ArticleProceedings of the National Academy of Sciences of the United States of America2012
Mechanism for Hypocretin-mediated sleep-to-wake transitions.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 152 papers.
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Who cites it
152 citing papers in PubMed, 276 citations in OpenAlex.
- Treatment effect and safety of seltorexant as monotherapy for patients with major depressive disorder: a randomized, placebo-controlled clinical trial.Molecular psychiatry · 2025Trial
- Trial
- Sleep circuit modulation: from animal models to human translation.Brain : a journal of neurology · 2026Review
- Therapeutic potential of targeting the orexin (hypocretin) system in sleep disorders.Nature reviews. Endocrinology · 2026Review
- Hypothalamic control of arousal.Reviews in endocrine & metabolic disorders · 2026Review
- Pth4 neurons define a novel hypothalamic circuit that promotes sleep via brainstem monoaminergic neurons.Current biology : CB · 2026Article
- Contributions of Zebrafish to Our Understanding of the Function and Regulation of Sleep.Current sleep medicine reports · 2026Review
- Orexin Deficiency in Narcolepsy: Molecular Mechanisms, Clinical Phenotypes, and Emerging Therapeutic Frontiers.Brain and behavior · 2025Review
- Pth4 neurons define a novel hypothalamic circuit that promotes sleep via brainstem monoaminergic neurons.bioRxiv : the preprint server for biology · 2025Article
- Neuropeptides as transmitters and regulators of the locus coeruleus noradrenergic system.Pharmacological reviews · 2025Review
- Alteration of Metabolic Profile in Patients with Narcolepsy Type 1.Metabolites · 2025Article
- The interaction between orexin, sleep deprivation and Alzheimer's disease: Unveiling an Emerging Connection.The journal of physiological sciences : JPS · 2025Review
- Temporal Association Cortex Gates Sound-Evoked Arousal from NREM Sleep.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Hypocretin: a promising target for the regulation of homeostasis.Frontiers in neuroscience · 2025Review
- The role of orexin and MCH neurons in the hypothalamus in sleep-wake regulation and learning-forgetting balance.Frontiers in neuroscience · 2025Review
- The Role and Mechanisms of the Hypocretin System in Zebrafish (International journal of molecular sciences · 2024Review
- Monosynaptic ventral tegmental area glutamate projections to the locus coeruleus enhance aversive processing.bioRxiv : the preprint server for biology · 2024Article
- Sleep Disturbances in Autoimmune Neurological Diseases: Mechanisms, Clinical Characteristics, Assessment, and Treatment Strategies.Current neurology and neuroscience reports · 2024Review
- A deleterious variant of INTS1 leads to disrupted sleep-wake cycles.Disease models & mechanisms · 2024Article
- Noradrenergic tone is not required for neuronal activity-induced rebound sleep in zebrafish.Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology · 2024Article
92 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Current models of sleep/wake regulation posit that Hypocretin (Hcrt)-expressing neurons in the lateral hypothalamus promote and stabilize wakefulness by projecting to subcortical arousal centers. However, the critical downstream effectors of Hcrt neurons are unknown. Here we use optogenetic, pharmacological, and computational tools to investigate the functional connectivity between Hcrt neurons and downstream noradrenergic neurons in the locus coeruleus (LC) during nonrapid eye movement (NREM) sleep. We found that photoinhibiting LC neurons during Hcrt stimulation blocked Hcrt-mediated sleep-to-wake transitions. In contrast, when LC neurons were optically stimulated to increase membrane excitability, concomitant photostimulation of Hcrt neurons significantly increased the probability of sleep-to-wake transitions compared with Hcrt stimulation alone. We also built a conductance-based computational model of Hcrt-LC circuitry that recapitulates our behavioral results using LC neurons as the main effectors of Hcrt signaling. These results establish the Hcrt-LC connection as a critical integrator-effector circuit that regulates NREM sleep/wake behavior during the inactive period. This coupling of distinct neuronal systems can be generalized to other hypothalamic integrator nuclei with downstream effector/output populations in the brain.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.