AANAT1 functions in astrocytes to regulate sleep homeostasis

How the brain controls the need and acquisition of recovery sleep after prolonged wakefulness is an important issue in sleep research. The monoamines serotonin and dopamine are key regulators of sleep in mammals and in Drosophila. We found that the enzyme arylalkylamine N-acetyltransferase 1 (AANAT1) is expressed by Drosophila astrocytes and specific subsets of neurons in the adult brain. AANAT1 acetylates monoamines and inactivates them, and we found that AANAT1 limited the accumulation of serotonin and dopamine in the brain upon sleep deprivation (SD). Loss of AANAT1 from astrocytes, but not from neurons, caused flies to increase their daytime recovery sleep following overnight SD. Together, these findings demonstrate a crucial role for AANAT1 and astrocytes in the regulation of monoamine bioavailability and homeostatic 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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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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008 ARC Genotype Modulates Slow Wave Sleep Following Total Sleep Deprivation

SLEEP ◽

10.1093/sleep/zsab072.007 ◽

2021 ◽

Vol 44 (Supplement_2) ◽

pp. A4-A4

Author(s):

Brieann Satterfield ◽

Darian Lawrence-Sidebottom ◽

Michelle Schmidt ◽

Jonathan Wisor ◽

Hans Van Dongen

Keyword(s):

Individual Differences ◽

Sleep Deprivation ◽

Slow Wave ◽

Molecular Mechanisms ◽

Slow Wave Sleep ◽

Early Gene ◽

Total Sleep Deprivation ◽

Recovery Sleep ◽

Sleep Homeostasis ◽

Arc Gene

Abstract Introduction The activity-regulated cytoskeleton associated protein (ARC) gene is an immediate early gene that is involved in synaptic plasticity. Recent evidence from a rodent model suggests that Arc may also be involved in sleep homeostasis. However, little is known about the molecular mechanisms regulating the sleep homeostat. In humans, sleep homeostasis is manifested by a marked increase in slow wave sleep (SWS) following acute total sleep deprivation (TSD). There are large, trait individual differences in the magnitude of this SWS rebound effect. We sought to determine whether a single nucleotide polymorphism (SNP) of the ARC gene is associated with individual differences in SWS rebound following TSD. Methods 64 healthy normal sleepers (ages 27.2 ± 4.8y; 32 females) participated in one of two in-laboratory TSD studies. In each study, subjects had a baseline day with 10h sleep opportunity (TIB 22:00–08:00) which was followed by 38h TSD. The studies concluded with 10h recovery sleep opportunity (TIB 22:00–08:00). Baseline and recovery sleep were recorded polysomnographically and scored visually by a trained technician. Genomic DNA was extracted from whole blood. The ARC c.*742 + 58C>T non-coding SNP, rs35900184, was assayed using real-time PCR. Heterozygotes and T/T homozygotes were combined for analysis. The genotype effect on time in SWS was assessed using mixed-effects ANOVA with fixed effects for ARC genotype (C/C vs. T carriers), night (baseline vs. recovery), and their interaction, controlling for study. Results The genotype distribution in this sample – C/C: 41; C/T: 17; T/T: 6 – did not vary significantly from Hardy-Weinberg equilibrium. There was a significant interaction between ARC genotype and night (F1,62=7.27, p=0.009). Following TSD, T allele carriers exhibited 47.6min more SWS compared to baseline, whereas C/C homozygotes exhibited 62.3min more SWS compared to baseline. There was no significant difference in SWS between genotypes at baseline (F1,61=0.69, p=0.41). Conclusion ARC T allele carriers exhibited an attenuated SWS rebound following TSD compared to those homozygous for the C allele. This suggests that the ARC SNP is associated with trait individual differences related to sleep homeostasis, and may thus influence molecular mechanisms involved in long-term memory. Support (if any) ONR N00014-13-1-0302, NIH R21CA167691, and USAMRDC W81XWH-18-1-0100.

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Galanin neurons in the hypothalamus link sleep homeostasis, body temperature and actions of the α2 adrenergic agonist dexmedetomidine

10.1101/565747 ◽

2019 ◽

Cited By ~ 1

Author(s):

Ying Ma ◽

Giulia Miracca ◽

Xiao Yu ◽

Edward C. Harding ◽

Andawei Miao ◽

...

