Advances in translational research provide key opportunities to explore the physiological and pathological effects of sleep in different neurodegenerative diseases. Recent findings suggest that sleep-wakefulness dysfunctions may predispose to neurodegenerative disorders such as Alzheimer's disease (AD), and vice versa. New theories on the link between sleep and β-amyloid and tau secretion, accumulation and clearance, and its interaction with hypocretins/orexins (key neuropeptides regulating wakefulness) suggest mechanistic ways to better understand the impact of sleep alterations in the pathogenesis of AD. Further studies should validate whether changes in circadian rhythm and sleep-wakefulness patterns could be used for early AD diagnosis and as prognostic markers for cognitive decline. Longitudinal studies are needed, not only to validate these biomarker interactions and to determine the cause-effect relationship and the role of sleep-wakefulness behavior in the regulation of amyloid plaque and neurofibrillary tangle formation, but also to identify the best sleep therapies and related preventive strategies for AD.

During the last decade, optogenetic-based circuit mapping has become one of the most common approaches to systems neuroscience, and amassing studies have expanded our understanding of brain structures causally involved in the regulation of sleep-wake cycles. Recent imaging technologies enable the functional mapping of cellular activity, from population down to single-cell resolution, across a broad repertoire of behaviors and physiological processes, including sleep-wake states. This chapter summarizes experimental evidence implicating hypocretins/orexins, melanin-concentrating hormone, and inhibitory neurons from the lateral hypothalamus (LH) in forming an intricate network involved in regulating sleep and metabolism, including feeding behaviors. It further confirms the dual sleep-metabolic functions of LH cells, and sheds light on a possible mechanism underlying brain plasticity during sleep and metabolic disorders.

Significant sleep impairments often accompany substance use disorders (SUDs). Sleep disturbances in SUD patients are associated with poor clinical outcomes and treatment adherence, emphasizing the importance of normalizing sleep when treating SUDs. Orexins (hypocretins) are neuropeptides exclusively produced by neurons in the posterior hypothalamus that regulate various behavioral and physiological processes, including sleep-wakefulness and motivated drug taking. Given its dual role in sleep and addiction, the orexin system represents a promising therapeutic target for treating SUDs and their comorbid sleep deficits. Here, we review the literature on the role of the orexin system in sleep and drug addiction and discuss the therapeutic potential of orexin receptor antagonists for SUDs. We argue that orexin receptor antagonists may be effective therapeutics for treating addiction because they target orexin's regulation of sleep (top-down) and motivation (bottom-up) pathways.

The multifunctional, hypothalamic hypocretin/orexin (HCRT)-producing neurons regulate an array of physiological and behavioral states including arousal, sleep, feeding, emotions, stress, and reward. How a presumably uniform HCRT neuron population regulates such a diverse set of functions is not clear. The role of the HCRT neuropeptides may vary depending on the timing and localization of secretion and neuronal activity. Moreover, HCRT neuropeptides may not mediate all functions ascribed to HCRT neurons. Some could be orchestrated by additional neurotransmitters and neuropeptides that are expressed in HCRT neurons. We hypothesize that HCRT neurons are segregated into genetically, anatomically and functionally distinct subpopulations. We discuss accumulating data that suggest the existence of such HCRT neuron subpopulations that may effectuate the diverse functions of these neurons in mammals and fish.

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.

Orexin receptors (OXRs) are promiscuous G-protein-coupled receptors that signal via several G-proteins and, putatively, via other proteins. On which basis the signal pathways are selected and orchestrated is largely unknown. We also have an insufficient understanding of the kind of signaling that is important for specific types of cellular responses. OXRs are able to form complexes with several other G-protein-coupled receptors in vitro, and one possibility is that the complexing partners regulate the use of certain signal transducers. In the central nervous system neurons, the main acute downstream responses of OXR activation are the inhibition of K+ channels and the activation of the Na+/Ca2+ exchanger and non-selective cation channels of unknown identity. The exact nature of the intracellular signal chain between the OXRs and these downstream targets is yet to be elucidated, but the Gq-phospholipase C (PLC) protein kinase C pathway - which is a significant signaling pathway for OXRs in recombinant cells - may be one of the players in neurons. The Gq-PLC pathway may also, under certain circumstances, take the route to diacylglycerol lipase, which leads to the production of the potent endocannabinoid (eCB), 2-arachidonoyl glycerol, and thereby connects orexins with eCB signaling. In addition, OXRs have been studied in the context of neurodegeneration and cancer cell death. Overall, OXR signaling is complex, and it can change depending on the cell type and environment.

