Review

Authors: Thomas E Scammell, Elda Arrigoni, Jonathan O Lipton...

Sleep remains one of the most mysterious yet ubiquitous animal behaviors. We review current perspectives on the neural systems that regulate sleep/wake states in mammals and the circadian mechanisms that control their timing. We also outline key models for the regulation of rapid eye movement (REM) sleep and non-REM sleep, how mutual inhibition between specific pathways gives rise to these distinct states, and how dysfunction in these circuits can give rise to sleep disorders.

Topics: Animals; Behavior, Animal; Circadian Rhythm; Humans; Neurons; Sleep; Sleep, REM; Wakefulness

PubMed: 28231463
DOI: 10.1016/j.neuron.2017.01.014

Review

Authors: Zachary Zamore, Sigrid C Veasey

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

Review

Authors: Amanda N Hudson, Hans P A Van Dongen, Kimberly A Honn...

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

Review

Authors: William J Schwartz, Elizabeth B Klerman

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

Authors: Yiwei Wang, Ling You, KaMun Tan...

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

Review

Authors: Danqian Liu, Yang Dan

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

Review

Authors: Lishan Huang, Wenwen Zhu, Nanxi Li...

Sleep is a natural and recurring state of life. Long-term insomnia can lead to physical and mental fatigue, inattention, memory loss, anxiety, depression and other symptoms, imposing immense public health and economic burden worldwide. The sleep and awakening regulation system is composed of many nerve nuclei and neurotransmitters in the brain, and it forms a neural network that interacts and restricts each other to regulate the occurrence and maintenance of sleep-wake. Adenosine (AD) is a neurotransmitter in the central nervous system and a driver of sleep. Meanwhile, the functions and mechanisms underlying sleep-promoting effects of adenosine and its receptors are still not entirely clear. However, in recent years, the increasing evidence indicated that adenosine can promote sleep through inhibiting arousal system and activating sleep-promoting system. At the same time, astrocyte-derived adenosine in modulating sleep homeostasis and sleep loss-induced related cognitive and memory deficits plays an important role. This review, therefore, summarizes the current research on the functions and possible mechanisms of adenosine and its receptors in the regulation of sleep and homeostatic control of sleep. Understanding these aspects will provide us better ideas on clinical problems such as insomnia, hypersomnia and other sleep disorders.

Topics: Humans; Adenosine; Sleep Initiation and Maintenance Disorders; Wakefulness; Sleep; Brain; Neurotransmitter Agents

PubMed: 38373361
DOI: 10.1016/j.sleep.2024.02.012

Review

Authors: Yu Sun, Ryan K Tisdale, Thomas S Kilduff...

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

Authors: Yu-Ting Tseng, Binghao Zhao, Shanping Chen...

When an animal faces a threatening situation while asleep, rapid arousal is the essential prerequisite for an adequate response. Here, we find that predator stimuli induce immediate arousal from REM sleep compared with NREM sleep. Using in vivo neural activity recording and cell-type-specific manipulations, we identify neurons in the medial subthalamic nucleus (mSTN) expressing corticotropin-releasing hormone (CRH) that mediate arousal and defensive responses to acute predator threats received through multiple sensory modalities across REM sleep and wakefulness. We observe involvement of the same neurons in the normal regulation of REM sleep and the adaptive increase in REM sleep induced by sustained predator stress. Projections to the lateral globus pallidus (LGP) are the effector pathway for the threat-coping responses and REM-sleep expression. Together, our findings suggest adaptive REM-sleep responses could be protective against threats and uncover a critical component of the neural circuitry at their basis.

Topics: Animals; Arousal; Corticotropin-Releasing Hormone; Neurons; Sleep; Sleep, REM; Wakefulness

PubMed: 35065715
DOI: 10.1016/j.neuron.2021.12.033

Authors: Brian L Edlow, Mark Olchanyi, Holly J Freeman...

Consciousness is composed of arousal (i.e., wakefulness) and awareness. Substantial progress has been made in mapping the cortical networks that underlie awareness in the human brain, but knowledge about the subcortical networks that sustain arousal in humans is incomplete. Here, we aimed to map the connectivity of a proposed subcortical arousal network that sustains wakefulness in the human brain, analogous to the cortical default mode network (DMN) that has been shown to contribute to awareness. We integrated data from ex vivo diffusion magnetic resonance imaging (MRI) of three human brains, obtained at autopsy from neurologically normal individuals, with immunohistochemical staining of subcortical brain sections. We identified nodes of the proposed default ascending arousal network (dAAN) in the brainstem, hypothalamus, thalamus, and basal forebrain. Deterministic and probabilistic tractography analyses of the ex vivo diffusion MRI data revealed projection, association, and commissural pathways linking dAAN nodes with one another and with DMN nodes. Complementary analyses of in vivo 7-tesla resting-state functional MRI data from the Human Connectome Project identified the dopaminergic ventral tegmental area in the midbrain as a widely connected hub node at the nexus of the subcortical arousal and cortical awareness networks. Our network-based autopsy methods and connectivity data provide a putative neuroanatomic architecture for the integration of arousal and awareness in human consciousness.

Topics: Humans; Brain Stem; Wakefulness; Consciousness; Magnetic Resonance Imaging; Multimodal Imaging; Connectome; Neural Pathways; Male; Female; Diffusion Magnetic Resonance Imaging; Adult; Arousal

PubMed: 38691619
DOI: 10.1126/scitranslmed.adj4303