-
Journal of Internal Medicine May 2022The hypocretins (Hcrts), also known as orexins, are two neuropeptides produced exclusively in the lateral hypothalamus. They act on two specific receptors that are... (Review)
Review
The hypocretins (Hcrts), also known as orexins, are two neuropeptides produced exclusively in the lateral hypothalamus. They act on two specific receptors that are widely distributed across the brain and involved in a myriad of neurophysiological functions that include sleep, arousal, feeding, reward, fear, anxiety and cognition. Hcrt cell loss in humans leads to narcolepsy with cataplexy (narcolepsy type 1), a disorder characterized by intrusions of sleep into wakefulness, demonstrating that the Hcrt system is nonredundant and essential for sleep/wake stability. The causal link between Hcrts and arousal/wakefulness stabilisation has led to the development of a new class of drugs, Hcrt receptor antagonists to treat insomnia, based on the assumption that blocking orexin-induced arousal will facilitate sleep. This has been clinically validated: currently, two Hcrt receptor antagonists are approved to treat insomnia (suvorexant and lemborexant), with a New Drug Application recently submitted to the US Food and Drug Administration for a third drug (daridorexant). Other therapeutic applications under investigation include reduction of cravings in substance-use disorders and prevention of neurodegenerative disorders such as Alzheimer's disease, given the apparent bidirectional relationship between poor sleep and worsening of the disease. Circuit neuroscience findings suggest that the Hcrt system is a hub that integrates diverse inputs modulating arousal (e.g., circadian rhythms, metabolic status, positive and negative emotions) and conveys this information to multiple output regions. This neuronal architecture explains the wealth of physiological functions associated with Hcrts and highlights the potential of the Hcrt system as a therapeutic target for a number of disorders. We discuss present and future possible applications of drugs targeting the Hcrt system for the treatment of circuit-related neuropsychiatric and neurodegenerative conditions.
Topics: Humans; Intracellular Signaling Peptides and Proteins; Narcolepsy; Neuropeptides; Orexins; Sleep Initiation and Maintenance Disorders
PubMed: 35043499
DOI: 10.1111/joim.13406 -
Frontiers in Neuroendocrinology Oct 2018The neuropeptides orexins are important in regulating the neurobiological systems that respond to stressful stimuli. Furthermore, orexins are known to play a role many... (Review)
Review
The neuropeptides orexins are important in regulating the neurobiological systems that respond to stressful stimuli. Furthermore, orexins are known to play a role many of the phenotypes associated with stress-related mental illness such as changes in cognition, sleep-wake states, and appetite. Interestingly, orexins are altered in stress-related psychiatric disorders such as Major Depressive Disorder and Anxiety Disorders. Thus, orexins may be a potential target for treatment of these disorders. In this review, we will focus on what is known about the role of orexins in acute and repeated stress, in stress-induced phenotypes relevant to psychiatric illness in preclinical models, and in stress-related psychiatric illness in humans. We will also briefly discuss how orexins may contribute to sex differences in the stress response and subsequent phenotypes relevant to mental health, as many stress-related psychiatric disorders are twice as prevalent in women.
Topics: Animals; Anxiety Disorders; Depressive Disorder, Major; Female; Humans; Hypothalamo-Hypophyseal System; Male; Orexins; Pituitary-Adrenal System; Stress, Psychological
PubMed: 29932958
DOI: 10.1016/j.yfrne.2018.06.003 -
Nutrients Aug 2023Orexin plays a significant role in the modulation of REM sleep, as well as in the regulation of appetite and feeding. This review explores, first, the current evidence... (Review)
Review
Orexin plays a significant role in the modulation of REM sleep, as well as in the regulation of appetite and feeding. This review explores, first, the current evidence on the role of orexin in the modulation of sleep and wakefulness and highlights that orexin should be considered essentially as a neurotransmitter inhibiting REM sleep and, to a much lesser extent, a wake promoting agent. Subsequently, the relationship between orexin, REM sleep, and appetite regulation is examined in detail, shedding light on their interconnected nature in both physiological conditions and diseases (such as narcolepsy, sleep-related eating disorder, idiopathic hypersomnia, and night eating syndrome). Understanding the intricate relationship between orexin, REM sleep, and appetite regulation is vital for unraveling the complex mechanisms underlying sleep-wake patterns and metabolic control. Further research in this field is encouraged in order to pave the way for novel therapeutic approaches to sleep disorders and metabolic conditions associated with orexin dysregulation.
