GABA neurons in the ventral tegmental area regulate non-rapid eye movement sleep in mice

Sleep/wakefulness cycle is regulated by coordinated interactions between sleep- and wakefulness-regulating neural circuitry. However, the detailed mechanism is far from understood. Here, we found that glutamic acid decarboxylase 67-positive GABAergic neurons in the ventral tegmental area (VTAGad67+) are a key regulator of non-rapid eye movement (NREM) sleep in mice. VTAGad67+ project to multiple brain areas implicated in sleep/wakefulness regulation such as the lateral hypothalamus (LH). Chemogenetic activation of VTAGad67+ promoted NREM sleep with higher delta power whereas optogenetic inhibition of these induced prompt arousal from NREM sleep, even under highly somnolescent conditions, but not from REM sleep. VTAGad67+ showed the highest activity in NREM sleep and the lowest activity in REM sleep. Moreover, VTAGad67+ directly innervated and inhibited wake-promoting orexin/hypocretin neurons by releasing GABA. As such, optogenetic activation of VTAGad67+ terminals in the LH promoted NREM sleep. Taken together, we revealed that VTAGad67+ play an important role in the regulation of NREM sleep.

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Vesicular GABA-transporter neurons in the zona incerta are maximally active during non rapid-eye movement (NREM) and rapid-eye movement (REM) sleep

10.1101/2020.04.15.043372 ◽

2020 ◽

Author(s):

Carlos Blanco-Centurion ◽

SiWei Luo ◽

Aurelio Vidal-Ortiz ◽

Priyattam J. Shiromani

Keyword(s):

Eye Movement ◽

Lateral Hypothalamus ◽

Rem Sleep ◽

Sleep Onset ◽

Nrem Sleep ◽

Zona Incerta ◽

Imaging Method ◽

Rapid Eye Movement ◽

Gaba Transporter

AbstractSleep and wake are opposing behavioral states controlled by the activity of specific neurons. The neurons responsible for sleep/wake control have not been fully identifed due to the lack of in-vivo high throughput technology. We use the deep-brain calcium (Ca2+) imaging method to identify activity of hypothalamic neurons expressing the vesicular GABA transporter (vGAT), a marker of GABAergic neurons. vGAT-cre mice (n=5) were microinjected with rAAV-FLEX-GCaMP6M into the lateral hypothalamus and 21d later the Ca2+ influx in vGAT neurons (n=372) was recorded in freely-behaving mice during waking (W), NREM and REM sleep. Post-mortem analysis revealed the lens tip located in the zona incerta/lateral hypothalamus (ZI-LH) and the change in fluorescence of neurons in the field of view was as follows: 54.9% of the vGAT neurons had peak fluorescence during REM sleep (REM-max), 17.2% were NREM-max, 22.8% were wake-max while 5.1% were both wake+REM max. Thus, three quarters of the recorded vGAT neurons in the ZI-LH were most active during sleep. In the NREM-max group Ca2+ fluorescence anticipated the initiation of NREM sleep onset and remained high throughout sleep (NREM and REM sleep). In the REM-max neurons Ca2+fluorescence increased before the onset of REM sleep and stayed elevated during the episode. Activation of the vGAT NREM-max neurons in the zona incerta and dorsal lateral hypothalamus would inhibit the arousal neurons to initiate and maintain sleep.

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Sleep Disorders

10.2310/psych.6176 ◽

2015 ◽

Author(s):

Sudhansu Chokroverty

Keyword(s):

