Abstract
The sleep disorder narcolepsy is now linked with a loss of neurons containing the neuropeptide hypocretin (also known as orexin). The hypocretin neurons are located exclusively in the lateral hypothalamus, a brain region that has been implicated in arousal based on observations made by von Economo during the viral encephalitic epidemic of 1916–1926. There are other neuronal phenotypes located in the lateral hypothalamus that are distinct and separate from the hypocretin neurons. Here the authors identify these neurons based on peptides and neurotransmitters that they express and review roles of these neurons in sleep. Given the heterogeneity of the neuronal phenotypes in the lateral hypothalamus, it is likely that hypocretin neurons, as well as other types of neurons in the lateral hypothalamus, influence sleep and provide state-dependent regulation of physiological functions.
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Lin L., Faraco J., Li R., Kadotani H., Rogers W., and Lin X., et al. (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98, 365–376.
Thannickal T. C., Moore R. Y., Nienhuis R., Ramanathan L., Gulyani S., Aldrich M., et al. (2000) Reduced number of hypocretin neurons in human narcolepsy. Neuron 27, 469–474.
Peyron C., Faraco J., Rogers W., Ripley B., Overeem S., Charnay Y., et al. (2000) A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat. Med. 6, 991–997.
De Lecea L., Kilduff T. S., Peyron C., Gao X., Foye P. E., Danielson P. E., et al. (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl. Acad. Sci. USA 95, 322–327.
Peyron C., Tighe D. K., van den Pol A. N., De Lecea L., Heller H. C., Sutcliffe J. G., and Kilduff T. S. (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J. Neurosci. 18, 9996–10,015.
Sakurai T., Amemiya A., Ishii M., Matsuzaki I., Chemelli R. M., Tanaka H., et al. (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585.
Kilduff T. S. and Peyron C. (2000) The hypocretin/orexin ligand-receptor system: implications for sleep and sleep disorders. Trends Neurosci. 23, 359–365.
Sutcliffe J. G. and de Lecea L. (2002) The hypocretins: setting the arousal threshold. Nat. Rev. Neurosci. 3, 339–349.
Veening J. G., Te L. S., Posthuma P., Geeraedts L. M., and Nieuwenhuys R. (1987) A topographical analysis of the origin of some efferent projections from the lateral hypothalamic area in the rat. Neuroscience 22, 537–551.
Von Economo C. (1930) Sleep as a problem of localization. J. Nerv. Ment. Dis. 71, 249–259.
Nauta W. J. H. (1946) Hypothalamic regulation of sleep in rats. An experimental study. J. Neurophysiol. 9, 285–316.
Harrison F. (1940) An attempt to produce sleep by diencephalic stimulation. J. Neurophysiol. 3, 156–165.
Ranson S. W. (1939) Somnolence caused by hypothalamic lesions in the monkey. Arch. Neurol. Psychiat. 41, 1–23.
McGinty D. J. (1969) Somnolence, recovery and hyposomnia following ventro-medial diencephalic lesions in the rat. Electroencephalogr. Clin. Neurophysiol. 26, 70–79.
Shoham S. and Teitelbaum P. (1982) Subcortical waking and sleep during lateral hypothalamic “somnolence” in rats. Physiol. Behav. 28, 323–333.
Nieuwenhuys R., Geeraedts L. M., and Veening J. G. (1982) The medial forebrain bundle of the rat. I. General introduction. J. Comp. Neurol. 206, 49–81.
Denoyer M., Sallanon M., Buda C., Kitahama K., and Jouvet M. (1991) Neurotoxic lesion of the mesencephalic reticular formation and/or the posterior hypothalamus does not alter waking in the cat. Brain Res. 539, 287–303.
Sallanon M., Sakai K., Buda C., Puymartin M., and Jouvet M. (1988) Increase of paradoxical sleep induced by microinjections of ibotenic acid into the ventrolateral part of the posterior hypothalamus in the cat. Arch. Ital. Biol. 126, 87–97.
Winn P., Tarbuck A., and Dunnett S. B. (1984) Ibotenic acid lesions of the lateral hypothalamus: comparison with the electrolytic lesion syndrome. Neuroscience 12, 225–240.