Topics: Appetite; Sleep, REM; Orexins; Appetite Regulation; Sleep
PubMed: 37686711
DOI: 10.3390/nu15173679 -
Handbook of Clinical Neurology 2021The hypocretins/orexins were discovered in 1998. Within 2 years, this led to the discovery of the cause of human narcolepsy, a 90% loss of hypothalamic neurons... (Review)
Review
The hypocretins/orexins were discovered in 1998. Within 2 years, this led to the discovery of the cause of human narcolepsy, a 90% loss of hypothalamic neurons containing these peptides. Further work demonstrated that these neurons were not simply linked to waking. Rather these neurons were active during pleasurable behaviors in waking and were silenced by aversive stimulation. This was seen in wild-type mice, rats, cats, and dogs. It was also evident in humans, with increased Hcrt release during pleasurable activities and decreased release, to the levels seen in sleep, during pain. We found that human heroin addicts have, on average, an increase of 54% in the number of detectable Hcrt neurons compared to "control" human brains and that these Hcrt neurons are substantially smaller than those in control brains. We found that in mice, chronic morphine administration induced the same changes in Hcrt neuron number and size. Our studies in the mouse allowed us to determine the specificity, dose response relations, time course of the change in the number of Hcrt neurons, and that the increased number of Hcrt neurons after opiates was not due to neurogenesis. Furthermore, we found that it took a month or longer for these anatomical changes in the mouse brain to return to baseline. Human narcoleptics, despite their prescribed use of several commonly addictive drugs, do not show significant evidence of dose escalation or substance use disorder. Similarly, mice in which the peptide has been eliminated are resistant to addiction. These findings are consistent with the concept that an increased number of Hcrt neurons may underlie and maintain opioid or cocaine use disorders.
Topics: Animals; Cats; Dogs; Humans; Hypothalamus; Mice; Narcolepsy; Neurons; Orexins; Pleasure; Rats
PubMed: 34225941
DOI: 10.1016/B978-0-12-820107-7.00022-7 -
Progress in Brain Research 2012Orexin, a small neuropeptide released from neurons in the hypothalamus with widespread projections throughout the central nervous system, has broad biological roles... (Review)
Review
Orexin, a small neuropeptide released from neurons in the hypothalamus with widespread projections throughout the central nervous system, has broad biological roles including the modulation of breathing and autonomic function. That orexin activity is fundamentally dependent on sleep-wake state, and circadian cycle requires consideration of orexin function in physiological control systems in respect to these two state-related activity patterns. Both transgenic mouse studies and focal orexin receptor antagonism support a role for orexins in respiratory chemosensitivity to CO₂ predominantly in wakefulness, with further observations limiting this role to the dark period. In addition, orexin neurons participate in the regulation of sympathetic activity, including effects on blood pressure and thermoregulation. Orexin is also essential in physiological responses to stress. Orexin-mediated processes may operate at two levels: (1) in sleep-wake and circadian states and (2) in stress, for example, the defense or "fight-or-flight" response and panic-anxiety syndrome.
Topics: Animals; Autonomic Nervous System; Circadian Rhythm; Humans; Intracellular Signaling Peptides and Proteins; Neuropeptides; Orexins; Respiration; Sleep; Wakefulness
PubMed: 22813968
DOI: 10.1016/B978-0-444-59489-1.00004-5 -
Current Hypertension Reports Jul 2018The aim of this review was to summarize collected data on the role of orexin and orexin neurons in the control of sleep and blood pressure. (Review)
Review
PURPOSE OF REVIEW
The aim of this review was to summarize collected data on the role of orexin and orexin neurons in the control of sleep and blood pressure.
RECENT FINDINGS
Although orexins (hypocretins) have been known for only 20 years, an impressive amount of data is now available regarding their physiological role. Hypothalamic orexin neurons are responsible for the control of food intake and energy expenditure, motivation, circadian rhythm of sleep and wake, memory, cognitive functions, and the cardiovascular system. Multiple studies show that orexinergic stimulation results in increased blood pressure and heart rate and that this effect may be efficiently attenuated by orexinergic antagonism. Increased activity of orexinergic neurons is also observed in animal models of hypertension. Pharmacological intervention in the orexinergic system is now one of the therapeutic possibilities in insomnia. Although the role of orexin in the control of blood pressure is well described, we are still lacking clinical evidence that this is a possibility for a new approach in the treatment of cardiovascular diseases.
Topics: Animals; Autonomic Nervous System; Blood Pressure; Humans; Orexin Receptors; Orexins; Sleep
PubMed: 29992504
DOI: 10.1007/s11906-018-0879-6 -
Brain Research Mar 2020Orexin-expressing neurons are located exclusively in the lateral hypothalamic and perifornical areas and exhibit complex connectivity. The intricate wiring pattern is... (Review)
Review
Orexin-expressing neurons are located exclusively in the lateral hypothalamic and perifornical areas and exhibit complex connectivity. The intricate wiring pattern is evident from a diverse function for orexin neurons in regulating many physiological processes and behaviors including sleep, metabolism, circadian cycles, anxiety, and reward. Nevertheless, the precise synaptic and circuitry-level mechanisms mediating these processes remain enigmatic, partially due to the wide spread connectivity of the orexin system, complex neurochemistry of orexin neurons, and previous lack of suitable tools to address its complexity. Here we summarize recent advances, focusing on synaptic regulatory mechanisms in the orexin neurocircuitry, including both the synaptic inputs to orexin neurons as well as their downstream targets in the brain. A clear and detailed elucidation of these mechanisms will likely provide novel insight into how dysfunction in orexin-mediated signaling leads to human disease and may ultimately be treated with more precise strategies.