Keyword(s):

Body Temperature ◽

Sleep Deprivation ◽

Core Body Temperature ◽

Neuronal Cell ◽

Nrem Sleep ◽

Temperature Characteristic ◽

Adrenergic Agonist ◽

Delta Power ◽

Recovery Sleep ◽

Sleep Homeostasis

AbstractSleep deprivation induces a characteristic rebound in NREM sleep accompanied by an immediate increase in the power of delta (0.5 - 4 Hz) oscillations, proportional to the prior time awake. To test the idea that galanin neurons in the mouse lateral preoptic hypothalamus (LPO) regulate this sleep homeostasis, they were selectively genetically ablated. The baseline sleep architecture of LPO-ΔGal mice became heavily fragmented, their average core body temperature permanently increased (by about 2°C) and the diurnal variations in body temperature across the sleep-wake cycle also markedly increased. Additionally, LPO-ΔGal mice showed a striking spike in body temperature and increase in wakefulness at a time (ZT24) when control mice were experiencing the opposite - a decrease in body temperature and becoming maximally sleepy (start of “lights on”). After sleep deprivation sleep homeostasis was largely abolished in LPO-ΔGal mice: the characteristic increase in the delta power of NREM sleep following sleep deprivation was absent, suggesting that LPO galanin neurons track the time spent awake. Moreover, the amount of recovery sleep was substantially reduced over the following hours. We also found that the α2 adrenergic agonist dexmedetomidine, used for long-term sedation during intensive care, requires LPO galanin neurons to induce both the NREM-like state with increased delta power and the reduction in body temperature, characteristic features of this drug. This suggests that dexmedetomidine over-activates the natural sleep homeostasis pathway via galanin neurons. Collectively, the results emphasize that NREM sleep and the concurrent reduction in body temperature are entwined at the circuit level.SignificanceCatching up on lost sleep (sleep homeostasis) is a common phenomenon in mammals, but there is no circuit explanation for how this occurs. We have discovered that galanin neurons in the hypothalamus are essential for sleep homeostasis as well as for the control of body temperature. This is the first time that a neuronal cell type has been identified that underlies sleep homeostasis. Moreover, we show that activation of these galanin neurons are also essential for the actions of the α2 adrenergic agonist dexmedetomidine, which induces both hypothermia together with powerful delta oscillations resembling NREM sleep. Thus, sleep homeostasis, temperature control and sedation by α2 adrenergic agonists can all be linked at the circuit level by hypothalamic galanin neurons.

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Dynamic changes in cerebral and peripheral markers of glutamatergic signaling across the human sleep-wake cycle

10.1101/458885 ◽

2018 ◽

Author(s):

Susanne Weigend ◽

Sebastian C. Holst ◽

Valérie Treyer ◽

Ruth L. O’Gorman Tuura ◽

Josefine Meier ◽

...

Keyword(s):