Orzel-Gryglewska J., Jurkowlaniec E., Nowacka A., Tokarski J., and Trojniar W. (2000) Anatomical correlates of the lateral hypothalamic influence on waking-sleep relationship in the rat. Acta Neurobiol. Exp. (Warsz.) 60, 309–322.
Danguir J. and Nicolaidis S. (1980) Cortical activity and sleep in the rat lateral hypothalamic syndrome. Brain Res. 185, 305–321.
Jurkowlaniec E., Trojniar W., and Tokarski J. (1994) Daily pattern of EEG activity in rats with lateral hypothalamic lesions. J. Physiol. Pharmacol. 45, 399–411.
Gerashchenko D., Kohls M. D., Greco M., Waleh N. S., Salin-Pascual R., Kilduff T. S., et al. (2001) Hypocretin-2-saporin lesions of the lateral hypothalamus produce narcoleptic-like sleep behavior in the rat. J. Neurosci. 21, 7273–7283.
Stirpe F., Barbieri L., Battelli M. G., Soria M., and Lappi D. A. (1992) Ribosome-inactivating proteins from plants: present status and future prospects. Biotechnology (NY) 10, 405–412.
Bergamaschi G., Perfetti V., Tonon L., Novella A., Lucotti C., Danova M., et al. (1996) Saporin, a ribosome-inactivating protein used to prepare immunotoxins, induces cell death via apoptosis. Br. J. Haematol. 93, 789–794.
Mantyh P. W., Rogers S. D., Honore P., Allen B. J., Ghilardi J. R., Li J., et al. (1997) Inhibition of hyperalgesia by ablation of lamina 1 spinal neurons expressing the substance P receptor. Science 278, 275–279.
Gerashchenko D., Blanco-Centurion C., Greco M. A., and Shiromani P. J. (2003) Effects of lateral hypothalamic lesion with the neurotoxin hypocretin-2-saporin on sleep in Long-Evans rats. Neuroscience 116, 223–235.
Nishino S., Ripley B., Overeem S., Lammers G. J., and Mignot E. (2000) Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355, 39–40.
Overeem S., Mignot E., van Dijk J. G., and Lammers G. J. (2001) Narcolepsy: clinical features, new pathophysiologic insights, and future perspectives. J. Clin. Neurophysiol. 18, 78–105.
Chemelli R. M., Willie J. T., Sinton C. M., Elmquist J. K., Scammell T., Lee C., et al. (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437–451.
Hara J., Beuckmann C. T., Nambu T., Willie J. T., Chemelli R. M., Sinton C. M., et al. (2001) Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30, 345–354.
Ripley B., Overeem S., Fujiki N., Nevsimalova S., Uchino M., Yesavage J., et al. (2001) CSF hypocretin/orexin levels in narcolepsy and other neurological conditions. Neurology 57, 2253–2258.
Abrahamson E. E. and Moore R. Y. (2001) The posterior hypothalamic area: chemoarchitecture and afferent connections. Brain Res. 889, 1–22.
Rao Z. R., Yamano M., Wanaka A., Tatehata T., Shiosaka S., and Tohyama M. (1987) Distribution of cholinergic neurons and fibers in the hypothalamus of the rat using choline acetyltransferase as a marker. Neuroscience 20, 923–934.
Allen G. V. and Cechetto D. F. (1995) Neurotensin in the lateral hypothalamic area: origin and function. Neuroscience 69, 533–544.
Kelly A. B. and Watts A. G. (1998) The region of the pontine parabrachial nucleus is a major target of dehydration-sensitive CRH neurons in the rat lateral hypothalamic area. J. Comp. Neurol. 394, 48–63.
Sawchenko P. E., Swanson L. W., Rivier J., and Vale W. W. (1985) The distribution of growth-hormone-releasing factor (GRF) immunoreactivity in the central nervous system of the rat: an immunohistochemical study using antisera directed against rat hypothalamic GRF. J. Comp. Neurol. 237, 100–115.
Lechan R. M., Nestler J. L., and Molitch M. E. (1981) Immunohistochemical identification of a novel substance with human growth hormone-like immunoreactivity in rat brain. Endocrinology 109, 1950–1962.
Larsen P. J. (1992) Distribution of substance P-immunoreactive elements in the preoptic area and the hypothalamus of the rat. J. Comp. Neurol. 316, 287–313.
