Optogenetic activation of cholinergic neurons in the PPT or LDT induces REM sleep

Rapid eye movement (REM) sleep is an important component of the natural sleep/wake cycle, yet the mechanisms that regulate REM sleep remain incompletely understood. Cholinergic neurons in the mesopontine tegmentum have been implicated in REM sleep regulation, but lesions of this area have had varying effects on REM sleep. Therefore, this study aimed to clarify the role of cholinergic neurons in the pedunculopontine tegmentum (PPT) and laterodorsal tegmentum (LDT) in REM sleep generation. Selective optogenetic activation of cholinergic neurons in the PPT or LDT during non-REM (NREM) sleep increased the number of REM sleep episodes and did not change REM sleep episode duration. Activation of cholinergic neurons in the PPT or LDT during NREM sleep was sufficient to induce REM sleep.

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0074 Inhibitory Neurons in the Dorsomedial Medulla Promote REM Sleep

SLEEP ◽

10.1093/sleep/zsaa056.072 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A30-A30

Author(s):

J Stucynski ◽

A Schott ◽

J Baik ◽

J Hong ◽

F Weber ◽

...

Keyword(s):

Rem Sleep ◽

Nrem Sleep ◽

Inhibitory Neurons ◽

Brain State ◽

Sleep Regulation ◽

Optogenetic Stimulation ◽

Electrophysiological Recordings ◽

Stimulation Of

Abstract Introduction The neural circuits controlling rapid eye movement (REM) sleep, and in particular the role of the medulla in regulating this brain state, remains an active area of study. Previous electrophysiological recordings in the dorsomedial medulla (DM) and electrical stimulation experiments suggested an important role of this area in the control of REM sleep. However the identity of the involved neurons and their precise role in REM sleep regulation are still unclear. Methods The properties of DM GAD2 neurons in mice were investigated through stereotaxic injection of CRE-dependent viruses in conjunction with implantation of electrodes for electroencephalogram (EEG) and electromyogram (EMG) recordings and optic fibers. Experiments included in vivo calcium imaging (fiber photometry) across sleep and wake states, optogenetic stimulation of cell bodies, chemogenetic excitation and suppression (DREADDs), and connectivity mapping using viral tracing and optogenetics. Results Imaging the calcium activity of DM GAD2 neurons in vivo indicates that these neurons are most active during REM sleep. Optogenetic stimulation of DM GAD2 neurons reliably triggered transitions into REM sleep from NREM sleep. Consistent with this, chemogenetic activation of DM GAD2 neurons increased the amount of REM sleep while inhibition suppressed its occurrence and enhanced NREM sleep. Anatomical tracing revealed that DM GAD2 neurons project to several areas involved in sleep / wake regulation including the wake-promoting locus coeruleus (LC) and the REM sleep-suppressing ventrolateral periaquaductal gray (vlPAG). Optogenetic activation of axonal projections from DM to LC, and DM to vlPAG was sufficient to induce REM sleep. Conclusion These experiments demonstrate that DM inhibitory neurons expressing GAD2 powerfully promote initiation of REM sleep in mice. These findings further characterize the dorsomedial medulla as a critical structure involved in REM sleep regulation and inform future investigations of the REM sleep circuitry. Support R01 HL149133

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REM-sleep timing is controlled homeostatically by accumulation of REM-sleep propensity in non-REM sleep

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1994.266.6.r1992 ◽

1994 ◽

Vol 266 (6) ◽

pp. R1992-R2000 ◽

Cited By ~ 10

Author(s):

J. H. Benington ◽

H. C. Heller

Keyword(s):

Rem Sleep ◽

Sleep Onset ◽

Nrem Sleep ◽

Sleep Episode ◽

Sleep Timing ◽

Sleep Maintenance ◽

Oscillatory Mechanism ◽

Episode Duration ◽

Full Day ◽

Sleep Propensity

Sleep structure in the rat was characterized during uninterrupted full-day recordings using an analytic procedure that identifies rapid eye movement (REM) sleep episodes based on REM-sleep-onset electroencephalograph phenomena, hence independently of REM-sleep duration. The data were used to determine whether REM-sleep timing is controlled homeostatically or by an oscillatory mechanism. The findings and conclusions are that 1) non-REM (NREM) sleep episode duration is positively correlated with prior REM-sleep episode duration, suggesting that REM-sleep expression is permissive of NREM sleep; 2) mean NREM-sleep episode duration decreases after repeated brief REM-sleep episodes (< 30 s), also suggesting that discharge of REM-sleep propensity is essential for NREM-sleep expression; 3) REM-sleep episode duration is independent of prior sleep history, suggesting that REM-sleep maintenance is controlled by factors other than accumulated REM-sleep propensity; 4) brief REM-sleep episodes occur progressively more frequently over the course of the NREM-sleep interval between sustained REM-sleep episodes (> 30 s), suggesting that REM-sleep propensity increases progressively within episodes of NREM sleep; and 5) the diurnal cycle of REM-sleep expression primarily reflects modulation in the efficiency of REM-sleep maintenance. These findings support the hypothesis that REM-sleep timing is controlled by accumulation of REM-sleep propensity during NREM sleep.

