Journal ArticleDOI
Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area
Carol F. Elias,Clifford B. Saper,Eleftheria Maratos-Flier,Nicholas A. Tritos,Charlotte E. Lee,Joseph Kelly,Jeffrey B. Tatro,Gloria E. Hoffman,Michael Martin Ollmann,Gregory S. Barsh,Takeshi Sakurai,Masashi Yanagisawa,Joel K. Elmquist +12 more
TLDR
Projections from populations of leptin‐responsive neurons in the mediobasal hypothalamus to MCH and ORX cells in the LHA may link peripheral metabolic cues with the cortical mantle and may play a critical role in the regulation of feeding behavior and body weight.Abstract:
Recent studies have identified several neuropeptide systems in the hypothalamus that are critical in the regulation of body weight. The lateral hypothalamic area (LHA) has long been considered essential in regulating food intake and body weight. Two neuropeptides, melanin-concentrating hormone (MCH) and the orexins (ORX), are localized in the LHA and provide diffuse innervation of the neuraxis, including monosynaptic projections to the cerebral cortex and autonomic preganglionic neurons. Therefore, MCH and ORX neurons may regulate both cognitive and autonomic aspects of food intake and body weight regulation. The arcuate nucleus also is critical in the regulation of body weight, because it contains neurons that express leptin receptors, neuropeptide Y (NPY), alpha-melanin-stimulating hormone (alpha-MSH), and agouti-related peptide (AgRP). In this study, we examined the relationships of these peptidergic systems by using dual-label immunohistochemistry or in situ hybridization in rat, mouse, and human brains. In the normal rat, mouse, and human brain, ORX and MCH neurons make up segregated populations. In addition, we found that AgRP- and NPY-immunoreactive neurons are present in the medial division of the human arcuate nucleus, whereas alpha-MSH-immunoreactive neurons are found in the lateral arcuate nucleus. In humans, AgRP projections were widespread in the hypothalamus, but they were especially dense in the paraventricular nucleus and the perifornical area. Moreover, in both rat and human, MCH and ORX neurons receive innervation from NPY-, AgRP-, and alpha-MSH-immunoreactive fibers. Projections from populations of leptin-responsive neurons in the mediobasal hypothalamus to MCH and ORX cells in the LHA may link peripheral metabolic cues with the cortical mantle and may play a critical role in the regulation of feeding behavior and body weight.read more
Citations
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Journal ArticleDOI
Narcolepsy in orexin knockout mice: Molecular genetics of sleep regulation
Richard M. Chemelli,Jon T. Willie,Christopher M. Sinton,Joel K. Elmquist,Thomas E. Scammell,Charlotte E. Lee,James A. Richardson,S. Clay Williams,Yumei Xiong,Yaz Y. Kisanuki,Thomas Fitch,Masamitsu Nakazato,Robert E. Hammer,Clifford B. Saper,Masashi Yanagisawa +14 more
TL;DR: It is proposed that orexin regulates sleep/wakefulness states, and that Orexin knockout mice are a model of human narcolepsy, a disorder characterized primarily by rapid eye movement (REM) sleep dysregulation.
Journal ArticleDOI
A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains
Christelle Peyron,Juliette Faraco,William J. Rogers,Beth Ripley,Sebastiaan Overeem,Sebastiaan Overeem,Yves Charnay,Sona Nevsimalova,Michael S. Aldrich,David Reynolds,Roger L. Albin,Robin Li,Marcel Hungs,Mario Pedrazzoli,Muralidhara Padigaru,Melanie H. Kucherlapati,Jun Fan,Richard A. Maki,Gert Jan Lammers,Constantin Bouras,Raju Kucherlapati,Seiji Nishino,Emmanuel Mignot +22 more
TL;DR: In situ hybridization of the perifornical area and peptide radioimmunoassays indicated global loss of hypocretins, without gliosis or signs of inflammation in all human cases examined, indicating most cases of human narcolepsy are associated with a deficient hypocretin system.
Journal ArticleDOI
The sleep switch: hypothalamic control of sleep and wakefulness
TL;DR: A model is proposed in which wake- and sleep-promoting neurons inhibit each other, which results in stable wakefulness and sleep and disruption of wake- or sleep- Promoting pathways results in behavioral state instability.
Journal ArticleDOI
Differential expression of orexin receptors 1 and 2 in the rat brain.
Jacob Marcus,Carl J. Aschkenasi,Charlotte E. Lee,Richard M. Chemelli,Clifford B. Saper,Masashi Yanagisawa,Joel K. Elmquist +6 more
TL;DR: The differential distribution of oxin receptors is consistent with the proposed multifaceted roles of orexin in regulating homeostasis and may explain the unique role of the OX2R receptor in regulating sleep state stability.
Journal ArticleDOI
Genetic Ablation of Orexin Neurons in Mice Results in Narcolepsy, Hypophagia, and Obesity
Junko Hara,Carsten T. Beuckmann,Tadahiro Nambu,Jon T. Willie,Richard M. Chemelli,Christopher M. Sinton,Fumihiro Sugiyama,Ken-ichi Yagami,Katsutoshi Goto,Masashi Yanagisawa,Takeshi Sakurai +10 more
TL;DR: Evidence is provided that orexin-containing neurons play important roles in regulating vigilance states and energy homeostasis and the pathophysiology and treatment of narcolepsy.
References
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TL;DR: A hypothalamus-specific mRNA is described that encodes preprohypocretin, the putative precursor of a pair of peptides that share substantial amino acid identities with the gut hormone secretin, suggesting that the hypocretins function within the CNS as neurotransmitters.
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