Yamada K., Emson P., and Hokfelt T. (1996) Immunohistochemical mapping of nitric oxide synthase in the rat hypothalamus and colocalization with neuropeptides. J. Chem. Neuroanat. 10, 295–316.
Sims K. B., Hoffman D. L., Said S. I., and Zimmerman E. A. (1980) Vasoactive intestinal polypeptide (VIP) in mouse and rat brain: an immunocytochemical study. Brain Res. 186, 165–183.
Abrahamson E. E., Leak R. K., and Moore R. Y. (2001) The suprachiasmatic nucleus projects to posterior hypothalamic arousal systems. Neuroreport 12, 435–440.
Bayer L., Mairet-Coello G., Risold P. Y., and Griffond B. (2002) Orexin/hypocretin neurons: chemical phenotype and possible interactions with melanin-concentrating hormone neurons. Regul. Pept. 104, 33–39.
Reti I. M., Reddy R., Worley P. F., and Baraban J. M. (2002) Selective expression of Narp, a secreted neuronal pentraxin, in orexin neurons. J. Neurochem. 82, 1561–1565.
Brown R. E., Sergeeva O. A., Eriksson K. S., and Haas H. L. (2002) Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine, and noradrenaline). J. Neurosci. 22, 8850–8859.
Hagan J. J., Leslie R. A., Patel S., Evans M. L., Wattam T. A., Holmes S., et al. (1999) Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc. Natl. Acad. Sci. USA 96, 10,911–10,916.
Bayer L., Eggermann E., Serafin M., Saint-Mleux B., Machard D., Jones B., and Muhlethaler M. (2001) Orexins (hypocretins) directly excite tuberomammillary neurons. Eur. J. Neurosci. 14, 1571–1575.
Eggermann E., Serafin M., Bayer L., Machard D., Saint-Mleux B., Jones B. E., and Muhlethaler M. (2001) Orexins/hypocretins excite basal forebrain cholinergic neurones. Neuroscience 108, 177–181.
Takahashi K., Koyama Y., Kayama Y., and Yamamoto M. (2002) Effects of orexin on the laterodorsal tegmental neurones. Psychiatry Clin. Neurosci. 56, 335–336.
Bayer L., Eggermann E., Saint-Mleux B., Machard D., Jones B. E., Muhlethaler M., and Serafin M. (2002) Selective action of orexin (hypocretin) on nonspecific thalamocortical projection neurons. J. Neurosci. 22, 7835–7839.
Korotkova T. M., Sergeeva O. A., Eriksson K. S., Haas H. L., and Brown R. E. (2003) Excitation of ventral tegmental area dopaminergic and nondopaminergic neurons by orexins/hypocretins. J. Neurosci. 23, 7–11.
Li Y., Gao X. B., Sakurai T., and van den Pol A. N. (2002) Hypocretin/Orexin Excites Hypocretin Neurons via a Local Glutamate Neuron-A Potential Mechanism for Orchestrating the Hypothalamic Arousal System. Neuron 36, 1169–1181.
Alam M. N., Gong H., Alam T., Jaganath R., McGinty D., and Szymusiak R. (2002) Sleep-waking discharge patterns of neurons recorded in the rat perifornical lateral hypothalamic area. J. Physiol. 538, 619–631.
Koyama Y., Kodama T., Takahashi K., Okai K., and Kayama Y. (2002) Firing properties of neurones in the laterodorsal hypothalamic area during sleep and wakefulness. Psychiatry Clin. Neurosci. 56, 339–340.
Methippara M. M., Alam M. N., Szymusiak R., and McGinty D. (2003) Preoptic area warming inhibits wake-active neurons in the perifornical lateral hypothalamus. Brain Res. 960, 165–173.
Steininger T. L., Alam M. N., Gong H., Szymusiak R., and McGinty D. (1999) Sleep-waking discharge of neurons in the posterior lateral hypothalamus of the albino rat. Brain Res. 840, 138–147.
Kiyashchenko L. I., Mileykovskiy B. Y., Maidment N., Lam H. A., Wu M. F., John J., et al. (2002) Release of hypocretin (orexin) during waking and sleep states. J. Neurosci. 22, 5282–5286.
Tyler-McMahon B. M., Boules M., and Richelson E. (2000) Neurotensin: peptide for the next millennium. Regul. Pept. 93, 125–136.
