Cerebral mGluR5 availability contributes to elevated sleep need and behavioral adjustment after sleep deprivation

Increased sleep time and intensity quantified as low-frequency brain electrical activity after sleep loss demonstrate that sleep need is homeostatically regulated, yet the underlying molecular mechanisms remain elusive. We here demonstrate that metabotropic glutamate receptors of subtype 5 (mGluR5) contribute to the molecular machinery governing sleep-wake homeostasis. Using positron emission tomography, magnetic resonance spectroscopy, and electroencephalography in humans, we find that increased mGluR5 availability after sleep loss tightly correlates with behavioral and electroencephalographic biomarkers of elevated sleep need. These changes are associated with altered cortical myo-inositol and glycine levels, suggesting sleep loss-induced modifications downstream of mGluR5 signaling. Knock-out mice without functional mGluR5 exhibit severe dysregulation of sleep-wake homeostasis, including lack of recovery sleep and impaired behavioral adjustment to a novel task after sleep deprivation. The data suggest that mGluR5 contribute to the brain's coping mechanisms with sleep deprivation and point to a novel target to improve disturbed wakefulness and sleep.

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

SLEEP ◽

10.1093/sleep/zsz161 ◽

2019 ◽

Vol 42 (11) ◽

Cited By ~ 4

Author(s):

Susanne Weigend ◽

Sebastian C Holst ◽

Valérie Treyer ◽

Ruth L O’Gorman Tuura ◽

Josefine Meier ◽

...

Keyword(s):

Sleep Deprivation ◽

Metabotropic Glutamate Receptors ◽

Fragile X ◽

Blood Levels ◽

Resonance Spectroscopy ◽

Clinical Trial Registration ◽

Human Sleep ◽

Recovery Sleep ◽

Positron Emission ◽

Glutamatergic Signaling

Abstract Sleep and brain glutamatergic signaling are homeostatically regulated. Recovery sleep following prolonged wakefulness restores efficient functioning of the brain, possibly by keeping glutamatergic signaling in a homeostatic range. Evidence in humans and mice suggested that metabotropic glutamate receptors of subtype-5 (mGluR5) contribute to the brain’s coping mechanisms with sleep deprivation. Here, proton magnetic resonance spectroscopy in 31 healthy men was used to quantify the levels of glutamate (Glu), glutamate-to-glutamine ratio (GLX), and γ-amino-butyric-acid (GABA) in basal ganglia (BG) and dorsolateral prefrontal cortex on 3 consecutive days, after ~8 (baseline), ~32 (sleep deprivation), and ~8 hours (recovery sleep) of wakefulness. Simultaneously, mGluR5 availability was quantified with the novel radioligand for positron emission tomography, [18F]PSS232, and the blood levels of the mGluR5-regulated proteins, fragile X mental retardation protein (FMRP) and brain-derived neurotrophic factor (BDNF) were determined. The data revealed that GLX (p = 0.03) in BG (for Glu: p < 0.06) and the serum concentration of FMRP (p < 0.04) were increased after sleep loss. Other brain metabolites (GABA, N-acetyl-aspartate, choline, glutathione) and serum BDNF levels were not altered by sleep deprivation (pall > 0.6). By contrast, the night without sleep enhanced whole-brain, BG, and parietal cortex mGluR5 availability, which was normalized by recovery sleep (pall < 0.05). The findings provide convergent multimodal evidence that glutamatergic signaling is affected by sleep deprivation and recovery sleep. They support a role for mGluR5 and FMRP in sleep–wake regulation and warrant further studies to investigate their causality and relevance for regulating human sleep in health and disease. Clinical Trial Registration: www.clinicaltrials.gov (study identifier: NCT03813082)

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Residual, differential neurobehavioral deficits linger after multiple recovery nights following chronic sleep restriction or acute total sleep deprivation

SLEEP ◽

10.1093/sleep/zsaa224 ◽

2020 ◽

Author(s):

Erika M Yamazaki ◽

Caroline A Antler ◽

Charlotte R Lasek ◽

Namni Goel

Keyword(s):

