Paradoxical (REM) sleep genesis by the brainstem is under hypothalamic control

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.rapid eye movement sleep | acetylcholine | optogenetics | mesopontine tegmentum | mouse R apid eye movement (REM) sleep is tightly regulated, yet the mechanisms that control REM sleep remain incompletely understood. Early pharmacological and unit recording studies suggested that ACh was important for REM sleep regulation (1, 2). For example, injection of cholinergic drugs into the dorsal mesopontine tegmentum reliably induced a state very similar to natural REM sleep in cats (3-6). Unit recordings from the cholinergic areas of the mesopontine tegmentum revealed cells that were active during wakefulness and REM sleep, as well as neurons active only during REM sleep (7-13). Electrical stimulation of the laterodorsal tegmentum (LDT) in cats increased the percentage of time spent in REM sleep (14), and activation of the pedunculopontine tegmentum (PPT) in rats induced wakefulness and REM sleep (15). If cholinergic PPT and LDT neurons are necessary for REM sleep to occur, as the early studies suggest, then lesioning the PPT or LDT should decrease REM sleep. In cats, lesions of the PPT and LDT do disrupt REM sleep (16, 17), but lesions in rodents have had little effect on REM sleep or increased REM sleep (18)(19)(20)(21)(22). Additionally, c-fos studies have found very few cholinergic cells activated under high-REM sleep conditions. When c-fos-positive cholinergic neurons in the PPT and LDT are found to correlate with the percentage of REM sleep, they still account for only a few of the total cholinergic cells in the area (23). Juxtacellular recordings of identified cholinergic neurons in the LDT found these cells had wake and REM active firing profiles, with the majority firing the highest during REM sleep (13). These discrepancies have led to alternative theories of REM sleep regulation, where cholinergic neurons do not play a key role (18, 19, 23, 24 and reviewed in 25, 26).The PPT and LDT are made up of heterogeneous populations of cells, including distinct populations of cholinergic, GABAergic, and glutamatergic neurons (27-29). Many GABAergic neurons are active during REM sleep, as indicated by c-fos (23), and both GABAergic and glutamatergic neurons have been found with maximal firing rates during REM sleep in the LDT and medial PPT (13...

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“…4C). As has been suggested before (34) PPT 60 150 151 80 168 146 180 171 99 LDT 60 196 181 80 226 219 180 163 …”

Section: Discussionmentioning

confidence: 68%

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

Dort

Zachs

Kenny

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

249

159

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“…22 The high selectivity of MPTP to midbrain dopaminergic neurons 23 suggests that the presence of REM sleep without atonia might reflect the early involvement of dopaminergic neurotransmission on pontine and medullary REM sleep-related structures. 24 The extent to which the nigrostriatal dopaminergic system contributes to the regulation of REM sleep and RBD needs to be confirmed in more extensive studies. In our study PD patients with and without RBD did not differ with regard to 123 I-FP-CIT binding in the putamen, and no relation was found between 123 I-FP-CIT binding and EMG-activity during REM sleep in both groups.…”

Section: Discussionmentioning

confidence: 99%

Increased Motor Activity During REM Sleep Is Linked with Dopamine Function in Idiopathic REM Sleep Behavior Disorder and Parkinson Disease