Kalivas P. W., Burgess S. K., Nemeroff C. B., and Prange A. J., Jr. (1983) Behavioral and neurochemical effects of neurotensin microinjection into the ventral tegmental area of the rat. Neuroscience 8, 495–505.
Zahm D. S., Grosu S., Williams E. A., Qin S., and Berod A. (2001) Neurons of origin of the neurotensinergic plexus enmeshing the ventral tegmental area in rat: retrograde labeling and in situ hybridization combined. Neuroscience 104, 841–851.
Morin A. J. and Beaudet A. (1998) Origin of the neurotensinergic innervation of the rat basal forebrain studied by retrograde transport of cholera toxin. J. Comp. Neurol. 391, 30–41.
Cape E. G., Manns I. D., Alonso A., Beaudet A., and Jones B. E. (2000) Neurotensin-induced bursting of cholinergic basal forebrain neurons promotes gamma and theta cortical activity together with waking and paradoxical sleep. J. Neurosci. 20, 8452–8461.
Jolas T. and Aghajanian G. K. (1997) Neurotensin and the serotonergic system. Prog. Neurobiol. 52, 455–468.
Petrov T., Jhamandas J. H., and Krukoff T. L. (1992) Characterization of peptidergic efferents from the lateral parabrachial nucleus to identified neurons in the rat dorsal raphe nucleus. J. Chem. Neuroanat. 5, 367–373.
Drolet G. and Rivest S. (2001) Corticotropin-releasing hormone and its receptors; an evaluation at the transcription level in vivo. Peptides 22, 761–767.
Chang F. C. and Opp M. R. (2001) Corticotropin-releasing hormone (CRH) as a regulator of waking. Neurosci. Biobehav. Rev. 25, 445–453.
Russell S. H., Small C. J., Dakin C. L., Abbott C. R., Morgan D. G., Ghatei M. A., and Bloom S. R. (2001) The central effects of orexin-A in the hypothalamic-pituitary-adrenal axis in vivo and in vitro in male rats. J. Neuroendocrinol. 13, 561–566.
Al Barazanji K. A., Wilson S., Baker J., Jessop D. S., and Harbuz M. S. (2001) Central orexin-A activates hypothalamic-pituitary-adrenal axis and stimulates hypothalamic corticotropin releasing factor and arginine vasopressin neurones in conscious rats. J. Neuroendocrinol. 13, 421–424.
Brischoux F., Cvetkovic V., Griffond B., Fellmann D., and Risold P. Y. (2002) Time of genesis determines projection and neurokinin-3 expression patterns of diencephalic neurons containing melanin-concentrating hormone. Eur. J. Neurosci. 16, 1672–1680.
Cvetkovic V., Brischoux F., Griffond B., Bernard G., Jacquemard C., Fellmann D., and Risold P. Y. (2003) Evidence of melanin-concentrating hormone-containing neurons supplying both cortical and neuroendocrine projections. Neuroscience 116, 31–35.
Cronin S. J., Mochizuki T., Papadopoulou M., Trombly D., Maratos-Flier E., and Scammell T. E. (2000) Sleep/wake behavior in mch overexpressing mice. Sleep 25, A168-A169.
Gomori A., Ishihara A., Ito M., Mashiko S., Matsushita H., Yumoto M., et al. (2002) Chronic intracerebroventricular infusion of MCH causes obesity in mice. Am. J. Physiol. Endocrinol. Metab. 284, E583-E588.
Wurts S. W., Nishino S., Ling N., Maki R., Edgar D. M., and Minot E. (2001) Differential effects of hypocretin-1, melanin-concentrating hormone and cocaine- and amphetamine-regulated transcript on sleep in rats. Sleep 24, A154-A155.
Nahon J. L. (1994) The melanin-concentrating hormone: from the peptide to the gene. Crit. Rev. Neurobiol. 8, 221–262.
Steiger A., Guldner J., Knisatschek H., Rothe B., Lauer C., and Holsboer F. (1991) Effects of an ACTH/MSH(4–9) analog (HOE 427) on the sleep EEG and nocturnal hormonal secretion in humans. Peptides 12, 1007–1010.