Sleep Deprivation ◽

Response Speed ◽

Sleep Loss ◽

Sleep Restriction ◽

Total Sleep Deprivation ◽

Psychomotor Vigilance Test ◽

Recovery Sleep ◽

Time In Bed ◽

Neurobehavioral Deficits ◽

Chronic Sleep

Abstract Study Objectives The amount of recovery sleep needed to fully restore well-established neurobehavioral deficits from sleep loss remains unknown, as does whether the recovery pattern differs across measures after total sleep deprivation (TSD) and chronic sleep restriction (SR). Methods In total, 83 adults received two baseline nights (10–12-hour time in bed [TIB]) followed by five 4-hour TIB SR nights or 36-hour TSD and four recovery nights (R1–R4; 12-hour TIB). Neurobehavioral tests were completed every 2 hours during wakefulness and a Maintenance of Wakefulness Test measured physiological sleepiness. Polysomnography was collected on B2, R1, and R4 nights. Results TSD and SR produced significant deficits in cognitive performance, increases in self-reported sleepiness and fatigue, decreases in vigor, and increases in physiological sleepiness. Neurobehavioral recovery from SR occurred after R1 and was maintained for all measures except Psychomotor Vigilance Test (PVT) lapses and response speed, which failed to completely recover. Neurobehavioral recovery from TSD occurred after R1 and was maintained for all cognitive and self-reported measures, except for vigor. After TSD and SR, R1 recovery sleep was longer and of higher efficiency and better quality than R4 recovery sleep. Conclusions PVT impairments from SR failed to reverse completely; by contrast, vigor did not recover after TSD; all other deficits were reversed after sleep loss. These results suggest that TSD and SR induce sustained, differential biological, physiological, and/or neural changes, which remarkably are not reversed with chronic, long-duration recovery sleep. Our findings have critical implications for the population at large and for military and health professionals.

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137 Recovery Dynamics in a Biomathematical Model of Fatigue

SLEEP ◽

10.1093/sleep/zsab072.136 ◽

2021 ◽

Vol 44 (Supplement_2) ◽

pp. A56-A56

Author(s):

Mark McCauley ◽

Peter McCauley ◽

Hans Van Dongen

Keyword(s):

Sleep Deprivation ◽

Goodness Of Fit ◽

Sleep Loss ◽

Sleep Restriction ◽

Commercial Aviation ◽

Circadian Misalignment ◽

Total Sleep Deprivation ◽

Homeostatic Process ◽

Recovery Sleep

Abstract Introduction In commercial aviation and other operational settings where biomathematical models of fatigue are used for fatigue risk management, accurate prediction of recovery during rest periods following duty periods with sleep loss and/or circadian misalignment is critical. The recuperative potential of recovery sleep is influenced by a variety of factors, including long-term, allostatic effects of prior sleep/wake history. For example, recovery tends to be slower after sustained sleep restriction versus acute total sleep deprivation. Capturing such dynamics has proven to be challenging. Methods Here we focus on the dynamic biomathematical model of McCauley et al. (2013). In addition to a circadian process, this model features differential equations for sleep/wake regulation including a short-term sleep homeostatic process capturing change in the order of hours/days and a long-term allostatic process capturing change in the order of days/weeks. The allostatic process modulates the dynamics of the homeostatic process by shifting its equilibrium setpoint, which addresses recently observed phenomena such as reduced vulnerability to sleep loss after banking sleep. It also differentiates the build-up and recovery rates of fatigue under conditions of chronic sleep restriction versus acute total sleep deprivation; nonetheless, it does not accurately predict the disproportionately rapid recovery seen after total sleep deprivation. To improve the model, we hypothesized that the homeostatic process may also modulate the allostatic process, with the magnitude of this effect scaling as a function of time awake. Results To test our hypothesis, we added a parameter to the model to capture modulation by the homeostatic process of the allostatic process build-up during wakefulness and dissipation during sleep. Parameter estimation using previously published laboratory datasets of fatigue showed this parameter as significantly different from zero (p<0.05) and yielding a 10%–20% improvement in goodness-of-fit for recovery without adversely affecting goodness-of-fit for pre-recovery days. Conclusion Inclusion of a modulation effect of the allostatic process by the homeostatic process improved prediction accuracy in a variety of sleep loss and circadian misalignment scenarios. In addition to operational relevance for duty/rest scheduling, this finding has implications for understanding mechanisms underlying the homeostatic and allostatic processes of sleep/wake regulation. Support (if any) Federal Express Corporation

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Autonomic Modulation During Baseline and Recovery Sleep in Adult Sleepwalkers

Frontiers in Neurology ◽

10.3389/fneur.2021.680596 ◽

2021 ◽

Vol 12 ◽

Author(s):

Geneviève Scavone ◽

Andrée-Ann Baril ◽

Jacques Montplaisir ◽

Julie Carrier ◽

Alex Desautels ◽

...

