽

Phosphoinositide 3 Kinase ◽

Protein Kinase Akt

Uncaria rhynchophylla is a plant highly used in the traditional Chinese and Japanese medicines. It has numerous health benefits, which are often attributed to its alkaloid components. Recent studies in humans show that drugs containing Uncaria ameliorate sleep quality and increase sleep time, both in physiological and pathological conditions. Rhynchophylline (Rhy) is one of the principal alkaloids in Uncaria species. Although treatment with Rhy alone has not been tested in humans, observations in rodents show that Rhy increases sleep time. However, the mechanisms by which Rhy could modulate sleep have not been comprehensively described. In this review, we are highlighting cellular pathways that are shown to be targeted by Rhy and which are also known for their implications in the regulation of wakefulness and sleep. We conclude that Rhy can impact sleep through mechanisms involving ion channels, N-methyl-d-aspartate (NMDA) receptors, tyrosine kinase receptors, extracellular signal-regulated kinases (ERK)/mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinase (PI3K)/RAC serine/threonine-protein kinase (AKT), and nuclear factor-kappa B (NF-κB) pathways. In modulating multiple cellular responses, Rhy impacts neuronal communication in a way that could have substantial effects on sleep phenotypes. Thus, understanding the mechanisms of action of Rhy will have implications for sleep pharmacology.

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250 AI-Supported Sleep Staging from Activity and Heart Rate

SLEEP ◽

10.1093/sleep/zsab072.249 ◽

2021 ◽

Vol 44 (Supplement_2) ◽

pp. A101-A101

Author(s):

Samadrita Chowdhury ◽

TzuAn Song ◽

Richa Saxena ◽

Shaun Purcell ◽

Joyita Dutta

Keyword(s):

Heart Rate ◽

Network Architecture ◽

Class Imbalance ◽

Nrem Sleep ◽

Sleep Time ◽

Deep Sleep ◽

Sleep Staging ◽

Temporal Correlations ◽

Stage Classification ◽

Small Form Factor

Abstract Introduction Polysomnography (PSG) is considered the gold standard for sleep staging but is labor-intensive and expensive. Wrist wearables are an alternative to PSG because of their small form factor and continuous monitoring capability. In this work, we present a scheme to perform such automated sleep staging via deep learning in the MESA cohort validated against PSG. This scheme makes use of actigraphic activity counts and two coarse heart rate measures (only mean and standard deviation for 30-s sleep epochs) to perform multi-class sleep staging. Our method outperforms existing techniques in three-stage classification (i.e., wake, NREM, and REM) and is feasible for four-stage classification (i.e., wake, light, deep, and REM). Methods Our technique uses a combined convolutional neural network coupled and sequence-to-sequence network architecture to appropriate the temporal correlations in sleep toward classification. Supervised training with PSG stage labels for each sleep epoch as the target was performed. We used data from MESA participants randomly assigned to non-overlapping training (N=608) and validation (N=200) cohorts. The under-representation of deep sleep in the data leads to class imbalance which diminishes deep sleep prediction accuracy. To specifically address the class imbalance, we use a novel loss function that is minimized in the network training phase. Results Our network leads to accuracies of 78.66% and 72.46% for three-class and four-class sleep staging respectively. Our three-stage classifier is especially accurate at measuring NREM sleep time (predicted: 4.98 ± 1.26 hrs. vs. actual: 5.08 ± 0.98 hrs. from PSG). Similarly, our four-stage classifier leads to highly accurate estimates of light sleep time (predicted: 4.33 ± 1.20 hrs. vs. actual: 4.46 ± 1.04 hrs. from PSG) and deep sleep time (predicted: 0.62 ± 0.65 hrs. vs. actual: 0.63 ± 0.59 hrs. from PSG). Lastly, we demonstrate the feasibility of our method for sleep staging from Apple Watch-derived measurements. Conclusion This work demonstrates the viability of high-accuracy, automated multi-class sleep staging from actigraphy and coarse heart rate measures that are device-agnostic and therefore well suited for extraction from smartwatches and other consumer wrist wearables. Support (if any) This work was supported in part by the NIH grant 1R21AG068890-01 and the American Association for University Women.

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Sleep after arousal from hibernation is not homeostatically regulated

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1999.276.2.r522 ◽

1999 ◽

Vol 276 (2) ◽

pp. R522-R529 ◽

Cited By ~ 10

Author(s):

Jennie E. Larkin ◽

H. Craig Heller

Keyword(s):

Sleep Deprivation ◽

Brain Function ◽

Extended Period ◽

Nrem Sleep ◽

Wave Activity ◽

Ground Squirrels ◽

Recovery Sleep ◽

Sleep Homeostasis ◽

Homeostatic Response ◽

Periodic Arousals

Electroencephalographic slow-wave activity (SWA) in non-rapid eye movement (NREM) sleep is directly related to prior sleep/wake history, with high levels of SWA following extended periods of wake. Therefore, SWA has been thought to reflect the level of accumulated sleep need. The discovery that euthermic intervals between hibernation bouts are spent primarily in sleep and that this sleep is characterized by high and monotonically declining SWA has led to speculation that sleep homeostasis may play a fundamental role in the regulation of the timing of bouts of hibernation and periodic arousals to euthermia. It was proposed that because the SWA profile seen after arousal from hibernation is strikingly similar to what is seen in nonhibernating mammals after extended periods of wakefulness, that hibernating mammals may arouse from hibernation with significant accumulated sleep need. This sleep need may accumulate during hibernation because the low brain temperatures during hibernation may not be compatible with sleep restorative processes. In the present study, golden-mantled ground squirrels were sleep deprived during the first 4 h of interbout euthermia by injection of caffeine (20 mg/kg ip). We predicted that if the SWA peaks after bouts of hibernation reflected a homeostatic response to an accumulated sleep need, sleep deprivation should simply have displaced and possibly augmented the SWA to subsequent recovery sleep. Instead we found that after caffeine-induced sleep deprivation of animals just aroused from hibernation, the anticipated high SWA typical of recovery sleep did not occur. Similar results were found in a study that induced sleep deprivation by gentle handling (19). These findings indicate that the SWA peak immediately after hibernation does not represent homeostatic regulation of NREM sleep, as it normally does after prolonged wakefulness during euthermia, but instead may reflect some other neurological process in the recovery of brain function from an extended period at low temperature.

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