Shimada M., Tritos N. A., Lowell B. B., Flier J. S., and Maratos-Flier E. (1998) Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature 396, 670–674.
Plotsky P. M. and Vale W. (1985) Patterns of growth hormone-releasing factor and somatostatin secretion into the hypophysial-portal circulation of the rat. Science 230, 461–463.
Yoshizato H., Fujikawa T., Soya H., Tanaka M., and Nakashima K. (1998) The growth hormone (GH) gene is expressed in the lateral hypothalamus: enhancement by GH_releasing hormone and repression by restraint stress. Endocrinology 139, 2545–2551.
Zhang J., Obal F., Jr., Zheng T., Fang J., Taishi P., and Krueger J. M. (1999) Intrapreoptic microinjection of GHRH or its antagonist alters sleep in rats. J. Neurosci. 19, 2187–2194.
Gardi J., Obal F., Jr., Fang J., Zhang J., and Krueger J. M. (1999) Diurnal variations and sleep deprivation-induced changes in rat hypothalamic GHRH and somatostatin contents. Am. J. Physiol. 277, R1339-R1344.
Obal F., Jr., Alfoldi P., Cady A. B., Johannsen L., Sary G., and Krueger J. M. (1988) Growth hormone-releasing factor enhances sleep in rats and rabbits. Am. J. Physiol. 255, R310-R316.
Marshall L., Derad I., Strasburger C. J., Fehm H. L., and Born J. (1999) A determinant factor in the efficacy of GHRH administration in promoting sleep: high peak concentration versus recurrent increasing slopes. Psychoneuroendocrinology 24, 363–370.
Drucker-Colin R. R., Spanis C. W., Hunyadi J., Sassin J. F., and McGaugh J. L. (1975) Growth hormone effects on sleep and wakefulness in the rat. Neuroendocrinology 18, 1–8.
Obal F., Jr., Fang J., Taishi P., Kacsoh B., Gardi J., and Krueger J. M. (2001) Deficiency of growth hormone-releasing hormone signaling is associated with sleep alterations in the dwarf rat. J. Neurosci. 21, 2912–2918.
Hajdu I., Obal F., Jr., Fang J., Krueger J. M., and Rollo C. D. (2002) Sleep of transgenic mice producing excess rat growth hormone. Am. J. Physiol. Regul. Integr. Comp. Physiol. 282, R70-R76.
Overeem S., Kok S. W., Lammers G. J., Vein A. A., Frolich M., Meinders A. E., et al. (2002) The somatotropic axis in hypocretin-deficient narcoleptic humans: altered circadian distribution of GH secretory events. Am. J. Physiol. Endocrinol. Metab. 284, E641-E647.
Steiger A. and Holsboer F. (1997) Neuropeptides and human sleep. Sleep 20, 1038–1052.
Opp M. R. (1995) Corticotropin-releasing hormone involvement in stressor-induced alterations in sleep and in the regulation of waking. Adv. Neuroimmunol. 5, 127–143.
Holsboer F., von Bardeleben U., and Steiger A. (1988) Effects of intravenous corticotropin-releasing hormone upon sleep-related growth hormone surge and sleep EEG in man. Neuroendocrinology 48, 32–38.
Kerkhofs M., Van Cauter E., Van Onderbergen A., Caufriez A., Thorner M. O., and Copinschi G. (1993) Sleep-promoting effects of growth hormone-releasing hormone in normal men. Am. J. Physiol. 264, E594-E598.
Heilig M. and Widerlov E. (1990) Neuropeptide Y: an overview of central distribution, functional aspects, and possible involvement in neuropsychiatric illnesses. Acta Psychiatr. Scand. 82, 95–114.
Leger L., Charnay Y., Danger J. M., Vaudry H., Pelletier G., Dubois P. M., and Jouvet M. (1987) Mapping of neuropeptide Y-like immunoreactivity in the feline hypothalamus and hypophysis. J. Comp. Neurol. 255, 283–292.
Elias C. F., Saper C. B., Maratos-Flier E., Tritos N. A., Lee C., Kelly J., et al. (1998) Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area. J. Comp. Neurol. 402, 442–459.
Fuxe K., Agnati L. F., Harfstrand A., Zini I., Tatemoto K., Pich E. M., et al. (1983) Central administration of neuropeptide Y induces hypotension bradypnea and EEG synchronization in the rat. Acta Physiol. Scand. 118, 189–192.