Prefrontal Cortex ◽

Sleep Deprivation ◽

Metabotropic Glutamate Receptors ◽

Molecular Mechanisms ◽

Fragile X ◽

Subject Area ◽

Resonance Spectroscopy ◽

Recovery Sleep ◽

Glutamatergic Signaling ◽

The Brain

AbstractBoth sleep and glutamatergic signaling in the brain are tightly controlled and homeostatically regulated. Sleep homeostasis is reliably reflected by predictable changes in brain electrical activity in waking and sleep, yet the underlying molecular mechanisms remain elusive. Current hypotheses posit that recovery sleep following prolonged waking restores efficient functioning of the brain, for example by keeping glutamatergic signaling in a homeostatic range. We recently provided evidence in humans and mice that metabotropic glutamate receptors of subtype-5 (mGluR5) contribute to the brain’s coping mechanisms with sleep deprivation. Here we combined in 31 healthy men, proton magnetic resonance spectroscopy to measure the levels of glutamate (Glu), GLX (glutamate-to-glutamine ratio) and GABA (γ-amino-butyric-acid) in basal ganglia (BG) and dorsolateral prefrontal cortex, simultaneous positron emission tomography to quantify mGluR5 availability with the novel radioligand, [18F]PSS232, and quantification in blood plasma of the mGluR5-regulated proteins, fragile-X mental retardation protein (FMRP) and brain-derived neurotrophic factor (BDNF). All measurements were conducted at the same circadian time in baseline, following sleep deprivation and after recovery sleep. We found that Glu and GLX in BG (pall < 0.01), but not in prefrontal cortex, and the plasma concentration of FMRP (p < 0.02), were increased after sleep loss and tended to normalize following recovery sleep (pall < 0.1). Furthermore, a night without sleep enhanced whole-brain and striatal mGluR5 availability and was normalized by recovery sleep (pall < 0.05). By contrast, other brain metabolites and plasma BDNF levels were not altered. The findings demonstrate convergent changes in distinct markers of glutamatergic signaling across prolonged wakefulness and recovery sleep in humans. They warrant further studies to elucidate the underlying mechanisms that link the homeostatic regulation of sleep and glutamatergic system activity in health and disease.One-sentence summarySleep-dependent recovery of wakefulness-induced changes in, cerebral glutamatergic signalingMajor subject areaNeuroscience; Human Biology & Medicine

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AANAT1 functions in astrocytes to regulate sleep homeostasis

10.1101/736223 ◽

2019 ◽

Cited By ~ 1

Author(s):

Sejal Davla ◽

Gregory Artiushin ◽

Daryan Chitsaz ◽

Sally Li ◽

Amita Sehgal ◽

...

Keyword(s):

Sleep Deprivation ◽

Critical Role ◽

Cholinergic Neurons ◽

Adult Brain ◽

List Type ◽

Sleep Regulation ◽

Control Functions ◽

The Brain

SummaryCharacteristic features of sleep are conserved among species [1], and from humans to insects sleep is influenced by neural circuits involving monoamines such as serotonin and dopamine [2]. Glial cells have been increasingly implicated in mechanisms of baseline and homeostatic sleep regulation in mammals and flies [3–11], but it remains unknown whether and how glia might influence monoaminergic control of sleep. Sleep is regulated by circadian rhythms and a homeostatic drive to compensate for prolonged wakefulness, and growing evidence suggests that neural mechanisms controlling homeostatic sleep can be discriminated from those controlling baseline sleep [12–15]. In Drosophila, mutants of arylalkylamine N-acetyltransferase 1 (AANAT1lo) have normal baseline amounts of sleep and motor activity, but increased rebound sleep following deprivation [16]. AANAT1 can acetylate and inactivate monoamines in vitro [17], but the role of AANAT1 in vivo remains poorly understood. We find AANAT1 to be expressed in astrocytes and subsets of neurons in the adult Drosophila brain, with levels in astrocytes declining markedly overnight. In sleep-deprived AANAT1 mutant flies, heightened rebound sleep is accompanied by increased serotonin and dopamine levels in the brain. In neurons, AANAT1 functions to limit the quantity and consolidation of nighttime sleep, but in astrocytes AANAT1 constrains the amount of rebound sleep that flies take in response to sleep deprivation. These findings distinguish sleep-control functions of AANAT1 in neurons and astrocytes, and identify a critical role for astrocytes in the regulation of monoamine bioavailability and calibration of the response to sleep need.HighlightsThe monoamine catabolic enzyme arylalkylamine N-acetyltransferase 1 (AANAT1) is expressed by astrocytes and subsets of serotonergic, glutamatergic, GABAergic and cholinergic neurons in the adult brain of Drosophila.AANAT1 limits accumulation of serotonin and dopamine in the brain upon sleep deprivation.Loss of AANAT1 from astrocytes, but not from neurons, causes flies to increase their daytime rebound sleep in response to overnight sleep deprivation.