Keyword(s):

Heart Rate ◽

Sleep Deprivation ◽

Slow Wave ◽

Slow Wave Sleep ◽

Low Frequency ◽

Medium Effect ◽

Sleep Cycle ◽

Autonomic Modulation ◽

Decomposition Group ◽

Recovery Sleep

Sleepwalking has been conceptualized as deregulation between slow-wave sleep and arousal, with its occurrence in predisposed patients increasing following sleep deprivation. Recent evidence showed autonomic changes before arousals and somnambulistic episodes, suggesting that autonomic dysfunctions may contribute to the pathophysiology of sleepwalking. We investigated cardiac autonomic modulation during slow-wave sleep in sleepwalkers and controls during normal and recovery sleep following sleep deprivation. Fourteen adult sleepwalkers (5M; 28.1 ± 5.8 years) and 14 sex- and age-matched normal controls were evaluated by video-polysomnography for one baseline night and during recovery sleep following 25 h of sleep deprivation. Autonomic modulation was investigated with heart rate variability during participants' slow-wave sleep in their first and second sleep cycles. 5-min electrocardiographic segments from slow-wave sleep were analyzed to investigate low-frequency (LF) and high-frequency (HF) components of heart rate spectral decomposition. Group (sleepwalkers, controls) X condition (baseline, recovery) ANOVAs were performed to compare LF and HF in absolute and normalized units (nLF and nHF), and LF/HF ratio. When compared to controls, sleepwalkers' recovery slow-wave sleep showed lower LF/HF ratio and higher nHF during the first sleep cycle. In fact, compared to baseline recordings, sleepwalkers, but not controls, showed a significant decrease in nLF and LF/HF ratio as well as increased nHF during recovery slow-wave sleep during the first cycle. Although non-significant, similar findings with medium effect sizes were observed for absolute values (LF, HF). Patterns of autonomic modulation during sleepwalkers' recovery slow-wave sleep suggest parasympathetic dominance as compared to baseline sleep values and to controls. This parasympathetic predominance may be a marker of abnormal neural mechanisms underlying, or interfere with, the arousal processes and contribute to the pathophysiology of sleepwalking.

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Hugin+ neurons provide a link between sleep homeostat and circadian clock neurons

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2111183118 ◽

2021 ◽

Vol 118 (47) ◽

pp. e2111183118

Author(s):

Jessica E. Schwarz ◽

Anna N. King ◽

Cynthia T. Hsu ◽

Annika F. Barber ◽

Amita Sehgal

Keyword(s):

Locomotor Activity ◽

Sleep Deprivation ◽

Circadian Clock ◽

Sleep Loss ◽

Daily Cycle ◽

Shaped Body ◽

Recovery Sleep ◽

Sleep Homeostat ◽

Central Clock ◽

Homeostatic Mechanisms

Sleep is controlled by homeostatic mechanisms, which drive sleep after wakefulness, and a circadian clock, which confers the 24-h rhythm of sleep. These processes interact with each other to control the timing of sleep in a daily cycle as well as following sleep deprivation. However, the mechanisms by which they interact are poorly understood. We show here that hugin+ neurons, previously identified as neurons that function downstream of the clock to regulate rhythms of locomotor activity, are also targets of the sleep homeostat. Sleep deprivation decreases activity of hugin+ neurons, likely to suppress circadian-driven activity during recovery sleep, and ablation of hugin+ neurons promotes sleep increases generated by activation of the homeostatic sleep locus, the dorsal fan-shaped body (dFB). Also, mutations in peptides produced by the hugin+ locus increase recovery sleep following deprivation. Transsynaptic mapping reveals that hugin+ neurons feed back onto central clock neurons, which also show decreased activity upon sleep loss, in a Hugin peptide–dependent fashion. We propose that hugin+ neurons integrate circadian and sleep signals to modulate circadian circuitry and regulate the timing of sleep.

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Sleep deprivation amplifies striatal activation to monetary reward

Psychological Medicine ◽

10.1017/s0033291712002875 ◽

2013 ◽

Vol 43 (10) ◽

pp. 2215-2225 ◽

Cited By ~ 56

Author(s):

B. C. Mullin ◽

M. L. Phillips ◽

G. J. Siegle ◽

D. J. Buysse ◽

E. E. Forbes ◽

...