Antonijevic I. A., Murck H., Bohlhalter S., Frieboes R. M., Holsboer F., and Steiger A. (2000) Neuropeptide Y promotes sleep and inhibits ACTH and cortisol release in young men. Neuropharmacology 39, 1474–1481.
Naveilhan P., Canals J. M., Valjakka A., Vartiainen J., Arenas E., and Ernfors P. (2001) Neuropeptide Y alters sedation through a hypothalamic Y1-mediated mechanism. Eur. J. Neurosci. 13, 2241–2246.
Naveilhan P., Canals J. M., Arenas E., and Ernfors P. (2001) Distinct roles of the Y1 and Y2 receptors on neuropeptide Y-induced sensitization to sedation. J. Neurochem. 78, 1201–1207.
Graf M. V. and Kastin A. J. (1986) Delta-sleep-inducing peptide (DSIP): an update. Peptides 7, 1165–1187.
Charnay Y., Bouras C., Vallet P. G., Golaz J., Guntern R., and Constantinidis J. (1989) Immunohistochemical distribution of delta sleep inducing peptide in the rabbit brain and hypophysis. Neuroendocrinology 49, 169–175.
Pollard B. J. and Pomfrett C. J. (2001) Delta sleep-inducing peptide. Eur. J. Anaesthesiol. 18, 419–422.
Umriukhin P. E. (2002) Delta sleep-inducing Peptide blocks excitatory effects of glutamate on rat brain neurons. Bull. Exp. Biol. Med. 134, 5–7.
Salieva R. M., Yanovskii K., Ratsak R., Trofimova Y., Oeme P., Sudakov K. V., and Yumatov E. A. (1992) Delta sleep-inducing peptide as a factor increasing the content of substance P in the hypothalamus and the resistance of rats to emotional stress. Neurosci. Behav. Physiol. 22, 275–279.
Strittmatter M., Isenberg E., Grauer M. T., Hamann G., and Schimrigk K. (1996) CSF substance P somatostatin and monoaminergic transmitter metabolites in patients with narcolepsy. Neurosci. Lett. 218, 99–102.
Gislason T., Hedner J., Terenius L., Bisette G., and Nemeroff C. B. (1992) Substance P, thyrotropin-releasing hormone, and monoamine metabolites in cerebrospinal fluid in sleep apnea patients. Am. Rev. Respir. Dis. 146, 784–786.
Wachtel E., Koplik E., Kolometsewa I. A., Balzer H. U., Hecht K., Oehme P., and Ivanow V. T. (1987) Comparison of the effects of DSIP and SP 1–11 on stress-induced chronic sleep disorders in rats. Pharmazie 42, 188–190.
Cutler D. J., Morris R., Evans M. L., Leslie R. A., Arch J. R., and Williams G. (2001) Orexin-A immunoreactive neurons in the rat hypothalamus do not contain neuronal nitric oxide synthase (nNOS). Peptides 22, 123–128.
Kapas L. and Krueger J. M. (1996) Nitric oxide donors SIN-1 and SNAP promote nonrapid-eye-movement sleep in rats. Brain Res. Bull. 41, 293–298.
Burlet S., Leger L., and Cespuglio R. (1999) Nitric oxide and sleep in the rat: a puzzling relationship. Neuroscience 92, 627–639.
Williams J. A., Vincent S. R., and Reiner P. B. (1997) Nitric oxide production in rat thalamus changes with behavioral state, local depolarization, and brainstem stimulation. J. Neurosci. 17, 420–427.
Burlet S. and Cespuglio R. (1997) Voltammetric detection of nitric oxide (NO) in the rat brain: its variations throughout the sleep-wake cycle. Neurosci. Lett. 226, 131–135.
Obal F., Jr., Sary G., Alfoldi P., Rubicsek G., and Obal F. (1986) Vasoactive intestinal polypeptide promotes sleep without effects on brain temperature in rats at night. Neurosci. Lett. 64, 236–240.
Prospero-Garcia O., Morales M., Arankowsky-Sandoval G., and Drucker-Colin R. (1986) Vasoactive intestinal polypeptide (VIP) and cerebrospinal fluid (CSF) of sleep-deprived cats restores REM sleep in insomniac recipients. Brain Res. 385, 169–173.