Topics: Animals; Brain; Humans; Hypothalamic Area, Lateral; Neural Pathways; Neurons; Orexins; Synapses; Synaptic Transmission
PubMed: 30296428
DOI: 10.1016/j.brainres.2018.10.003 -
International Journal of Environmental... Jul 2022Orexins, or hypocretins, are excitatory neuropeptides involved in the regulation of feeding behavior and the sleep and wakefulness states. Since their discovery, several... (Review)
Review
Orexins, or hypocretins, are excitatory neuropeptides involved in the regulation of feeding behavior and the sleep and wakefulness states. Since their discovery, several lines of evidence have highlighted that orexin neurons regulate a great range of physiological functions, giving it the definition of a multitasking system. In the present review, we firstly describe the mechanisms underlining the orexin system and their interactions with the central nervous system (CNS). Then, the system's involvement in goal-directed behaviors, sleep/wakefulness state regulation, feeding behavior and energy homeostasis, reward system, and aging and neurodegenerative diseases are described. Advanced evidence suggests that the orexin system is crucial for regulating many physiological functions and could represent a promising target for therapeutical approaches to obesity, drug addiction, and emotional stress.
Topics: Intracellular Signaling Peptides and Proteins; Neuropeptides; Orexins; Sleep; Wakefulness
PubMed: 35886210
DOI: 10.3390/ijerph19148353 -
Current Topics in Behavioral... 2017An enigmatic feature of behavioural state control is the rich diversity of wake-promoting neural systems. This diversity has been rationalized as 'robustness via... (Review)
Review
An enigmatic feature of behavioural state control is the rich diversity of wake-promoting neural systems. This diversity has been rationalized as 'robustness via redundancy', wherein wakefulness control is not critically dependent on one type of neuron or molecule. Studies of the brain orexin/hypocretin system challenge this view by demonstrating that wakefulness control fails upon loss of this neurotransmitter system. Since orexin neurons signal arousal need, and excite other wake-promoting neurons, their actions illuminate nonredundant principles of arousal control. Here, we suggest such principles by reviewing the orexin system from a collective viewpoint of biology, physics and engineering. Orexin peptides excite other arousal-promoting neurons (noradrenaline, histamine, serotonin, acetylcholine neurons), either by activating mixed-cation conductances or by inhibiting potassium conductances. Ohm's law predicts that these opposite conductance changes will produce opposite effects on sensitivity of neuronal excitability to current inputs, thus enabling orexin to differentially control input-output gain of its target networks. Orexin neurons also produce other transmitters, including glutamate. When orexin cells fire, glutamate-mediated downstream excitation displays temporal decay, but orexin-mediated excitation escalates, as if orexin transmission enabled arousal controllers to compute a time integral of arousal need. Since the anatomical and functional architecture of the orexin system contains negative feedback loops (e.g. orexin ➔ histamine ➔ noradrenaline/serotonin-orexin), such computations may stabilize wakefulness via integral feedback, a basic engineering strategy for set point control in uncertain environments. Such dynamic behavioural control requires several distinct wake-promoting modules, which perform nonredundant transformations of arousal signals and are connected in feedback loops.
Topics: Animals; Brain; Humans; Neurons; Orexins; Signal Transduction; Wakefulness
PubMed: 27830577
DOI: 10.1007/7854_2016_45 -
Nature Neuroscience Jul 2023Brain orexin (hypocretin) neurons are implicated in sleep-wake switching and reward-seeking but their roles in rapid arousal dynamics and reward perception are unclear....
Brain orexin (hypocretin) neurons are implicated in sleep-wake switching and reward-seeking but their roles in rapid arousal dynamics and reward perception are unclear. Here, cell-specific stimulation, deletion and in vivo recordings revealed strong correlative and causal links between pupil dilation-a quantitative arousal marker-and orexin cell activity. Coding of arousal and reward was distributed across orexin cells, indicating that they specialize in rapid, multiplexed communication of momentary arousal and reward states.
Topics: Orexins; Neuropeptides; Pupil; Intracellular Signaling Peptides and Proteins; Neurons
PubMed: 37336973
DOI: 10.1038/s41593-023-01365-w