Sleep Apnea ◽

Sleep Disorders ◽

Eye Movement ◽

Rem Sleep ◽

Sleep Apnea Syndrome ◽

Nrem Sleep ◽

Rapid Eye Movement ◽

Circadian Rhythm Sleep Disorders ◽

Apnea Syndrome ◽

Sleep Mechanism

Recent research has generated an enormous fund of knowledge about the neurobiology of sleep and wakefulness. Sleeping and waking brain circuits can now be studied by sophisticated neuroimaging techniques that map different areas of the brain during different sleep states and stages. Although the exact biologic functions of sleep are not known, sleep is essential, and sleep deprivation leads to impaired attention and decreased performance. Sleep is also believed to have restorative, conservative, adaptive, thermoregulatory, and consolidative functions. This review discusses the physiology of sleep, including its two independent states, rapid eye movement (REM) and non–rapid eye movement (NREM) sleep, as well as functional neuroanatomy, physiologic changes during sleep, and circadian rhythms. The classification and diagnosis of sleep disorders are discussed generally. The diagnosis and treatment of the following disorders are described: obstructive sleep apnea syndrome, narcolepsy-cataplexy sydrome, idiopathic hypersomnia, restless legs syndrome (RLS) and periodic limb movements in sleep, circadian rhythm sleep disorders, insomnias, nocturnal frontal lobe epilepsy, and parasomnias. Sleep-related movement disorders and the relationship between sleep and psychiatric disorders are also discussed. Tables describe behavioral and physiologic characteristics of states of awareness, the international classification of sleep disorders, common sleep complaints, comorbid insomnia disorders, causes of excessive daytime somnolence, laboratory tests to assess sleep disorders, essential diagnostic criteria for RLS and Willis-Ekbom disease, and drug therapy for insomnia. Figures include polysomnographic recording showing wakefulness in an adult; stage 1, 2, and 3 NREM sleep in an adult; REM sleep in an adult; a patient with sleep apnea syndrome; a patient with Cheyne-Stokes breathing; a patient with RLS; and a patient with dream-enacting behavior; schematic sagittal section of the brainstem of the cat; schematic diagram of the McCarley-Hobson model of REM sleep mechanism; the Lu-Saper “flip-flop” model; the Luppi model to explain REM sleep mechanism; and a wrist actigraph from a man with bipolar disorder. This review contains 14 highly rendered figures, 8 tables, 115 references, and 5 MCQs.

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Sleep Disorders

10.2310/neuro.6176 ◽

2015 ◽

Author(s):

Sudhansu Chokroverty

Keyword(s):

Sleep Apnea ◽

Sleep Disorders ◽

Eye Movement ◽

Rem Sleep ◽

Sleep Apnea Syndrome ◽

Nrem Sleep ◽

Rapid Eye Movement ◽

Circadian Rhythm Sleep Disorders ◽

Apnea Syndrome ◽

Sleep Mechanism

Recent research has generated an enormous fund of knowledge about the neurobiology of sleep and wakefulness. Sleeping and waking brain circuits can now be studied by sophisticated neuroimaging techniques that map different areas of the brain during different sleep states and stages. Although the exact biologic functions of sleep are not known, sleep is essential, and sleep deprivation leads to impaired attention and decreased performance. Sleep is also believed to have restorative, conservative, adaptive, thermoregulatory, and consolidative functions. This review discusses the physiology of sleep, including its two independent states, rapid eye movement (REM) and non–rapid eye movement (NREM) sleep, as well as functional neuroanatomy, physiologic changes during sleep, and circadian rhythms. The classification and diagnosis of sleep disorders are discussed generally. The diagnosis and treatment of the following disorders are described: obstructive sleep apnea syndrome, narcolepsy-cataplexy sydrome, idiopathic hypersomnia, restless legs syndrome (RLS) and periodic limb movements in sleep, circadian rhythm sleep disorders, insomnias, nocturnal frontal lobe epilepsy, and parasomnias. Sleep-related movement disorders and the relationship between sleep and psychiatric disorders are also discussed. Tables describe behavioral and physiologic characteristics of states of awareness, the international classification of sleep disorders, common sleep complaints, comorbid insomnia disorders, causes of excessive daytime somnolence, laboratory tests to assess sleep disorders, essential diagnostic criteria for RLS and Willis-Ekbom disease, and drug therapy for insomnia. Figures include polysomnographic recording showing wakefulness in an adult; stage 1, 2, and 3 NREM sleep in an adult; REM sleep in an adult; a patient with sleep apnea syndrome; a patient with Cheyne-Stokes breathing; a patient with RLS; and a patient with dream-enacting behavior; schematic sagittal section of the brainstem of the cat; schematic diagram of the McCarley-Hobson model of REM sleep mechanism; the Lu-Saper “flip-flop” model; the Luppi model to explain REM sleep mechanism; and a wrist actigraph from a man with bipolar disorder. This review contains 14 highly rendered figures, 8 tables, 115 references, and 5 MCQs.