The discovery of the hypocretins/orexins (HCRTs) has revolutionized sleep science in the last two decades. A combination of anatomical tracing methods, optogenetics, and pharmacology is delineating a blueprint of functional inputs and outputs of the HCRT system. Here, we discuss several models of HCRT action that involve the integration between physiological variables, circadian output, and sleep homeostasis. Generation of activity maps during the sleep-wake cycle at the cellular level will allow investigators to decipher computational frameworks modeling operations of HCRT networks.

Orexins regulate a wide variety of biological functions, most notably the sleep-wake cycle, reward and stress processing, alertness, vigilance, and cognitive functioning. Alterations of central and peripheral orexin levels are linked to conditions such as narcolepsy, anorexia nervosa, age-related cognitive decline, and neurodegenerative disease. Preliminary studies suggest that orexin mimetics can safely promote the wake signal via orexin agonism during the day and that orexin receptor antagonists can promote the sleep signal during the night. Thus, novel orexin therapies have the potential to either improve memory, cognition, and daytime performance directly or indirectly, through promotion of good sleep. The full scope of the therapeutic potential of orexin therapies remains to be elucidated.

Since its description in the 19th century, narcolepsy type 1 (NT1) has been considered as a model sleep disorder, and after the discovery of rapid eye movement (REM) sleep onset in the disorder, a gateway to understanding REM sleep. The discovery that NT1 is caused by hypocretin/orexin deficiency, together with neurochemical studies of this system, has helped to establish how this neuropeptide regulates the organization of sleep and wake in humans. Current analyses suggest that the main functions of the hypocretin/orexin system are (1) maintenance of wakefulness in the face of moderate sleep deprivation; (2) passive wake promotion, especially in the evening, driven by the circadian clock; (3) inhibition of REM sleep, with possible differential modulating effects on various subcomponents of the sleep-stage, explaining REM sleep dissociation events in NT1. Narcolepsy is also associated with an inability to consolidate sleep, a more complex phenotype that may result from secondary changes or be central to the role of hypocretin in coordinating the activity of other sleep- and wake-promoting systems. Novel technologies, such as the use of deep learning analysis of electroencephalographic signals, is revealing a complex pattern of sleep abnormalities in human narcolepsy that can be used diagnostically. The availability of novel devices measuring sleep 24 h per day also holds promise to provide new insights into how brain electrical activity and muscle tone are regulated by hypocretin.

Hypothalamic hypocretin/orexin neurons have been initially conceptualized as slow, modulatory controllers of behavior. Furthermore, their behavioral effects have been assumed to be a secondary consequence of their impact on arousal. However, cellular-resolution calcium imaging and optogenetic studies show that orexin neurons regulate self-generated and sensory-evoked movement on rapid, subsecond timescales. Orexin cell activity rapidly and transiently peaks before and during movements. Optogenetic prevention of this activation reduces the probability of locomotion initiation, and optogenetic mimicry of orexin cell activation rapidly causes locomotion. Neural ensemble calcium imaging experiments reveal that the same orexin cells whose activity underlies movement initiation display subsecond-latency responses to diverse sensory stimuli. These findings establish orexin neurons as rapid and strong sensorimotor controllers that are in many ways operationally similar to classic subcortical movement controllers, such as midbrain dopamine neurons. While a scientific definition of "arousal" is still lacking, the subsecond-scale sensorimotor control by orexin neurons could be viewed as reminiscent of a motor rather than an arousal system.