Obal F., Jr., Opp M., Cady A. B., Johannsen L., and Krueger J. M. (1989) Prolactin, vasoactive intestinal peptide, and peptide histidine methionine elicit selective increases in REM sleep in rabbits. Brain Res. 490, 292–300.
Mirmiran M., Kruisbrink J., Bos N. P., Van der W. D., and Boer G. J. (1988) Decrease of rapid-eye-movement sleep in the light by intraventricular application of a VIP-antagonist in the rat. Brain Res. 458, 192–194.
el Kafi B., Cespuglio R., Leger L., Marinesco S., and Jouvet M. (1994) Is the nucleus raphe dorsalis a target for the peptides possessing hypnogenic properties? Brain Res. 637, 211–221.
Bourgin P., Lebrand C., Escourrou P., Gaultier C., Franc B., Hamon M., and Adrien J. (1997) Vasoactive intestinal polypeptide microinjections into the oral pontine tegmentum enhance rapid eye movement sleep in the rat. Neuroscience 77, 351–360.
Kuenzel W. J. and Blahser S. (1994) Vasoactive intestinal polypeptide (VIP)-containing neurons: distribution throughout the brain of the chick (Gallus domesticus) with focus upon the lateral septal organ. Cell Tissue Res. 275, 91–107.
Laemle L. K. and Cotter J. R. (1988) Immunocytochemical localization of vasoactive intestinal polypeptide (VIP) in the brain of the little brown bat (Myotis lucifugus). J. Neurocytol. 17, 117–129.
Obata-Tsuto H. L., Okamura H., Tsuto T., Terubayashi H., Fukui K., Yanaihara N., and Ibata Y. (1983) Distribution of the VIP-like immunoreactive neurons in the cat central nervous system. Brain Res. Bull. 10, 653–660.
Baek S. Y., Yamano M., Shiotani Y., and Tohyama M. (1988) Distribution and origin of vasoactive intestinal polypeptide-like immunoreactive fibers in the central amygdaloid nucleus of the rat: an immunocytochemical analysis. Peptides 9, 661–668.
Goffin V., Binart N., Touraine P., and Kelly P. A. (2002) Prolactin: the new biology of an old hormone. Annu. Rev. Physiol. 64, 47–67.
Paut-Pagano L., Roky R., Valatx J. L., Kitahama K., and Jouvet M. (1993) Anatomical distribution of prolactin-like immunoreactivity in the rat brain. Neuroendocrinology 58, 682–695.
Risold P. Y., Griffond B., Kilduff T. S., Sutcliffe J. G., and Fellmann D. (1999) Preprohypocretin (orexin) and prolactin-like immunoreactivity are coexpressed by neurons of the rat lateral hypothalamic area. Neurosci. Lett. 259, 153–156.
Roky R., Paut-Pagano L., Goffin V., Kitahama K., Valatx J. L., Kelly P. A., and Jouvet M. (1996) Distribution of prolactin receptors in the rat forebrain. Immunohistochemical study. Neuroendocrinology 63, 422–429.
Roky R., Obal F., Jr., Valatx J. L., Bredow S., Fang J., Pagano L. P., and Krueger J. M. (1995) Prolactin and rapid eye movement sleep regulation. Sleep 18, 536–542.
Roky R., Valatx J. L., and Jouvet M. (1993) Effect of prolactin on the sleep-wake cycle in the rat. Neurosci. Lett. 156, 117–120.
Roky R., Valatx J. L., Paut-Pagano L., and Jouvet M. (1994) Hypothalamic injection of prolactin or its antibody alters the rat sleep-wake cycle. Physiol. Behav. 55, 1015–1019.
Meldrum B. S. (2000) Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J. Nutr. 130, 1007S-1015S.
Ziegler D. R., Cullinan W. E., and Herman J. P. (2002) Distribution of vesicular glutamate tansporter mRNA in rat hypothalamus. J. Comp. Neurol. 448, 217–229.
Lancel M. (1999) Role of GABAA receptors in the regulation of sleep: initial sleep responses to peripherally administered modulators and agonists. Sleep 22, 33–42.