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Arousal Characteristics in Patients with Parkinson’s Disease and Isolated Rapid Eye Movement Sleep Behavior Disorder

SLEEP ◽

10.1093/sleep/zsab167 ◽

2021 ◽

Author(s):

Andreas Brink-Kjær ◽

Matteo Cesari ◽

Friederike Sixel-Döring ◽

Brit Mollenhauer ◽

Claudia Trenkwalder ◽

...

Keyword(s):

Parkinson’S Disease ◽

Eye Movement ◽

Rem Sleep ◽

Regression Models ◽

Muscle Tone ◽

Behavior Disorder ◽

Nrem Sleep ◽

Rapid Eye Movement ◽

Sleep Behavior

Abstract Study objectives Patients diagnosed with isolated rapid eye movement (REM) sleep behavior disorder (iRBD) and Parkinson’s disease (PD) have altered sleep stability reflecting neurodegeneration in brainstem structures. We hypothesize that neurodegeneration alters the expression of cortical arousals in sleep. Methods We analyzed polysomnography data recorded from 88 healthy controls (HC), 22 iRBD patients, 82 de novo PD patients without RBD and 32 with RBD (PD+RBD). These patients were also investigated at a 2-year follow-up. Arousals were analyzed using a previously validated automatic system, which used a central EEG lead, electrooculography, and chin electromyography. Multiple linear regression models were fitted to compare group differences at baseline and change to follow-up for arousal index (ArI), shifts in electroencephalographic signals associated with arousals, and arousal chin muscle tone. The regression models were adjusted for known covariates affecting the nature of arousal. Results In comparison to HC, patients with iRBD and PD+RBD showed increased ArI during REM sleep and their arousals showed a significantly lower shift in α-band power at arousals and a higher muscle tone during arousals. In comparison to HC, the PD patients were characterized by a decreased ArI in NREM sleep at baseline. ArI during NREM sleep decreased further at the 2-year follow-up, although not significantly Conclusions Patients with PD and iRBD present with abnormal arousal characteristics as scored by an automated method. These abnormalities are likely to be caused by neurodegeneration of the reticular activation system due to alpha-synuclein aggregation.

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Nonrapid eye movement sleep electroencephalographic oscillations in idiopathic rapid eye movement sleep behavior disorder: a study of sleep spindles and slow oscillations

SLEEP ◽

10.1093/sleep/zsaa160 ◽

2020 ◽

Author(s):

Jun-Sang Sunwoo ◽

Kwang Su Cha ◽

Jung-Ick Byun ◽

Jin-Sun Jun ◽

Tae-Joon Kim ◽

...

Keyword(s):

Eye Movement ◽

Rem Sleep ◽

Rem Sleep Behavior Disorder ◽

Behavior Disorder ◽

Nrem Sleep ◽

Sleep Spindles ◽

Rapid Eye Movement ◽

Sleep Behavior ◽

Slow Oscillations ◽

Lower Amplitude

Abstract Study Objectives We investigated electroencephalographic (EEG) slow oscillations (SOs), sleep spindles (SSs), and their temporal coordination during nonrapid eye movement (NREM) sleep in patients with idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD). Methods We analyzed 16 patients with video-polysomnography-confirmed iRBD (age, 65.4 ± 6.6 years; male, 87.5%) and 10 controls (age, 62.3 ± 7.5 years; male, 70%). SSs and SOs were automatically detected during stage N2 and N3. We analyzed their characteristics, including density, frequency, duration, and amplitude. We additionally identified SO-locked spindles and examined their phase distribution and phase locking with the corresponding SO. For inter-group comparisons, we used the independent samples t-test or Wilcoxon rank-sum test, as appropriate. Results The SOs of iRBD patients had significantly lower amplitude, longer duration (p = 0.005 for both), and shallower slope (p < 0.001) than those of controls. The SS power of iRBD patients was significantly lower than that of controls (p = 0.002), although spindle density did not differ significantly. Furthermore, SO-locked spindles of iRBD patients prematurely occurred during the down-to-up-state transition of SOs, whereas those of controls occurred at the up-state peak of SOs (p = 0.009). The phase of SO-locked spindles showed a positive correlation with delayed recall subscores (p = 0.005) but not with tonic or phasic electromyography activity during REM sleep. Conclusions In this study, we found abnormal EEG oscillations during NREM sleep in patients with iRBD. The impaired temporal coupling between SOs and SSs may reflect early neurodegenerative changes in iRBD.