Sleep is one of the pillars of health. Experimental models of acute sleep loss, of chronic partial sleep deprivation, and of sleep fragmentation in healthy sleepers are helpful models of sleep deficiency produced by insufficient sleep duration, sleep timing, and sleep disorders. Sleep deficiency is associated with changes in markers associated with risk for disease. These include metabolic, inflammatory, and autonomic markers of risk. In addition, sleep disruption and sleep deficits lead to mood instability, lack of positive outlook, and impaired neurobehavioral functioning. On a population level, insufficient sleep is associated with increased risk for hypertension and diabetes. Sleep disturbance is very common, and about half the population will report that they have experienced insomnia at some time in their lives. Approximately 10% of the population describe daytime impairment due to sleep disturbance at night, consistent with a diagnosis of insomnia disorder. The hypothalamic neuropeptides, orexin-A and orexin-B, act through G-protein-coupled receptors (orexin-1 and orexin-2 receptors). Dual and selective orexin-2 receptor antagonists have shown efficacy in inducing sleep in men and women with insomnia disorder by accelerating sleep onset and improving sleep efficiency and total sleep time. Further study comparing these medications, in short- and longer-term use models, is recommended. Greater understanding of comparative effects on mood, neurobehavioral, and physiological systems will help determine the extent of clinical utility of dual versus selective orexin receptor antagonists.

Orexins have received a lot of attention as potent endogenous arousal-promoting peptides, and orexin receptor antagonists have shown clinical efficacy for the treatment of insomnia. Orexin neurons are thought to act primarily on monoaminergic neurons to maintain arousal and vigilance. In this chapter, we discuss the functional interaction between monoaminergic systems, including noradrenaline, serotonin and histamine, and orexin neurons, as well as interactions between the acetylcholine system and the orexin neurons, focusing, in particular, on their function in the regulation of sleep-wakefulness states. Orexin also has close interactions with the dopaminergic system, and many studies have suggested roles of orexin signaling in the reward system and roles for orexins in drug addiction.

Hallucinations, delusions, and confabulations are common symptoms between neurology and psychiatry. The neurological diseases manifesting with such symptoms (dementia, epilepsy, Korsakoff's disease, brain tumors, Parkinson's disease, migraine, right hemisphere stroke and others) would be the key to understand their biological mechanisms, while the cognitive sciences, neuropharmacology and functional neuroimaging would be the tools of such researches. It is possible to understand the perceptive rules of the mind and the mechanisms of the human consciousness based on these symptoms. However, hallucinations and delusions manifest with extraordinary vehemence with psychiatric disorders such as psychosis and schizophrenia, with which there is no evidence of brain lesions. Furthermore, they are subjective symptoms, and they do not have biological markers. Hence, they are prone to high inter-individual variability and depend on other variables (such as education, history of trauma), and are therefore difficult to reduce to unequivocal constructs. Causative mechanisms are probably multiple. For understanding these symptoms, a common framework between neurology and psychiatry is still missing. The psychopathology of French alienists over the 19th century, of S. Freud, and of Henry Ey over the 20th century gave way, in the second half of the 20th century, to the adoption of the DSM and neurosciences, to pursue a pure neurological perspective. However, although psychodynamic models seem nowadays (in a technological era) less influential, detailed clinical evaluations focusing on emotional-cognitive paradigms are probably the only way to lead to new neurobiological researches.

Neuropsychological rehabilitation is one of the subspecialties of neuropsychology, along with neuropsychological assessment, cognitive process descriptions, and anatomo-functional correlation, but it is still frequently underrecognized, even from a historical point of view. In this chronological review, we propose following some of the historical descriptions of cognitive recovery, and the suggested procedures and therapies to improve this recovery from mythological periods and the antiquity to recent contemporary periods and the birth of formal neuropsychological rehabilitation in neurological and psychiatric conditions.