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An Asymmetrical Hypothesis for the NREM-REM Sleep Alternation—What Is the NREM-REM Cycle?

Frontiers in Neuroscience ◽

10.3389/fnins.2021.627193 ◽

2021 ◽

Vol 15 ◽

Author(s):

Olivier Le Bon

Keyword(s):

Eye Movement ◽

Rem Sleep ◽

Refractory Period ◽

High Variability ◽

Oscillator Model ◽

Rapid Eye Movement ◽

Sleep Regulation ◽

Short Term ◽

Sleep Episode ◽

Sleep Homeostasis

Since the discovery of rapid eye movement (REM) sleep (Aserinsky and Kleitman, 1953), sleep has been described as a succession of cycles of non-REM (NREM) and REM sleep episodes. The hypothesis of short-term REM sleep homeostasis, which is currently the basis of most credible theories on sleep regulation, is built upon a positive correlation between the duration of a REM sleep episode and the duration of the interval until the next REM sleep episode (inter-REM interval): the duration of REM sleep would therefore predict the duration of this interval. However, the high variability of inter-REM intervals, especially in polyphasic sleep, argues against a simple oscillator model. A new “asymmetrical” hypothesis is presented here, where REM sleep episodes only determine the duration of a proportional post-REM refractory period (PRRP), during which REM sleep is forbidden and the only remaining options are isolated NREM episodes or waking. After the PRRP, all three options are available again (NREM, REM, and Wake). I will explain why I think this hypothesis also calls into question the notion of NREM-REM sleep cycles.

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State-dependent pontine ensemble dynamics and interactions with cortex across sleep states

10.1101/752683 ◽

2019 ◽

Cited By ~ 1

Author(s):

Tomomi Tsunematsu ◽

Amisha A Patel ◽

Arno Onken ◽

Shuzo Sakata

Keyword(s):

Rem Sleep ◽

Hippocampal Neurons ◽

Specific Activity ◽

Nrem Sleep ◽

Dependent Manner ◽

Sleep Regulation ◽

Population Activity ◽

P Waves ◽

State Dependent ◽

Global Coordination

AbstractThe pontine nuclei play a crucial role in sleep-wake regulation. However, pontine ensemble dynamics underlying sleep regulation remain poorly understood. By monitoring population activity in multiple pontine and adjacent brainstem areas, here we show slow, state-predictive pontine ensemble dynamics and state-dependent interactions between the pons and the cortex in mice. On a timescale of seconds to minutes, pontine populations exhibit diverse firing across vigilance states, with some of these dynamics being attributed to cell type-specific activity. Pontine population activity can predict pupil dilation and vigilance states: pontine neurons exhibit longer predictable power compared with hippocampal neurons. On a timescale of sub-seconds, pontine waves (P-waves) are observed as synchronous firing of pontine neurons primarily during rapid eye movement (REM) sleep, but also during non-REM (NREM) sleep. Crucially, P-waves functionally interact with cortical activity in a state-dependent manner: during NREM sleep, hippocampal sharp wave-ripples (SWRs) precede P-waves. On the other hand, P-waves during REM sleep are phase-locked with ongoing hippocampal theta oscillations and are followed by burst firing in a subset of hippocampal neurons. Thus, the directionality of functional interactions between the hippocampus and pons changes depending on sleep states. This state-dependent global coordination between pontine and cortical regions implicates distinct functional roles of sleep.