Keyword(s):

Young Adults ◽

Sleep Deprivation ◽

Sleep Time ◽

Sleep Loss ◽

Monetary Reward ◽

Late Adolescents ◽

Compulsive Gambling ◽

Reward Seeking ◽

Normal Sleep ◽

Reinforcing Stimuli

BackgroundSleep loss produces abnormal increases in reward seeking but the mechanisms underlying this phenomenon are poorly understood. The present study examined the influence of one night of sleep deprivation on neural responses to a monetary reward task in a sample of late adolescents/young adults.MethodUsing a within-subjects crossover design, 27 healthy, right-handed late adolescents/young adults (16 females, 11 males; mean age 23.1 years) underwent functional magnetic resonance imaging (fMRI) following a night of sleep deprivation and following a night of normal sleep. Participants' recent sleep history was monitored using actigraphy for 1 week prior to each sleep condition.ResultsFollowing sleep deprivation, participants exhibited increased activity in the ventral striatum (VS) and reduced deactivation in the medial prefrontal cortex (mPFC) during the winning of monetary reward, relative to the same task following normal sleep conditions. Shorter total sleep time over the five nights before the sleep-deprived testing condition was associated with reduced deactivation in the mPFC during reward.ConclusionsThese findings support the hypothesis that sleep loss produces aberrant functioning in reward neural circuitry, increasing the salience of positively reinforcing stimuli. Aberrant reward functioning related to insufficient sleep may contribute to the development and maintenance of reward dysfunction-related disorders, such as compulsive gambling, eating, substance abuse and mood disorders.

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Effects of Sleep Deprivation on Brain Bioenergetics, Sleep, and Cognitive Performance in Cocaine-Dependent Individuals

The Scientific World JOURNAL ◽

10.1155/2013/947879 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 5

Author(s):

George H. Trksak ◽

Bethany K. Bracken ◽

J. Eric Jensen ◽

David T. Plante ◽

David M. Penetar ◽

...

Keyword(s):

Sleep Deprivation ◽

Cognitive Performance ◽

Sleep Loss ◽

Continuous Performance ◽

Digit Symbol ◽

Continuous Performance Task ◽

Performance Task ◽

Recovery Sleep ◽

Symbol Substitution ◽

Healthy Control

In cocaine-dependent individuals, sleep is disturbed during cocaine use and abstinence, highlighting the importance of examining the behavioral and homeostatic response to acute sleep loss in these individuals. The current study was designed to identify a differential effect of sleep deprivation on brain bioenergetics, cognitive performance, and sleep between cocaine-dependent and healthy control participants. 14 healthy control and 8 cocaine-dependent participants experienced consecutive nights of baseline, total sleep deprivation, and recovery sleep in the research laboratory. Participants underwent[31]P magnetic resonance spectroscopy (MRS) brain imaging, polysomnography, Continuous Performance Task, and Digit Symbol Substitution Task. Following recovery sleep,[31]P MRS scans revealed that cocaine-dependent participants exhibited elevated global brainβ-NTP (direct measure of adenosine triphosphate),α-NTP, and total NTP levels compared to those of healthy controls. Cocaine-dependent participants performed worse on the Continuous Performance Task and Digit Symbol Substitution Task at baseline compared to healthy control participants, but sleep deprivation did not worsen cognitive performance in either group. Enhancements of brain ATP levels in cocaine dependent participants following recovery sleep may reflect a greater impact of sleep deprivation on sleep homeostasis, which may highlight the importance of monitoring sleep during abstinence and the potential influence of sleep loss in drug relapse.

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Genetic Markers of Differential Vulnerability to Sleep Loss in Adults

Genes ◽

10.3390/genes12091317 ◽

2021 ◽

Vol 12 (9) ◽

pp. 1317

Author(s):

Courtney E. Casale ◽

Namni Goel

Keyword(s):

Sleep Deprivation ◽

Genetic Markers ◽

Clock Genes ◽

Association Studies ◽

Sleep Loss ◽

Future Research ◽

Candidate Gene Approach ◽

Genome Wide Association Studies ◽

Recovery Sleep ◽

Differential Vulnerability

In this review, we discuss reports of genotype-dependent interindividual differences in phenotypic neurobehavioral responses to total sleep deprivation or sleep restriction. We highlight the importance of using the candidate gene approach to further elucidate differential resilience and vulnerability to sleep deprivation in humans, although we acknowledge that other omics techniques and genome-wide association studies can also offer insights into biomarkers of such vulnerability. Specifically, we discuss polymorphisms in adenosinergic genes (ADA and ADORA2A), core circadian clock genes (BHLHE41/DEC2 and PER3), genes related to cognitive development and functioning (BDNF and COMT), dopaminergic genes (DRD2 and DAT), and immune and clearance genes (AQP4, DQB1*0602, and TNFα) as potential genetic indicators of differential vulnerability to deficits induced by sleep loss. Additionally, we review the efficacy of several countermeasures for the neurobehavioral impairments induced by sleep loss, including banking sleep, recovery sleep, caffeine, and naps. The discovery of reliable, novel genetic markers of differential vulnerability to sleep loss has critical implications for future research involving predictors, countermeasures, and treatments in the field of sleep and circadian science.

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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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