REM sleep: Out-dreaming fear.

The ability to forget fear-inducing situations is essential for adapting to our environment, but the neural mechanisms underlying 'fear forgetting' remain unclear. Novel findings reveal that the activity of the infralimbic cortex - specifically during REM sleep - contributes to the extinction of fear memory.

Sleep: How stress keeps you up at night.

Stress disrupts sleep, but the neural mechanisms underlying this relationship remain unclear. Novel findings in mice reveal a hypothalamic circuit that fragments sleep and promotes arousal after stress.

The association between sleep quality and obstructive sleep apnea with health-related quality of life in children with obesity.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) and poor sleep quality are highly prevalent in children with obesity, but their individual associations with health-related quality of life (HRQOL) are unknown in this population. The primary objective was to describe the independent association of OSA and sleep quality with HRQOL in children with obesity. METHODS: This was a cross-sectional study of children with obesity at 2 tertiary care centers. Sleep quality and HRQOL were measured with the Pittsburgh Sleep Quality Index and Pediatric Quality of Life Inventory questionnaires, respectively. Multivariable regression models were created to evaluate associations between OSA and sleep quality with HRQOL. RESULTS: There were 98 children (median age 15.0 years, median body mass index z-score 3.8, 44% females). Among the study population, 49/98 (50%) children reported poor sleep quality, 41/98 (42%) children had OSA, and 52/98 (53%) children reported impaired HRQOL. Self-reported poor sleep quality was independently associated with reduced HRQOL, whereas the presence of OSA was not. Children with poor sleep quality had a reduced Pediatric Quality of Life Inventory score by 8.8 compared to children with good sleep quality (95% confidence interval, 2.6-14.9; P = .006), when adjusting for age, sex, body mass index z-score, attention-deficit/hyperactivity disorder, mood/anxiety disorder, and study site. CONCLUSIONS: In the current study of children with obesity, we found that HRQOL was more strongly associated with the self-reported experience of sleep than the presence of OSA. Clinicians should assess and optimize sleep quality as part of the evaluation for OSA in children with obesity. CITATION: Xiao L, Voutsas G, Ryan CM, Katz SL, Narang I. The association between sleep quality and obstructive sleep apnea with health-related quality of life in children with obesity. J Clin Sleep Med. 2023;19(11):1877-1883.

Immortal orexin cell transplants restore motor-arousal synchrony during cataplexy.

Waking behaviors such as sitting or standing require suitable levels of muscle tone. But it is unclear how arousal and motor circuits communicate with one another so that appropriate motor tone occurs during wakefulness. Cataplexy is a peculiar condition in which muscle tone is involuntarily lost during normal periods of wakefulness. Cataplexy therefore provides a unique opportunity for identifying the signaling mechanisms that synchronize motor and arousal behaviors. Cataplexy occurs when hypothalamic orexin neurons are lost in narcolepsy; however, it is unclear if motor-arousal decoupling in cataplexy is directly or indirectly caused by orexin cell loss. Here, we used genomic, proteomic, chemogenetic, electrophysiological, and behavioral assays to determine if grafting orexin cells into the brain of cataplectic (i.e., orexin-/-) mice restores normal motor-arousal behaviors by preventing cataplexy. First, we engineered immortalized orexin cells and found that they not only produce and release orexin but also exhibit a gene profile that mimics native orexin neurons. Second, we show that engineered orexin cells thrive and integrate into host tissue when transplanted into the brain of mice. Next, we found that grafting only 200-300 orexin cells into the dorsal raphe nucleus-a region densely innervated by native orexin neurons-reduces cataplexy. Last, we show that real-time chemogenetic activation of orexin cells restores motor-arousal synchrony by preventing cataplexy. We suggest that orexin signaling is critical for arousal-motor synchrony during wakefulness and that the dorsal raphe plays a pivotal role in coupling arousal and motor behaviors.

A novel machine learning system for identifying sleep-wake states in mice.