Zoetmulder

Nikolic

Biernat

et al. 2016

Journal of Clinical Sleep Medicine

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Study Objectives: Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by impaired motor inhibition during REM sleep, and dream-enacting behavior. RBD is especially associated with α-synucleinopathies, such as Parkinson disease (PD). Follow-up studies have shown that patients with idiopathic RBD (iRBD) have an increased risk of developing an α-synucleinopathy in later life. Although abundant studies have shown that degeneration of the nigrostriatal dopaminergic system is associated with daytime motor function in Parkinson disease, only few studies have investigated the relation between this system and electromyographic (EMG) activity during sleep. The objective of this study was to investigate the relationship between the nigrostriatal dopamine system and muscle activity during sleep in iRBD and PD. Methods: 10 iRBD patients, 10 PD patients with PD, 10 PD patients without RBD, and 10 healthy controls were included and assessed with (123)I-N-omegafluoropropyl-2-beta-carboxymethoxy-3beta-(4-iodophenyl) nortropane ((123)I-FP-CIT) Single-photon emission computed tomography (SPECT) scanning ( 123 I-FP-CIT SPECT), neurological examination, and polysomnography. Results: iRBD patients and PD patients with RBD had increased EMG-activity compared to healthy controls.123 I-FP-CIT uptake in the putamen-region was highest in controls, followed by iRBD patients, and lowest in PD patients. In iRBD patients, EMG-activity in the mentalis muscle was correlated to 123 I-FP-CIT uptake in the putamen. In PD patients, EMG-activity was correlated to anti-Parkinson medication. Conclusions: Our results support the hypothesis that increased EMG-activity during REM sleep is at least partly linked to the nigrostriatal dopamine system in iRBD, and with dopamine function in PD. I NTRO DUCTI O NREM sleep behavior disorder (RBD) is a parasomnia characterized by REM sleep without atonia , dream enactment behavior, and vivid (and/or) violent dreams. Longitudinal studies have shown that patients with idiopathic RBD (iRBD) have an increased risk for developing an α-synucleinopathy, such as Parkinson disease (PD).1,2 The high proportion of iRBD patients developing PD may indicate a link between nigrostriatal degeneration and increased night-time motor activity. It is increasingly recognized that the dopaminergic system is associated with sleep-wake disturbances.3,4 Previous studies have shown that basal ganglia structures, such as the substantia nigra pars reticulata and the internal segment of the globus pallidus, have caudal connections to regions that modulate REM sleep atonia. 5 Imaging studies in iRBD patients have shown microstructural changes in substantia nigra, 6 reduced volume of the putamen, 7 as well as reduced density of the striatal dopamine transporter, which decreases in the course of disease progression. 8 In addition monkeys treated sub-chronic with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP), a neurotoxin which specifically targets dopaminergic neurons of the substantia nigra...

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“…Optogenetic activation of MCH neurons during NREM sleep significantly increases the probability of transitions to REM sleep [96]. Mechanisms of MCH REM sleep enhancement involve disinhibition of SLD REM on neurons via MCH/GABA inhibition of REM off neurons in the TMN, vlPAG, DRN, and LC [93,96].…”

Section: Rem Sleepmentioning

confidence: 99%

“…Neurons expressing the inhibitory peptide melaninconcentrating hormone (MCH) are localized in the lateral hypothalamus, zona incerta, and dorsomedial hypothalamus [93]. Included among the targets of MCH neurons are LC, DRN, and vlPAG.…”

Section: Rem Sleepmentioning

confidence: 99%

Neurobiology of Arousal and Sleep: Updates and Insights Into Neurological Disorders

Lim

Szymusiak

2015

Curr Sleep Medicine Rep

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Brain activation during wakefulness is sustained by multiple arousal systems. Dysfunction of one or more arousal systems is a feature of neurological disorders associated with hypersomnolence and/or sleep-wake cycle disturbance. Narcolepsy, Alzheimer's disease (AD), Parkinson's disease (PD), and traumatic brain injury appear to involve hypocretin (HCT) and possibly histamine insufficiency as a mechanism related to excessive daytime sleepiness. Loss of cholinergic neurons in AD and of dopamine neurons in PD contributes to sleepwake disturbance. GABAergic neurons in the preoptic hypothalamus and rostral medulla promote sleep through inhibition of arousal systems. Pathology of preoptic sleep regulatory circuits is correlated with sleep disturbance in AD. An unidentified endogenous somnogen that potentiates the actions of gamma-aminobutyric acid (GABA) is present in the cerebrospinal fluid (CSF) of patients with primary hypersomnia.Descending pathways from the dorsal lateral pons to the ventral medulla and spinal cord are responsible for the inhibition of spinal motoneurons during rapid eye movement (REM) sleep and are implicated in human REM sleep behavior disorder.

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Paradoxical (REM) sleep genesis by the brainstem is under hypothalamic control

Cited by 100 publications

References 48 publications

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

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

Increased Motor Activity During REM Sleep Is Linked with Dopamine Function in Idiopathic REM Sleep Behavior Disorder and Parkinson Disease

Neurobiology of Arousal and Sleep: Updates and Insights Into Neurological Disorders

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