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Journal ArticleDOI

Neurons Containing Hypocretin (Orexin) Project to Multiple Neuronal Systems

TL;DR: The results of this immunohistochemical study suggest that hypocretins are likely to have a role in physiological functions in addition to food intake such as regulation of blood pressure, the neuroendocrine system, body temperature, and the sleep–waking cycle.
Abstract: The novel neuropeptides called hypocretins (orexins) have recently been identified as being localized exclusively in cell bodies in a subregion of the tuberal part of the hypothalamus. The structure of the hypocretins, their accumulation in vesicles of axon terminals, and their excitatory effect on cultured hypothalamic neurons suggest that the hypocretins function in intercellular communication. To characterize these peptides further and to help understand what physiological functions they may serve, we undertook an immunohistochemical study to examine the distribution of preprohypocretin-immunoreactive neurons and fibers in the rat brain. Preprohypocretin-positive neurons were found in the perifornical nucleus and in the dorsal and lateral hypothalamic areas. These cells were distinct from those that express melanin-concentrating hormone. Although they represent a restricted group of cells, their projections were widely distributed in the brain. We observed labeled fibers throughout the hypothalamus. The densest extrahypothalamic projection was found in the locus coeruleus. Fibers were also seen in the septal nuclei, the bed nucleus of the stria terminalis, the paraventricular and reuniens nuclei of the thalamus, the zona incerta, the subthalamic nucleus, the central gray, the substantia nigra, the raphe nuclei, the parabrachial area, the medullary reticular formation, and the nucleus of the solitary tract. Less prominent projections were found in cortical regions, central and anterior amygdaloid nuclei, and the olfactory bulb. These results suggest that hypocretins are likely to have a role in physiological functions in addition to food intake such as regulation of blood pressure, the neuroendocrine system, body temperature, and the sleep–waking cycle.
Citations
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Journal ArticleDOI
20 Aug 1999-Cell
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.

2,935 citations

Journal ArticleDOI
06 Aug 1999-Cell
TL;DR: It is determined that canine narcolepsy is caused by disruption of the hypocretin (orexin) receptor 2 gene (Hcrtr2) and this result identifies hypocretins as major sleep-modulating neurotransmitters and opens novel potential therapeutic approaches for Narcoleptic patients.

2,450 citations


Cites background or result from "Neurons Containing Hypocretin (Orex..."

  • ...…basal forebrain area, the nucleus ac-In order to determine the neuroanatomical basis for the sleep abnormalities observed in narcolepsy, several cumbens, and the amygdala (Peyron et al., 1998; Date et al., 1999; Nambu et al., 1999), are also consistent withcomplementary approaches have been taken....

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  • ...These experiments have shown that tine nucleus, parabrachial nucleus, locus coeruleus, raphe nuclei, subtantia nigra pars compacta, and ventral widespread hypersensitivity to cholinergic stimulation likely explains abnormal REM sleep tendencies in narcotegmental area (Peyron et al., 1998; Date et al., 1999; Nambu et al., 1999; van den Pol, 1999)....

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  • ...In narcoleptic animals, the most consistent abnormalities were observed in the areas, their projections are widely distributed throughout the brain (Peyron et al., 1998; Date et al., 1999; amygdala where significant increases in dopamine and metabolite levels were reported in two independent Mondal et al., 1999; Nambu et al., 1999; van den Pol, 1999)....

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  • ...In narcoleptic animals, the most consistent abnormalities were observed in theareas, their projections are widely distributed through- out the brain (Peyron et al., 1998; Date et al., 1999; amygdala where significant increases in dopamine and metabolite levels were reported in two independentMondal…...

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  • ...…interaction between pontine cholinergic REM-on cells and aminergic locus ceptive pontine reticular formation and associated cholinergic cell groups (Peyron et al., 1998; Date et al., 1999;coeruleus (LC) REM-off cells and their projection sites (Mignot et al., 1993b; Nishino and Mignot, 1997)....

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Journal ArticleDOI
27 Oct 2005-Nature
TL;DR: These findings explain how various drugs affect sleep and wakefulness, and provide the basis for a wide range of environmental influences to shape wake–sleep cycles into the optimal pattern for survival.
Abstract: A series of findings over the past decade has begun to identify the brain circuitry and neurotransmitters that regulate our daily cycles of sleep and wakefulness. The latter depends on a network of cell groups that activate the thalamus and the cerebral cortex. A key switch in the hypothalamus shuts off this arousal system during sleep. Other hypothalamic neurons stabilize the switch, and their absence results in inappropriate switching of behavioural states, such as occurs in narcolepsy. These findings explain how various drugs affect sleep and wakefulness, and provide the basis for a wide range of environmental influences to shape wake-sleep cycles into the optimal pattern for survival.

2,295 citations


Cites background from "Neurons Containing Hypocretin (Orex..."

  • ...They have ascending projections to the cerebral cortex, as well as descending projections to all the monoaminergic and cholinergic cell groups of the arousal system...

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Journal ArticleDOI
TL;DR: It is suggested that dysregulation of locus coeruleus-noradrenergic neurotransmission may contribute to cognitive and/or arousal dysfunction associated with a variety of psychiatric disorders, including attention-deficit hyperactivity disorder, sleep and arousal disorders, as well as certain affective Disorders, including post-traumatic stress disorder.

