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Nature Neuroscience Feb 2023Although considered an inactive state for centuries, sleep entails many active processes occurring at the cellular, circuit and organismal levels. Over the last decade,... (Review)
Review
Although considered an inactive state for centuries, sleep entails many active processes occurring at the cellular, circuit and organismal levels. Over the last decade, several key technological advances, including calcium imaging and optogenetic and chemogenetic manipulations, have facilitated a detailed understanding of the functions of different neuronal populations and circuits in sleep-wake regulation. Here, we present recent progress and summarize our current understanding of the circuitry underlying the initiation, maintenance and coordination of wakefulness, rapid eye movement sleep (REMS) and non-REMS (NREMS). We propose a de-arousal model for sleep initiation, in which the neuromodulatory milieu necessary for sleep initiation is achieved by engaging in repetitive pre-sleep behaviors that gradually reduce vigilance to the external environment and wake-promoting neuromodulatory tone. We also discuss how brain processes related to thermoregulation, hunger and fear intersect with sleep-wake circuits to control arousal. Lastly, we discuss controversies and lingering questions in the sleep field.
Topics: Wakefulness; Sleep; Sleep, REM; Arousal; Brain; Electroencephalography
PubMed: 36581730
DOI: 10.1038/s41593-022-01236-w -
Advances in Experimental Medicine and... 2021Sleep and wakefulness are complex, tightly regulated behaviors that occur in virtually all animals. With recent exciting developments in neuroscience methodologies such... (Review)
Review
Sleep and wakefulness are complex, tightly regulated behaviors that occur in virtually all animals. With recent exciting developments in neuroscience methodologies such as optogenetics, chemogenetics, and cell-specific calcium imaging technology, researchers can advance our understanding of how discrete neuronal groups precisely modulate states of sleep and wakefulness. In this chapter, we provide an overview of key neurotransmitter systems, neurons, and circuits that regulate states of sleep and wakefulness. We also describe long-standing models for the regulation of sleep/wake and non-rapid eye movement/rapid eye movement cycling. We contrast previous knowledge derived from classic approaches such as brain stimulation, lesions, cFos expression, and single-unit recordings, with emerging data using the newest technologies. Our understanding of neural circuits underlying the regulation of sleep and wakefulness is rapidly evolving, and this knowledge is critical for our field to elucidate the enigmatic function(s) of sleep.
Topics: Animals; Neurobiology; Neurons; Optogenetics; Sleep; Wakefulness
PubMed: 33537937
DOI: 10.1007/978-3-030-61663-2_5 -
Sleep Medicine Reviews Aug 2022Understanding the associations between adequate sleep, performance and health outcomes is vital, yet a major limitation in the design and interpretation of studies of... (Review)
Review
Understanding the associations between adequate sleep, performance and health outcomes is vital, yet a major limitation in the design and interpretation of studies of sleep and performance is the variability of subjective and objective markers used to assess sleep quality. The aim of this scoping review is to investigate how various physiological signals recorded during sleep or wakefulness relate to objective measures of cognitive or physical performance and subjectively perceived sleep quality to inform conceptual understanding of the elusive, amorphous, and multi-dimensional construct of sleep quality. We also aimed to suggest priorities for future areas of research in sleep quality and performance. We searched six databases ultimately yielding 439 studies after duplicate removal. Sixty-five studies were selected for full review. In general, correlations between objectively measured sleep and objective performance or subjectively assessed sleep quality were weak to moderate. Slow wave sleep was moderately correlated with better performance on tasks of vigilance, motor speed, and executive function as well as better subjective sleep quality and feeling well-rested, suggesting that slow wave sleep may be important for sleep quality and optimal daytime performance. However, these findings were inconsistent across studies. Increased sleep fragmentation was associated with poorer subjective sleep quality in both polysomnographic and actigraphic studies. Studies which simultaneously assessed physiologic sleep measures, performance measures and subjective sleep perception were few, limiting the ability to evaluate correlations between subjective and objective outcomes concurrently in the same individuals. Factors influencing the relationship between sleep quality and performance include circadian variability, sleep inertia, and mismatch between sleep stages studied and outcome measures of choice. Ultimately, the determination of "quality sleep" remains largely subjective and inconsistently quantifiable by current measures. Methods evaluating sleep as a continuous measure rather than traditional sleep stages may provide an intriguing approach to future studies of sleep and performance. Future well-designed studies using novel measures of sleep or multimodal ambulatory wearables assessing the three domains of sleep and performance (objective sleep physiology, objective performance, and subjective sleep quality) are needed to better define quality sleep.