Research into sleep-wake behaviors relies on scoring sleep states, normally done by manual inspection of electroencephalogram (EEG) and electromyogram (EMG) recordings. This is a highly time-consuming process prone to inter-rater variability. When studying relationships between sleep and motor function, analyzing arousal states under a four-state system of active wake (AW), quiet wake (QW), nonrapid-eye-movement (NREM) sleep, and rapid-eye-movement (REM) sleep provides greater precision in behavioral analysis but is a more complex model for classification than the traditional three-state identification (wake, NREM, and REM sleep) usually used in rodent models. Characteristic features between sleep-wake states provide potential for the use of machine learning to automate classification. Here, we devised SleepEns, which uses a novel ensemble architecture, the time-series ensemble. SleepEns achieved 90% accuracy to the source expert, which was statistically similar to the performance of two other human experts. Considering the capacity for classification disagreements that are still physiologically reasonable, SleepEns had an acceptable performance of 99% accuracy, as determined blindly by the source expert. Classifications given by SleepEns also maintained similar sleep-wake characteristics compared to expert classifications, some of which were essential for sleep-wake identification. Hence, our approach achieves results comparable to human ability in a fraction of the time. This new machine-learning ensemble will significantly impact the ability of sleep researcher to detect and study sleep-wake behaviors in mice and potentially in humans.

Brain Circuits Underlying Narcolepsy.

Narcolepsy is a sleep disorder manifesting symptoms such as excessive daytime sleepiness and often cataplexy, a sudden and involuntary loss of muscle activity during wakefulness. The underlying neuropathological basis of narcolepsy is the loss of orexin neurons from the lateral hypothalamus. To date numerous animal models of narcolepsy have been produced in the laboratory, being invaluable tools for delineating the brain circuits of narcolepsy. This review will examine the evidence regarding the function of the orexin system, and how loss of this wake-promoting system manifests in excessive daytime sleepiness. This review will also outline the brain circuits controlling cataplexy, focusing on the contribution of orexin signaling loss in narcolepsy. Although our understanding of the brain circuits of narcolepsy has made great progress in recent years, much remains to be understood.

Neuroscience: Glutamate neurons in the medial septum control wakefulness.

Despite intensive research efforts, biologists still do not have a clear picture of the brain circuitry that controls behavioural arousal. However, new research has identified a novel septo-hypothalamic circuit that functions to promote wakefulness.

John Peever.

Interview with John Peever, who studies the brain mechanisms that control REM sleep and how their dysfunction underlies sleep disorders at the University of Toronto.

Neuroscience: An Arousal Circuit that Senses Danger in Sleep.

Dangerous or alerting stimuli typically trigger arousal from sleep; however, the brain circuitry responsible for threat detection during sleep remains unclear. New research in mice identified a specific class of neuron in the basal forebrain that causes arousal from sleep by responding to threatening stimuli.

The Sublaterodorsal Tegmental Nucleus Functions to Couple Brain State and Motor Activity during REM Sleep and Wakefulness.

Appropriate levels of muscle tone are needed to support waking behaviors such as sitting or standing. However, it is unclear how the brain functions to couple muscle tone with waking behaviors. Cataplexy is a unique experiment of nature in which muscle paralysis involuntarily intrudes into otherwise normal periods of wakefulness. Cataplexy therefore provides the opportunity to identify the circuit mechanisms that couple muscle tone and waking behaviors. Here, we tested the long-standing hypothesis that muscle paralysis during cataplexy is caused by recruitment of the brainstem circuit that induces muscle paralysis during REM sleep. Using behavioral, electrophysiological, and chemogenetic strategies, we found that muscle tone and arousal state can be decoupled by manipulation of the REM sleep circuit (the sublaterodorsal tegmental nucleus [SLD]). First, we show that silencing SLD neurons prevents motor suppression during REM sleep. Second, we show that activating these same neurons promotes cataplexy in narcoleptic (orexin-/-) mice, whereas silencing these neurons prevents cataplexy. Most importantly, we show that SLD neurons can decouple motor activity and arousal state in healthy mice. We show that SLD activation triggers cataplexy-like attacks in wild-type mice that are behaviorally and electrophysiologically indistinguishable from cataplexy in orexin-/- mice. We conclude that the SLD functions to engage arousal-motor synchrony during both wakefulness and REM sleep, and we propose that pathological recruitment of SLD neurons could underlie cataplexy in narcolepsy.

Neurobiological and immunogenetic aspects of narcolepsy: Implications for pharmacotherapy.