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I. Time course of interventions and recovery sleep

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00462.2001 ◽

2002 ◽

Vol 283 (2) ◽

pp. R521-R526 ◽

Cited By ~ 10

Author(s):

Esther Werth ◽

Kimberly A. Cote ◽

Eva Gallmann ◽

Alexander A. Borbély ◽

Peter Achermann

Keyword(s):

Sleep Deprivation ◽

Rem Sleep ◽

Time Course ◽

Early Morning ◽

Adult Males ◽

Sleep Regulation ◽

Rem Sleep Deprivation ◽

Sleep Episode ◽

Recovery Sleep ◽

Sleep Propensity

Although repeated selective rapid eye movement (REM) sleep deprivation by awakenings during nighttime has shown that the number of sleep interruptions required to prevent REM sleep increases within and across consecutive nights, the underlying regulatory processes remained unspecified. To assess the role of circadian and homeostatic factors in REM sleep regulation, REM sleep was selectively deprived in healthy young adult males during a daytime sleep episode (7–15 h) after a night without sleep. Circadian REM sleep propensity is known to be high in the early morning. The number of interventions required to prevent REM sleep increased from the first to the third 2-h interval by a factor of two and then leveled off. Only a minor REM sleep rebound (11.6%) occurred in the following undisturbed recovery night. It is concluded that the limited rise of interventions during selective daytime REM sleep deprivation may be due to the declining circadian REM sleep propensity, which may partly offset the homeostatic drive and the sleep-dependent disinhibition of REM sleep.

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The Regulation of Sleep

10.1093/acrefore/9780190264086.013.30 ◽

2021 ◽

Author(s):

Craig Heller

Keyword(s):

Eye Movement ◽

Rem Sleep ◽

Nrem Sleep ◽

Control Mechanisms ◽

Rapid Eye Movement ◽

Sleep Regulation ◽

Short Article ◽

Feedback Information ◽

State Changes ◽

And Control

The words “regulation” and “control” have different meanings. A rich literature exists on the control mechanisms of sleep—the genomic, molecular, cellular, and circuit processes responsible for arousal state changes and characteristics. The regulation of sleep refers to functions and homeostatic maintenance of those functions. Much less is known about sleep regulation than sleep control, largely because functions of sleep are still unknown. Regulation requires information about the regulated variable that can be used as feedback information to achieve optimal levels. The circadian timing of sleep is regulated, and the feedback information is entraining stimuli such as the light–dark cycle. Sleep itself is homeostatically regulated, as evidenced by sleep deprivation experiments. Eletroenceophalography (EEG) slow-wave activity (SWA) is regulated, and it appears that adenosine is the major source of feedback information, and that fact indicates an energetic function for sleep. The last aspect of sleep regulation discussed in this short article is the non-rapid eye movement (NREM) and rapid eye movement (REM) sleep cycling. Evidence is discussed that supports the argument that NREM sleep is in a homeostatic relationship with wake, and REM sleep is in a homeostatic relationship with NREM sleep.

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Homeostatic sleep regulation in habitual short sleepers and long sleepers

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1996.270.1.r41 ◽

1996 ◽

Vol 270 (1) ◽

pp. R41-R53 ◽

Cited By ~ 15

Author(s):

D. Aeschbach ◽

C. Cajochen ◽

H. Landolt ◽

A. A. Borbely

Keyword(s):

Rem Sleep ◽

Process Model ◽

Sleep Latency ◽

Spectral Power ◽

Spectral Power Density ◽

Sleep Time ◽

Sleep Regulation ◽

Sleep Episode ◽

Rem Density ◽

Electroencephalogram Eeg

Homeostatic sleep regulation in habitual short sleepers (sleep episode < 6 h, n = 9) and long sleepers (> 9 h, n = 7) was investigated by studying their sleep structure and sleep electroencephalogram (EEG) during baseline conditions and after prolonging their habitual waking time by 24 h. In each sleep episode, total sleep time was > 3 h longer in the long sleepers than in the short sleepers. Sleep deprivation decreased sleep latency and rapid eye movement (REM) density in REM sleep more in long sleepers than in short sleepers. The enhancement of EEG slow-wave activity (SWA; spectral power density in the 0.75-4.5 Hz range) in non-REM sleep after sleep loss was larger in long sleepers (47%) than in short sleepers (19%). This difference in the SWA response was predicted by the two-process model of sleep regulation on the basis of the different sleep durations. The results indicate that short sleepers live under a higher “non-REM sleep pressure” than long sleepers. However, the two groups do not differ with respect to the homeostatic sleep regulatory mechanisms.