Topics: Humans; Sleep; Sleep Initiation and Maintenance Disorders; Sleep Quality; Sleep Stages; Wakefulness
PubMed: 35753151
DOI: 10.1016/j.smrv.2022.101657 -
Neuropsychopharmacology : Official... Jan 2020Vigilant attention is a major component of a wide range of cognitive performance tasks. Vigilant attention is impaired by sleep deprivation and restored after rest... (Review)
Review
Vigilant attention is a major component of a wide range of cognitive performance tasks. Vigilant attention is impaired by sleep deprivation and restored after rest breaks and (more enduringly) after sleep. The temporal dynamics of vigilant attention deficits across hours and days are driven by physiologic, sleep regulatory processes-a sleep homeostatic process and a circadian process. There is also evidence of a slower, allostatic process, which modulates the sleep homeostatic setpoint across days and weeks and is responsible for cumulative deficits in vigilant attention across consecutive days of sleep restriction. There are large inter-individual differences in vulnerability to sleep loss, and these inter-individual differences constitute a pronounced human phenotype. However, this phenotype is multi-dimensional; vulnerability in terms of vigilant attention impairment can be dissociated from vulnerability in terms of other cognitive processes such as attentional control. The vigilance decrement, or time-on-task effect-a decline in performance across the duration of a vigilant attention task-is characterized by progressively increasing response variability, which is exacerbated by sleep loss. This variability, while crucial to understanding the impact of sleep deprivation on performance in safety-critical tasks, is not well explained by top-down regulatory mechanisms, such as the homeostatic and circadian processes. A bottom-up, neuronal pathway-dependent mechanism involving use-dependent, local sleep may be the main driver of response variability. This bottom-up mechanism may also explain the dissociation between cognitive processes with regard to trait vulnerability to sleep loss.
Topics: Arousal; Attention; Brain; Humans; Sleep Deprivation; Wakefulness
PubMed: 31176308
DOI: 10.1038/s41386-019-0432-6 -
Trends in Neurosciences Sep 2022Recent studies in both humans and animal models call into question the completeness of recovery after chronic sleep disruption. Studies in humans have identified... (Review)
Review
Recent studies in both humans and animal models call into question the completeness of recovery after chronic sleep disruption. Studies in humans have identified cognitive domains particularly vulnerable to delayed or incomplete recovery after chronic sleep disruption, including sustained vigilance and episodic memory. These findings, in turn, provide a focus for animal model studies to critically test the lasting impact of sleep loss on the brain. Here, we summarize the human response to sleep disruption and then discuss recent findings in animal models examining recovery responses in circuits pertinent to vigilance and memory. We then propose pathways of injury common to various forms of sleep disruption and consider the implications of this injury in aging and in neurodegenerative disorders.
Topics: Aging; Animals; Brain; Humans; Memory, Episodic; Sleep; Wakefulness
PubMed: 35691776
DOI: 10.1016/j.tins.2022.05.007 -
Frontiers of Neurology and Neuroscience 2021The hypocretins/orexins are two excitatory neuropeptides, alternately called HCRT1 or orexin-A and HCRT2 or orexin-B, that are the endogenous ligands for two... (Review)
Review
The hypocretins/orexins are two excitatory neuropeptides, alternately called HCRT1 or orexin-A and HCRT2 or orexin-B, that are the endogenous ligands for two G-protein-coupled receptors, HCRTR1/OX1R and HCRTR2/OX2R. Shortly after the discovery of this system, degeneration of hypocretin/orexin-producing neurons was implicated in the etiology of the sleep disorder narcolepsy. The involvement of this system in a disorder characterized by the loss of control over arousal state boundaries also suggested its role as a critical component of endogenous sleep-wake regulatory circuitry. The broad projections of the hypocretin/orexin-producing neurons, along with differential expression of the two receptors in the projection fields of these neurons, suggest distinct roles for these receptors. While HCRTR1/OX1R is associated with regulation of motivation, reward, and autonomic functions, HCRTR2/OX2R is strongly linked to sleep-wake control. The association of hypocretin/orexin with these physiological processes has led to intense interest in the therapeutic potential of compounds targeting these receptors. Agonists and antagonists for the hypocretin/orexin receptors have shown potential for the treatment of disorders of excessive daytime somnolence and nocturnal hyperarousal, respectively, with the first antagonists approved by the US Food and Drug Administration (FDA) in 2014 and 2019 for the treatment of insomnia. These and related compounds have also been useful tools to advance hypocretin/orexin neurobiology.