Excessive daytime sleepiness (EDS) and cataplexy are common symptoms of narcolepsy, a sleep disorder associated with the loss of hypocretin/orexin (Hcrt) neurons. Although only a few drugs have received regulatory approval for narcolepsy to date, treatment involves diverse medications that affect multiple biochemical targets and neural circuits. Clinical trials have demonstrated efficacy for the following classes of drugs as narcolepsy treatments: alerting medications (amphetamine, methylphenidate, modafinil/armodafinil, solriamfetol [JZP-110]), antidepressants (tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors), sodium oxybate, and the H3-receptor inverse agonist/antagonist pitolisant. Enhanced catecholamine availability and regulation of locus coeruleus (LC) norepinephrine (NE) neuron activity is likely central to the therapeutic activity of most of these compounds. LC NE neurons are integral to sleep/wake regulation and muscle tone; reduced excitatory input to the LC due to compromise of Hcrt/orexin neurons (likely due to autoimmune factors) results in LC NE dysregulation and contributes to narcolepsy/cataplexy symptoms. Agents that increase catecholamines and/or LC activity may mitigate EDS and cataplexy by elevating NE regulation of GABAergic inputs from the amygdala. Consequently, novel medications and treatment strategies aimed at preserving and/or modulating Hcrt/orexin-LC circuit integrity are warranted in narcolepsy/cataplexy.

Brainstem Nuclei Associated with Mediating Apnea-Induced Respiratory Motor Plasticity.

The respiratory control system is plastic. It has a working memory and is capable of retaining how respiratory stimuli affect breathing by regulating synaptic strength between respiratory neurons. For example, repeated airway obstructions trigger a form of respiratory plasticity that strengthens inspiratory activity of hypoglossal (XII) motoneurons. This form of respiratory plasticity is known as long-term facilitation (LTF) and requires noradrenaline released onto XII motoneurons. However, the brainstem regions responsible for this form of LTF remain unidentified. Here, we used electrophysiology, neuropharmacology and immunohistochemistry in adult rats to identify the brainstem regions involved in mediating LTF. First, we show that repeated airway obstructions induce LTF of XII motoneuron activity and that inactivation of the noradrenergic system prevents LTF. Second, we show that noradrenergic cells in the locus coeruleus (LC), which project to XII motoneurons, are recruited during LTF induction. Third, we show that targeted inactivation of noradrenergic LC cells during LTF induction prevents LTF. And lastly, we show that the nucleus tractus solitarius (NTS), which has known projections to the LC, is critical for LTF because its inactivation prevents LTF. Our results suggest that both the LC and NTS are involved in mediating apnea-induced LTF, and we hypothesize that a NTS → LC → XII circuit mechanism mediates this form of respiratory motor plasticity.

Neuroscience: A 'Skin Warming' Circuit that Promotes Sleep and Body Cooling.

Skin and body warming help initiate sleep, but the underlying neural mechanisms remain unclear. New research in mice shows that skin warming recruits a previously unidentified hypothalamic circuit that functions to promote sleep and body cooling.

The Biology of REM Sleep.

Considerable advances in our understanding of the mechanisms and functions of rapid-eye-movement (REM) sleep have occurred over the past decade. Much of this progress can be attributed to the development of new neuroscience tools that have enabled high-precision interrogation of brain circuitry linked with REM sleep control, in turn revealing how REM sleep mechanisms themselves impact processes such as sensorimotor function. This review is intended to update the general scientific community about the recent mechanistic, functional and conceptual developments in our current understanding of REM sleep biology and pathobiology. Specifically, this review outlines the historical origins of the discovery of REM sleep, the diversity of REM sleep expression across and within species, the potential functions of REM sleep (e.g., memory consolidation), the neural circuits that control REM sleep, and how dysfunction of REM sleep mechanisms underlie debilitating sleep disorders such as REM sleep behaviour disorder and narcolepsy.

Brain Circuitry Controlling Sleep and Wakefulness.

PURPOSE OF REVIEW: This article outlines the fundamental brain mechanisms that control sleep-wake patterns and reviews how pathologic changes in these control mechanisms contribute to common sleep disorders. RECENT FINDINGS: Discrete but interconnected clusters of cells located within the brainstem and hypothalamus comprise the circuits that generate wakefulness, non-rapid eye movement (non-REM) sleep, and REM sleep. These clusters of cells use specific neurotransmitters, or collections of neurotransmitters, to inhibit or excite their respective sleep- and wake-promoting target sites. These excitatory and inhibitory connections modulate not only the presence of wakefulness or sleep, but also the levels of arousal within those states, including the depth of sleep, degree of vigilance, and motor activity. Dysfunction or degeneration of wake- and sleep-promoting circuits is associated with narcolepsy, REM sleep behavior disorder, and age-related sleep disturbances. SUMMARY: Research has made significant headway in identifying the brain circuits that control wakefulness, non-REM, and REM sleep and has led to a deeper understanding of common sleep disorders and disturbances.