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Unique transcriptional signatures of sleep loss across independently evolved cavefish populations

10.1101/734673 ◽

2019 ◽

Cited By ~ 1

Author(s):

Suzanne E. McGaugh ◽

Courtney N. Passow ◽

James Brian Jaggard ◽

Bethany A. Stahl ◽

Alex C. Keene

Keyword(s):

Sleep Deprivation ◽

Sleep Duration ◽

Differentially Expressed Genes ◽

Sleep Loss ◽

Differentially Expressed ◽

Molecular Response ◽

Recovery Sleep ◽

Sleep Homeostasis ◽

Surface Population ◽

Physiological Homeostasis

AbstractAnimals respond to sleep loss with compensatory rebound sleep, and this is thought to be critical for the maintenance of physiological homeostasis. Sleep duration varies dramatically across animal species, but it is not known whether evolutionary differences in sleep duration are associated with differences in sleep homeostasis. The Mexican cavefish, Astyanax mexicanus, has emerged as a powerful model for studying the evolution of sleep. While eyed surface populations of A. mexicanus sleep approximately eight hours each day, multiple blind cavefish populations have converged on sleep patterns that total as little as two hours each day, providing the opportunity to examine whether the evolution of sleep loss is accompanied by changes in sleep homeostasis. Here, we examine the behavioral and molecular response to sleep deprivation across four independent populations of A. mexicanus. Our behavioral analysis indicates that surface fish and all three cavefish populations display robust recovery sleep during the day following nighttime sleep deprivation, suggesting sleep homeostasis remains intact in cavefish. We profiled transcriptome-wide changes associated with sleep deprivation in surface fish and cavefish. While the total number of differentially expressed genes was not greater for the surface population, the surface population exhibited the highest number of uniquely differentially expressed genes than any other population. Strikingly, a majority of the differentially expressed genes are unique to individual cave populations, suggesting unique expression responses are exhibited across independently evolved cavefish populations. Together, these findings suggest sleep homeostasis is intact in cavefish despite a dramatic reduction in overall sleep duration.

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Drosophila insulin-like peptide 2 mediates dietary regulation of sleep intensity

10.1101/681551 ◽

2019 ◽

Author(s):

Elizabeth B. Brown ◽

Kreesha D. Shah ◽

Richard Faville ◽

Benjamin Kottler ◽

Alex C. Keene

Keyword(s):

Sleep Deprivation ◽

Sleep Duration ◽

Critical Role ◽

Genetic Regulation ◽

Sleep Loss ◽

Fruit Flies ◽

Recovery Sleep ◽

Sleep Depth ◽

Sleep Homeostasis ◽

Induced Changes

AbstractSleep is a nearly universal behavior that is regulated by diverse environmental and physiological stimuli. A defining feature of sleep is a homeostatic rebound following deprivation, where animals compensate for lost sleep by increasing sleep duration and/or sleep depth. Fruit flies exhibit robust recovery sleep following deprivation and represent a powerful model to study neural circuits regulating sleep homeostasis. Numerous neuronal populations have been identified in modulating sleep homeostasis as well as depth, raising the possibility that recovery sleep is differentially regulated by environmental or physiological processes that induce sleep deprivation. Here, we find that unlike most pharmacological and environmental manipulations commonly used to restrict sleep, starvation potently induces sleep loss without a subsequent rebound in sleep duration or depth. We find that both starvation and a sucrose-only diet result in reduced metabolic rate and increased sleep depth, suggesting that dietary yeast protein is essential for normal sleep depth and homeostasis. Finally, we find that Drosophila insulin like peptide 2 (Dilp2) is required for starvation-induced changes in sleep depth without regulating the duration of sleep. Remarkably, Dilp2 mutant flies require rebound sleep following sleep deprivation, suggesting Dilp2 underlies resilience to sleep loss. Together, these findings reveal innate resilience to starvation-induced sleep loss and identify distinct mechanisms that underlie starvation-induced changes in sleep duration and depth.Author SummarySleep is nearly universal throughout the animal kingdom and homeostatic regulation represents a defining feature of sleep, where animals compensate for lost sleep by increasing sleep over subsequent time periods. Despite the robustness of this feature, surprisingly little is known about how recovery-sleep is regulated in response to different types of sleep deprivation. Fruit flies provide a powerful model for investigating the genetic regulation of sleep, and like mammals, display robust recovery sleep following deprivation. Here, we find that unlike most stimuli that suppress sleep, sleep deprivation by starvation does not require a homeostatic rebound. These findings appear to be due to flies engaging in deeper sleep during the period of partial deprivation, suggesting a natural resilience to starvation-induced sleep loss. This unique resilience to starvation-induced sleep loss is dependent on Drosophila insulin-like peptide 2, suggesting a critical role for insulin signaling in regulating interactions between diet and sleep homeostasis.

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