Topics: Animals; Disorders of Excessive Somnolence; Humans; Orexin Receptor Antagonists; Orexin Receptors; Orexins; Sleep; Sleep Initiation and Maintenance Disorders; Sleep Wake Disorders; Wakefulness
PubMed: 34052813
DOI: 10.1159/000514963 -
Neurologic Clinics Aug 2019Endogenous central and peripheral circadian oscillators are key to organizing multiple aspects of mammalian physiology; this clock tracks the day-night cycle and governs... (Review)
Review
Endogenous central and peripheral circadian oscillators are key to organizing multiple aspects of mammalian physiology; this clock tracks the day-night cycle and governs behavioral and physiologic rhythmicity. Flexibility in the timing and duration of sleep and wakefulness, critical to the survival of species, is the result of a complex, dynamic interaction between 2 regulatory processes: the clock and a homeostatic drive that increases with wake duration and decreases during sleep. When circadian rhythmicity and sleep homeostasis are misaligned-as in shifted schedules, time zone transitions, aging, or disease-sleep, metabolic, and other disorders may ensue.
Topics: Animals; Circadian Rhythm; Homeostasis; Humans; Sleep; Wakefulness
PubMed: 31256784
DOI: 10.1016/j.ncl.2019.03.001 -
Annual Review of Neuroscience Jul 2019Wakefulness, rapid eye movement (REM) sleep, and non-rapid eye movement (NREM) sleep are characterized by distinct electroencephalogram (EEG), electromyogram (EMG), and... (Review)
Review
Wakefulness, rapid eye movement (REM) sleep, and non-rapid eye movement (NREM) sleep are characterized by distinct electroencephalogram (EEG), electromyogram (EMG), and autonomic profiles. The circuit mechanism coordinating these changes during sleep-wake transitions remains poorly understood. The past few years have witnessed rapid progress in the identification of REM and NREM sleep neurons, which constitute highly distributed networks spanning the forebrain, midbrain, and hindbrain. Here we propose an arousal-action circuit for sleep-wake control in which wakefulness is supported by separate arousal and action neurons, while REM and NREM sleep neurons are part of the central somatic and autonomic motor circuits. This model is well supported by the currently known sleep and wake neurons. It can also account for the EEG, EMG, and autonomic profiles of wake, REM, and NREM states and several key features of their transitions. The intimate association between the sleep and autonomic/somatic motor control circuits suggests that a primary function of sleep is to suppress motor activity.
Topics: Animals; Arousal; Brain; Electroencephalography; Humans; Models, Neurological; Nerve Net; Neurons; Sleep; Sleep Stages; Wakefulness
PubMed: 30699051
DOI: 10.1146/annurev-neuro-080317-061813 -
Neuron Oct 2023The expression of defensive responses to alerting sensory cues requires both general arousal and a specific arousal state associated with defensive emotions. However, it...
The expression of defensive responses to alerting sensory cues requires both general arousal and a specific arousal state associated with defensive emotions. However, it remains unclear whether these two forms of arousal can be regulated by common brain regions. We discovered that the medial sector of the auditory thalamus (ATm) in mice is a thalamic hub controlling both general and defensive arousal. The spontaneous activity of VGluT2-expressing ATm (ATm) neurons was correlated with and causally contributed to wakefulness. In sleeping mice, sustained ATm population responses were predictive of sensory-induced arousal, the likelihood of which was markedly decreased by inhibiting ATm neurons or multiple downstream pathways. In awake mice, ATm activation led to heightened arousal accompanied by excessive anxiety and avoidance behavior. Notably, blocking their neurotransmission abolished alerting stimuli-induced defensive behaviors. These findings may shed light on the comorbidity of sleep disturbances and abnormal sensory sensitivity in specific brain disorders.
Topics: Mice; Animals; Arousal; Thalamus; Wakefulness; Neurons; Synaptic Transmission
PubMed: 37557180
DOI: 10.1016/j.neuron.2023.07.007 -
Nature Communications Jul 2022Humans and animals lacking orexin neurons exhibit daytime sleepiness, sleep attacks, and state instability. While the circuit basis by which orexin neurons contribute to...
Humans and animals lacking orexin neurons exhibit daytime sleepiness, sleep attacks, and state instability. While the circuit basis by which orexin neurons contribute to consolidated wakefulness remains unclear, existing models posit that orexin neurons provide their wake-stabilizing influence by exerting excitatory tone on other brain arousal nodes. Here we show using in vivo optogenetics, in vitro optogenetic-based circuit mapping, and single-cell transcriptomics that orexin neurons also contribute to arousal maintenance through indirect inhibition of sleep-promoting neurons of the ventrolateral preoptic nucleus. Activation of this subcortical circuit rapidly drives wakefulness from sleep by differentially modulating the activity of ventrolateral preoptic neurons. We further identify and characterize a feedforward circuit through which orexin (and co-released glutamate) acts to indirectly target and inhibit sleep-promoting ventrolateral preoptic neurons to produce arousal. This revealed circuitry provides an alternate framework for understanding how orexin neurons contribute to the maintenance of consolidated wakefulness and stabilize behavioral state.
Topics: Animals; Arousal; Humans; Neurons; Orexins; Sleep; Wakefulness
PubMed: 35851580
DOI: 10.1038/s41467-022-31591-y