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The truncated TrkB receptor influences mammalian sleep

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00422.2014 ◽

2015 ◽

Vol 308 (3) ◽

pp. R199-R207 ◽

Cited By ~ 8

Author(s):

Adam J. Watson ◽

Kyle Henson ◽

Susan G. Dorsey ◽

Marcos G. Frank

Keyword(s):

Rem Sleep ◽

Knockout Mice ◽

Psychiatric Illness ◽

Sleep Latency ◽

Sleep Time ◽

Sleep Regulation ◽

Trkb Receptor ◽

Adult Mice ◽

The Relationship

Brain-derived neurotrophic factor (BDNF) is a neurotrophin hypothesized to play an important role in mammalian sleep expression and regulation. In order to investigate the role of the truncated receptor for BDNF, TrkB.T1, in mammalian sleep, we examined sleep architecture and sleep regulation in adult mice constitutively lacking this receptor. We find that TrkB.T1 knockout mice have increased REM sleep time, reduced REM sleep latency, and reduced sleep continuity. These results demonstrate a novel role for the TrkB.T1 receptor in sleep expression and provide new insights into the relationship between BDNF, psychiatric illness, and sleep.

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Regular Caffeine Intake Delays REM Sleep Promotion and Attenuates Sleep Quality in Healthy Men

Journal of Biological Rhythms ◽

10.1177/07487304211013995 ◽

2021 ◽

pp. 074873042110139

Author(s):

Janine Weibel ◽

Yu-Shiuan Lin ◽

Hans-Peter Landolt ◽

Christian Berthomier ◽

Marie Brandewinder ◽

...

Keyword(s):

Sleep Quality ◽

Rem Sleep ◽

Sleep Time ◽

Caffeine Intake ◽

Sleep Regulation ◽

Caffeine Consumption ◽

Subjective Sleep Quality ◽

Placebo Condition ◽

Double Blind ◽

Sleep Episode

Acute caffeine intake can attenuate homeostatic sleep pressure and worsen sleep quality. Caffeine intake—particularly in high doses and close to bedtime—may also affect circadian-regulated rapid eye movement (REM) sleep promotion, an important determinant of subjective sleep quality. However, it is not known whether such changes persist under chronic caffeine consumption during daytime. Twenty male caffeine consumers (26.4 ± 4 years old, habitual caffeine intake 478.1 ± 102.8 mg/day) participated in a double-blind crossover study. Each volunteer completed a caffeine (3 × 150 mg caffeine daily for 10 days), a withdrawal (3 × 150 mg caffeine for 8 days then placebo), and a placebo condition. After 10 days of controlled intake and a fixed sleep-wake cycle, we recorded electroencephalography for 8 h starting 5 h after habitual bedtime (i.e., start on average at 04:22 h which is around the peak of circadian REM sleep promotion). A 60-min evening nap preceded each sleep episode and reduced high sleep pressure levels. While total sleep time and sleep architecture did not significantly differ between the three conditions, REM sleep latency was longer after daily caffeine intake compared with both placebo and withdrawal. Moreover, the accumulation of REM sleep proportion was delayed, and volunteers reported more difficulties with awakening after sleep and feeling more tired upon wake-up in the caffeine condition compared with placebo. Our data indicate that besides acute intake, also regular daytime caffeine intake affects REM sleep regulation in men, such that it delays circadian REM sleep promotion when compared with placebo. Moreover, the observed caffeine-induced deterioration in the quality of awakening may suggest a potential motive to reinstate caffeine intake after sleep.

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Selectively driving cholinergic fibers optically in the thalamic reticular nucleus promotes sleep

eLife ◽

10.7554/elife.10382 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 22

Author(s):

Kun-Ming Ni ◽

Xiao-Jun Hou ◽

Ci-Hang Yang ◽

Ping Dong ◽

Yue Li ◽

...

Keyword(s):

Eye Movement ◽

Nicotinic Acetylcholine Receptors ◽

Rem Sleep ◽

Sleep Onset ◽

Cholinergic Neurons ◽

Nrem Sleep ◽

Gabaergic Neurons ◽

Thalamic Reticular Nucleus ◽

Reticular Nucleus ◽

Rapid Eye Movement

Cholinergic projections from the basal forebrain and brainstem are thought to play important roles in rapid eye movement (REM) sleep and arousal. Using transgenic mice in which channelrhdopsin-2 is selectively expressed in cholinergic neurons, we show that optical stimulation of cholinergic inputs to the thalamic reticular nucleus (TRN) activates local GABAergic neurons to promote sleep and protect non-rapid eye movement (NREM) sleep. It does not affect REM sleep. Instead, direct activation of cholinergic input to the TRN shortens the time to sleep onset and generates spindle oscillations that correlate with NREM sleep. It does so by evoking excitatory postsynaptic currents via α7-containing nicotinic acetylcholine receptors and inducing bursts of action potentials in local GABAergic neurons. These findings stand in sharp contrast to previous reports of cholinergic activity driving arousal. Our results provide new insight into the mechanisms controlling sleep.

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