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The European starling (Sturnus vulgaris) shows signs of NREM sleep homeostasis but has very little REM sleep and no REM sleep homeostasis

SLEEP ◽

10.1093/sleep/zsz311 ◽

2019 ◽

Vol 43 (6) ◽

Cited By ~ 4

Author(s):

Sjoerd J van Hasselt ◽

Maria Rusche ◽

Alexei L Vyssotski ◽

Simon Verhulst ◽

Niels C Rattenborg ◽

...

Keyword(s):

Sleep Deprivation ◽

Eye Movement ◽

Rem Sleep ◽

Spectral Power ◽

Nrem Sleep ◽

Sleep Time ◽

European Starling ◽

Dark Phase ◽

Rapid Eye Movement ◽

Sleep Homeostasis

Abstract Most of our knowledge about the regulation and function of sleep is based on studies in a restricted number of mammalian species, particularly nocturnal rodents. Hence, there is still much to learn from comparative studies in other species. Birds are interesting because they appear to share key aspects of sleep with mammals, including the presence of two different forms of sleep, i.e. non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. We examined sleep architecture and sleep homeostasis in the European starling, using miniature dataloggers for electroencephalogram (EEG) recordings. Under controlled laboratory conditions with a 12:12 h light–dark cycle, the birds displayed a pronounced daily rhythm in sleep and wakefulness with most sleep occurring during the dark phase. Sleep mainly consisted of NREM sleep. In fact, the amount of REM sleep added up to only 1~2% of total sleep time. Animals were subjected to 4 or 8 h sleep deprivation to assess sleep homeostatic responses. Sleep deprivation induced changes in subsequent NREM sleep EEG spectral qualities for several hours, with increased spectral power from 1.17 Hz up to at least 25 Hz. In contrast, power below 1.17 Hz was decreased after sleep deprivation. Sleep deprivation also resulted in a small compensatory increase in NREM sleep time the next day. Changes in EEG spectral power and sleep time were largely similar after 4 and 8 h sleep deprivation. REM sleep was not noticeably compensated after sleep deprivation. In conclusion, starlings display signs of NREM sleep homeostasis but the results do not support the notion of important REM sleep functions.

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Quantitative electroencephalography measures in rapid eye movement and nonrapid eye movement sleep are associated with apnea–hypopnea index and nocturnal hypoxemia in men

SLEEP ◽

10.1093/sleep/zsz092 ◽

2019 ◽

Vol 42 (7) ◽

Cited By ~ 6

Author(s):

Sarah L Appleton ◽

Andrew Vakulin ◽

Angela D’Rozario ◽

Andrew D Vincent ◽

Alison Teare ◽

...

Keyword(s):

Eye Movement ◽

Rem Sleep ◽

Nrem Sleep ◽

Community Dwelling ◽

Total Power ◽

Apnea Hypopnea Index ◽

Rapid Eye Movement ◽

Quantitative Electroencephalography ◽

Nocturnal Hypoxemia ◽

Eeg Power

AbstractStudy ObjectivesQuantitative electroencephalography (EEG) measures of sleep may identify vulnerability to obstructive sleep apnea (OSA) sequelae, however, small clinical studies of sleep microarchitecture in OSA show inconsistent alterations. We examined relationships between quantitative EEG measures during rapid eye movement (REM) and non-REM (NREM) sleep and OSA severity among a large population-based sample of men while accounting for insomnia.MethodsAll-night EEG (F4-M1) recordings from full in-home polysomnography (Embletta X100) in 664 men with no prior OSA diagnosis (age ≥ 40) were processed following exclusion of artifacts. Power spectral analysis included non-REM and REM sleep computed absolute EEG power for delta, theta, alpha, sigma, and beta frequency ranges, total power (0.5–32 Hz) and EEG slowing ratio.ResultsApnea–hypopnea index (AHI) ≥10/h was present in 51.2% (severe OSA [AHI ≥ 30/h] 11.6%). In mixed effects regressions, AHI was positively associated with EEG slowing ratio and EEG power across all frequency bands in REM sleep (all p < 0.05); and with beta power during NREM sleep (p = 0.06). Similar associations were observed with oxygen desaturation index (3%). Percentage total sleep time with oxygen saturation <90% was only significantly associated with increased delta, theta, and alpha EEG power in REM sleep. No associations with subjective sleepiness were observed.ConclusionsIn a large sample of community-dwelling men, OSA was significantly associated with increased EEG power and EEG slowing predominantly in REM sleep, independent of insomnia. Further study is required to assess if REM EEG slowing related to nocturnal hypoxemia is more sensitive than standard PSG indices or sleepiness in predicting cognitive decline.