Elias C. F., Lee C. E., Kelly J. F., Ahima R. S., Kuhar M., Saper C. B., and Elmquist J. K. (2001) Characterization of CART neurons in the rat and human hypothalamus. J. Comp. Neurol. 432, 1–19.
Gao X. B. and van den Pol A. N. (2001) GABA, not glutamate, a primary transmitter driving action potentials in developing hypothalamic neurons. J. Neurophysiol. 85, 425–434.
Jo Y. H. and Role L. W. (2002) Coordinate release of ATP and GABA at in vitro synapses of lateral hypothalamic neurons. J. Neurosci. 22, 4794–4804.
Jo Y. H. and Role L. W. (2002) Cholinergic modulation of purinergic and GABAergic cotransmission at in vitro hypothalamic synapses. J. Neurophysiol. 88, 2501–2508.
Ford B., Holmes C. J., Mainville L., and Jones B. E. (1995) GABAergic neurons in the rat pontomesencephalic tegmentum: codistribution with cholinergic and other tegmental neurons projecting to the posterior lateral hypothalamus. J. Comp. Neurol. 363, 177–196.
Brown R. E., Stevens D. R., and Haas H. L. (2001) The physiology of brain histamine. Prog. Neurobiol. 63, 637–672.
Parmentier R., Ohtsu H., Djebbara-Hannas Z., Valatx J. L., Watanabe T., and Lin J. S. (2002) Anatomical, physiological, and pharmacological characteristics of histidine decarboxylase knock-out mice: evidence for the role of brain histamine in behavioral and sleep-wake control. J. Neurosci. 22, 7695–7711.
Huang Z. L., Qu W. M., Li W. D., Mochizuki T., Eguchi N., Watanabe T., et al. (2001) Arousal effect of orexin A depends on activation of the histaminergic system. Proc. Natl. Acad. Sci. USA 98, 9965–9970.
Haas H. and Panula P. (2003) The role of histamine and the tuberomamillary nucleus in the nervous system. Nat. Rev. Neurosci. 4, 121–130.
Saper C. B., Swanson L. W., and Cowan W. M. (1979) An autoradiographic study of the efferent connections of the lateral hypothalamic area in the rat. J. Comp. Neurol. 183, 689–706.
Saper C. B. (1985) Organization of cerebral cortical afferent systems in the rat. II. Hypothalamocortical projections. J. Comp. Neurol. 237, 21–46.
Chou T. C., Bjorkum A. A., Gaus S. E., Lu J., Scammell T. E., and Saper C. B. (2002) Afferents to the ventrolateral preoptic nucleus. J. Neurosci. 22, 977–990.
Sherin J. E., Shiromani P. J., McCarley R. W., and Saper C. B. (1996) Activation of ventrolateral preoptic neurons during sleep. Science 271, 216–219.
Jones B. E. (1993) The organization of central cholinergic systems and their functional importance in sleep-waking states. Prog. Brain Res. 98, 61–71.
Gritti I., Mainville L., and Jones B. E. (1994) Projections of GABAergic and cholinergic basal forebrain and GABAergic preoptic-anterior hypothalamic neurons to the posterior lateral hypothalamus of the rat. J. Comp. Neurol. 339, 251–268.
Sim L. J. and Joseph S. A. (1992) Efferent projections of the nucleus raphe magnus. Brain Res. Bull. 28, 679–682.
Sakai K., Yoshimoto Y., Luppi P. H., Fort P., el Mansari M., Salvert D., and Jouvet M. (1990) Lower brainstem afferents to the cat posterior hypothalamus: a double-labeling study. Brain Res. Bull. 24, 437–455.
Inagaki N., Yamatodani A., Ando-Yamamoto M., Tohyama M., Watanabe T., and Wada H. (1988) Organization of histaminergic fibers in the rat brain. J. Comp. Neurol. 273, 283–300.
McGinty D. and Szymusiak R. (1990) Keeping cool: a hypothesis about the mechanisms and functions of slow-wave sleep. Trends Neurosci. 13, 480–487.
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Gerashchenko, D., Shiromani, P.J. Different neuronal phenotypes in the lateral hypothalamus and their role in sleep and wakefulness. Mol Neurobiol 29, 41–59 (2004). https://doi.org/10.1385/MN:29:1:41
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DOI: https://doi.org/10.1385/MN:29:1:41