Degeneration of rapid eye movement sleep circuitry underlies rapid eye movement sleep behavior disorder.

During healthy rapid eye movement sleep, skeletal muscles are actively forced into a state of motor paralysis. However, in rapid eye movement sleep behavior disorder-a relatively common neurological disorder-this natural process is lost. A lack of motor paralysis (atonia) in rapid eye movement sleep behavior disorder allows individuals to actively move, which at times can be excessive and violent. At first glance this may sound harmless, but it is not because rapid eye movement sleep behavior disorder patients frequently injure themselves or the person they sleep with. It is hypothesized that the degeneration or dysfunction of the brain stem circuits that control rapid eye movement sleep paralysis is an underlying cause of rapid eye movement sleep behavior disorder. The link between brain stem degeneration and rapid eye movement sleep behavior disorder stems from the fact that rapid eye movement sleep behavior disorder precedes, in the majority (∼80%) of cases, the development of synucleinopathies such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, which are known to initially cause degeneration in the caudal brain stem structures where rapid eye movement sleep circuits are located. Furthermore, basic science and clinical evidence demonstrate that lesions within the rapid eye movement sleep circuits can induce rapid eye movement sleep-specific motor deficits that are virtually identical to those observed in rapid eye movement sleep behavior disorder. This review examines the evidence that rapid eye movement sleep behavior disorder is caused by synucleinopathic neurodegeneration of the core brain stem circuits that control healthy rapid eye movement sleep and concludes that rapid eye movement sleep behavior disorder is not a separate clinical entity from synucleinopathies but, rather, it is the earliest symptom of these disorders. © 2017 International Parkinson and Movement Disorder Society.

Activation of the Hypoglossal to Tongue Musculature Motor Pathway by Remote Control.

Reduced tongue muscle tone precipitates obstructive sleep apnea (OSA), and activation of the tongue musculature can lessen OSA. The hypoglossal motor nucleus (HMN) innervates the tongue muscles but there is no pharmacological agent currently able to selectively manipulate a channel (e.g., Kir2.4) that is highly restricted in its expression to cranial motor pools such as the HMN. To model the effect of manipulating such a restricted target, we introduced a "designer" receptor into the HMN and selectively modulated it with a "designer" drug. We used cre-dependent viral vectors (AAV8-hSyn-DIO-hM3Dq-mCherry) to transduce hypoglossal motoneurons of ChAT-Cre+ mice with hM3Dq (activating) receptors. We measured sleep and breathing in three conditions: (i) sham, (ii) after systemic administration of clozapine-N-oxide (CNO; 1 mg/kg) or (iii) vehicle. CNO activates hM3Dq receptors but is otherwise biologically inert. Systemic administration of CNO caused significant and sustained increases in tongue muscle activity in non-REM (261 ± 33% for 10 hrs) and REM sleep (217 ± 21% for 8 hrs), both P < 0.01 versus controls. Responses were specific and selective for the tongue with no effects on diaphragm or postural muscle activities, or sleep-wake states. These results support targeting a selective and restricted "druggable" target at the HMN (e.g., Kir2.4) to activate tongue motor activity during sleep.

Circuit mechanisms of sleepiness and cataplexy in narcolepsy.

Narcolepsy is a debilitating sleep disorder caused by loss of orexin neurons in the lateral hypothalamus. Excessive daytime sleepiness and cataplexy are the major complaints in narcolepsy, and are associated with impaired quality of life. Although it is unclear how orexin loss causes sleepiness and cataplexy, animal models have been instrumental in identifying the neurobiological underpinnings of narcolepsy because they reliably recapitulate disease symptoms. Current evidence indicates that orexin cell loss causes sleepiness and cataplexy by destabilizing the ability of the circuits that initiate and sustain normal levels of arousal and motor activity. This review highlights the latest research concerning the normal function of the orexin system and how its dysfunction causes narcolepsy symptoms.