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Mechanism controlling sleep organization of the obese Zucker rats

Journal of Applied Physiology ◽

10.1152/jappl.1998.84.1.253 ◽

1998 ◽

Vol 84 (1) ◽

pp. 253-256 ◽

Cited By ~ 29

Author(s):

David Megirian ◽

Jacek Dmochowski ◽

Gaspar A. Farkas

Keyword(s):

Eye Movement ◽

Rem Sleep ◽

Nrem Sleep ◽

Zucker Rats ◽

Rapid Eye Movement ◽

Zucker Rat ◽

Obese Zucker Rat ◽

Obese Rats ◽

Obese Zucker Rats ◽

The Mean

Megirian, David, Jacek Dmochowski, and Gaspar A. Farkas. Mechanism controlling sleep organization of the obese Zucker rat. J. Appl. Physiol. 84(1): 253–256, 1998.—We tested the hypothesis that the obese ( fa/fa) Zucker rat has a sleep organization that differs from that of lean Zucker rats. We used the polygraphic technique to identify and to quantify the distribution of the three main states of the rat: wakefulness (W), non-rapid-eye-movement (NREM), and rapid-eye-movement (REM) sleep states. Assessment of states was made with light present (1000–1600), at the rats thermoneutral temperature of 29°C. Obese rats, compared with lean ones, did not show significant differences in the total time spent in the three main states. Whereas the mean durations of W and REM states did not differ statistically, that of NREM did ( P = 0.046). However, in the obese rats, the frequencies of switching from NREM sleep to W, which increased, and from NREM to REM sleep, which decreased, were statistically significantly different ( P = 0.019). Frequency of switching from either REM or W state was not significantly different. We conclude that sleep organization differs between lean and obese Zucker rats and that it is due to a disparity in switching from NREM sleep to either W or REM sleep and the mean duration of NREM sleep.

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Cricothyroid muscle activity during sleep in normal adult humans

Journal of Applied Physiology ◽

10.1152/jappl.1994.76.6.2326 ◽

1994 ◽

Vol 76 (6) ◽

pp. 2326-2332 ◽

Cited By ~ 17

Author(s):

S. T. Kuna ◽

J. S. Smickley ◽

C. R. Vanoye ◽

T. H. McMillan

Keyword(s):

Eye Movement ◽

Rem Sleep ◽

Positive Pressure Ventilation ◽

Nrem Sleep ◽

Normal Adult ◽

Positive Pressure ◽

Rapid Eye Movement ◽

Adult Humans ◽

Inspiratory Activity ◽

Continuous Positive Pressure

Previous investigators reported that cricothyroid (CT) muscle usually exhibits phasic inspiratory activity in normal adult humans during wakefulness. The purpose of this study was to determine respiratory-related CT activity in normal adult humans during sleep. Nighttime polysomnograms were performed in 16 subjects. Hooked-wire electrodes were percutaneously implanted in CT with 21-gauge needle-catheter unit that allowed artifact-free monopolar recordings during electrode placement. During wakefulness, CT was usually phasically active on inspiration, with tonic activity throughout the respiratory cycle. Phasic inspiratory activity was present throughout sleep in all subjects, even those without respiratory-related CT activity during wakefulness. Compared with non-rapid-eye-movement (NREM) sleep, phasic CT activity uniformly increased in rapid-eye-movement (REM) sleep. No differences were apparent in height of phasic CT activity between phasic and tonic REM sleep. Application of nasal continuous positive pressure in stage 3/4 NREM sleep was associated with a decrease in phasic CT activity. Passively induced hypocapnia with positive-pressure ventilation via a nose mask in stage 3/4 NREM sleep was associated with a disappearance of phasic CT activity. Cessation of positive-pressure ventilation under hypocapnic conditions frequently resulted in apnea. Phasic CT activity remained absent during apnea but reappeared coincident with or soon after resumption of spontaneous respiration. In summary, CT′s phasic inspiratory activity and respiratory-related response to various stimuli during sleep were very similar to those of posterior cricoarytenoid muscle, the principal vocal cord abductor.

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