2,207 citations

Journal ArticleDOI
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.
Abstract: We explored the role of hypocretins in human narcolepsy through histopathology of six narcolepsy brains and mutation screening of Hcrt, Hcrtr1 and Hcrtr2 in 74 patients of various human leukocyte antigen and family history status. One Hcrt mutation, impairing peptide trafficking and processing, was found in a single case with early onset narcolepsy. 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. Although hypocretin loci do not contribute significantly to genetic predisposition, most cases of human narcolepsy are associated with a deficient hypocretin system.

1,939 citations


Cites background from "Neurons Containing Hypocretin (Orex..."

  • ...However, the widespread distribution of Hcrt projection fields, with dense localization in monoaminergic cell groups, suggested other physiological function...

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References
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Book
01 Jan 1983
TL;DR: This paper presents a meta-analyses of the determinants of earthquake-triggered landsliding in the Czech Republic over a period of 18 months in order to establish a probabilistic framework for estimating the intensity of the earthquake.
Abstract: Preface. Acknowledgements. Introduction. References. List of Structures. Index of Abbreviations. Diagrams.

57,116 citations

Journal ArticleDOI
20 Feb 1998-Cell
TL;DR: Two novel neuropeptides are identified, both derived from the same precursor by proteolytic processing, that bind and activate two closely related (previously) orphan G protein-coupled receptors in the hypothalamus of rats.

5,162 citations


"Neurons Containing Hypocretin (Orex..." refers background in this paper

  • ...More recently, screening of high-resolution HPLC fractions on cell lines expressing orphan G-protein–coupled receptors resulted in the isolation of two peptides called orexin A and B (Sakurai et al., 1998) that are identical to hypocretin 1 and 2, respectively....

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  • ...Sakurai et al. (1998) described orexin (hcrt) neurons as a discrete set of cells in the hypothalamic and subthalamic areas such as the zona incerta and the subincertal and the subthalamic nuclei....

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  • ...These two peptides activate two distinct G-protein– coupled receptors, OX1 and OX2 (Sakurai et al., 1998)....

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  • ...Sakurai et al. (1998) reported that intracerebroventricular injection of hcrt stimulates food intake....

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  • ...Indeed, Sakurai et al. (1998) recently showed that orexin A (hcrt-1) and B (hcrt-2) stimulate food intake when injected intracerebroventricularly and that the mRNA accumulates during fasting....

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Journal ArticleDOI

4,344 citations


"Neurons Containing Hypocretin (Orex..." refers methods in this paper

  • ...Using the method of Abercrombie (1946), we found 682.62 6 11.97 neurons on each side based on four brains stained with each antibody....

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  • ...The number of labeled cells in the brain was estimated using the method of Abercrombie (1946)....

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Journal ArticleDOI
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.
Abstract: We describe a hypothalamus-specific mRNA that encodes preprohypocretin, the putative precursor of a pair of peptides that share substantial amino acid identities with the gut hormone secretin. The hypocretin (Hcrt) protein products are restricted to neuronal cell bodies of the dorsal and lateral hypothalamic areas. The fibers of these neurons are widespread throughout the posterior hypothalamus and project to multiple targets in other areas, including brainstem and thalamus. Hcrt immunoreactivity is associated with large granular vesicles at synapses. One of the Hcrt peptides was excitatory when applied to cultured, synaptically coupled hypothalamic neurons, but not hippocampal neurons. These observations suggest that the hypocretins function within the CNS as neurotransmitters.

3,558 citations


"Neurons Containing Hypocretin (Orex..." refers background or methods in this paper

  • ...The cell body staining obtained with both antisera (#2050 and #2123) and by autoradiographic (refer to de Lecea et al., 1998) and colorimetric in situ hybridization is indistinguishable (Figs....

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  • ...A nucleotide sequence encoding a 130 residue protein called preprohypocretin (hcrt) was isolated from this hypothalamus-enriched cDNA library (Sutcliffe et al., 1997; de Lecea et al., 1998)....

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  • ...We have shown previously that hcrt has an excitatory effect on hypothalamic cells in vitro (de Lecea et al., 1998) and, in the present study, that the perifornical input to the PVN includes hcrt axons....

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  • ...…its expression in hypothalamic neurons, and its accumulation in vesicles of axon terminals suggested that the hcrt peptides may have intercellular signaling activity, and synthetic hcrt-2 was excitatory when applied to synaptically coupled rat hypothalamic neurons in vitro (de Lecea et al., 1998)....

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Journal ArticleDOI

1,571 citations


"Neurons Containing Hypocretin (Orex..." refers background in this paper

  • ...These brainstem structures are known to be closely associated with cardiovascular function (Lindgren, 1961; Reis and Cuénod, 1965; Calaresu and Ciriello, 1980; for review, see Dampney, 1994)....

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  • ...…regulation such as the rostral ventrolateral medulla, the lateral paragigantocellular nucleus, the locus coeruleus, the nucleus of the solitary tract, the midbrain periaqueductal gray, the A5 noradrenergic cell group, the parabrachial region, and the area postrema (for review, see Dampney, 1994)....

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