European Journal of Neuroscience, Vol. 14, pp. 1571±1575, 2001
ã Federation of European Neuroscience Societies
SHORT COMMUNICATION Orexins (hypocretins) directly excite tuberomammillary neurons Laurence Bayer,1* Emmanuel Eggermann,1* Mauro Sera®n,1* BenoõÃt Saint-Mleux,1 D. Machard,1 Barbara Jones2 and Michel MuÈhlethaler1 1
DeÂpartement de Physiologie, Centre MeÂdical Universitaire, 1 rue Michel-Servet, 1211 GeneÁve 4, Switzerland Department of Neurology and Neurosurgery, McGill University, Montreal Neurological, Institute, 3801 University Street, Montreal, Quebec, Canada H3A 2B4 2
Keywords: arousal, histamine, rat, sleep, wakefulness
Abstract Wakefulness has recently been shown to depend upon the newly identi®ed orexin (or hypocretin) neuropeptides by the ®ndings that alteration in their precursor protein, their receptors or the neurons that produce them leads to the sleep disorder narcolepsy in both animals and humans. The questions of how and where these brain peptides act to maintain wakefulness remain unresolved. The purpose of the present study was to determine whether the orexins could directly affect hypothalamic histaminergic neurons, which are known to contribute to the state of wakefulness by their diffuse projections through the brain. Using brain slices, we recorded in the ventral tuberomammillary nuclei from neurons identi®ed as histaminergic on the basis of their previously described morphological and electrophysiological characteristics and found that they were depolarized and excited by the orexins through a direct postsynaptic action. We then compared the depolarizing effect of orexin A and B and found that they were equally effective upon these cells. This latter ®nding suggests that the effect of orexins is mediated by orexin type 2 receptors, which are those lacking in narcoleptic dogs. Our results therefore show that the histaminergic neurons of the tuberomammillary nuclei represent an important target for the orexin system in the maintenance of wakefulness.
Introduction Orexin A and B (also known as hypocretin 1 and 2) are two recently identi®ed neuropeptides (de Lecea et al., 1998; Sakurai et al., 1998) produced by a collection of neurons located in the perifornical and dorso-lateral area of the hypothalamus. From there, the orexin cells send extensive projections through the entire brain and spinal cord (Broberger et al., 1998; Peyron et al., 1998; Cutler et al., 1999; Date et al., 1999; Nambu et al., 1999; van den Pol, 1999; Date et al., 2000). Along with the characterization of both peptides, two different orexin receptors (OX1 and OX2, or Hcrtr1 and Hcrtr2) were also demonstrated (Sakurai et al., 1998) and their widespread differential distribution in the CNS described (Trivedi et al., 1998; Lu et al., 2000; Marcus et al., 2001). The implication of the orexin system in the regulation of wakefulness (for reviews, see Siegel, 1999; van den Pol, 2000; Chicurel, 2000; Kilduff & Peyron, 2000; Hungs & Mignot, 2001; Sutcliffe & de Lecea, 2000; Willie et al., 2001) stems from the discovery that narcolepsy in the dog model of this disease results from a mutation in orexin receptors (Lin et al., 1999) and that prepro-orexin knock-out mice (Chemelli et al., 1999) apparently Correspondence: Dr M. MuÈhlethaler, as above. E-mail:
[email protected] *L.B., E.E. and M.S. contributed equally to the work Received 28 June 2001, revised 7 September 2001, accepted 21 September 2001
suffer from an equivalent syndrome. It is noteworthy that human narcolepsy is also linked to the orexin system, albeit in the majority of cases it does not depend upon a defect of orexin receptors but upon a degeneration of the orexin neurons themselves (Peyron et al., 2000; Thannickal et al., 2000). The de®cit, which is possibly related to a genetic predisposition (Gencik et al., 2001; Mignot et al., 2001), is accompanied by a decrease of orexin in the cerebrospinal ¯uid (Nishino et al., 2000). Interestingly, an equivalent of the human syndrome has recently been reproduced in transgenic mice in which a progressive degeneration of orexin neurons also leads to narcolepsy (Hara et al., 2001). The extensive presence of orexin ®bers (Peyron et al., 1998) and receptors (Marcus et al., 2001) in the brain has led to the suggestion (Siegel, 1999; Chicurel, 2000; Kilduff & Peyron 2000; Sutcliffe & de Lecea, 2000; van den Pol, 2000; Willie et al., 2001) that the orexins could promote wakefulness by acting concomitantly in several regions associated with the control of behavioural states. Among the potentially important sites in that respect (reviewed in McCormick & Bal, 1997; Jones, 2000) are the ventral tuberomammillary nuclei (VTM) of the posterior hypothalamus that contain histamine and by diffuse projections through the brain play an important role in maintaining the state of wakefulness. The purpose of the present study was thus to test in vitro whether the histaminergic neurons of the VTM can be directly modulated by the orexins.
1572 L. Bayer et al.
Materials and methods The optimal brain slices for recording from VTM neurons were chosen on the basis of the atlas of Paxinos & Watson (1997). Following decapitation, coronal slices (300 mm thick) obtained from young rats (17±19 days, n = 14) were incubated at room temperature in arti®cial cerebrospinal ¯uid which contained (in mM): NaCl, 130; KCl, 5; KH2PO4, 1.25; MgSO4, 1.3; NaHCO3, 20; glucose, 10 and CaCl2, 2.4; bubbled with a mixture of 95% O2 and 5% CO2. Individual slices were transferred to a thermoregulated (32 °C) chamber on a Zeiss Axioskop equipped with an infrared camera (Dodt & Zieglgansberger, 1994). Slices were maintained immersed and continuously superfused at 3±5 mL/min. Patch electrodes were pulled on a DMZ universal puller (Zeitz-Instrumente, Germany) from borosilicate glass capillaries (GC150F-10, Clark Instruments, UK). For whole-cell recordings, the pipettes (5±12 MW) contained the following solution (in mM): KMeSO4, 126; phosphocreatine, 8; KCl, 4; MgCl2, 5; HEPES, 10; Na2ATP, 3; GTP, 0.1; and Bapta, 0.1 (pH 7.4; 290±310 mOsm). Neurobiotin (0.2%) was added to the intrapipette solution. Cells' membrane potential was always negative to ±50 mV. Orexins (Bachem, Switzerland) were tested by dissolving the peptides at the proper concentration in the perfusion solution. Synaptic blockade was realized by lowering calcium and increasing magnesium (0.1 mM Ca2+/10 mM Mg2+), a condition which we found to completely impede synaptic potentials evoked upon VTM neurons by electrical stimulation in the vicinity of the VTM. After electrophysiological recordings, slices of VTM were ®xed in an ice-cold solution containing 3% paraformaldehyde. Neurobiotin®lled neurons were then visualized using the avidin-biotinylated horseradish peroxydase complex reaction (Vectastain, ABC Elite kit, Vector Laboratories, USA) with 3±3¢-diaminobenzidine (Sigma) as a chromogen. In this condition, the limits of the VTM could be determined visually under the microscope by the differential background staining with respect to surrounding structures. In order to con®rm the location of stained cells within the boundaries of this nucleus, two slices were in addition re-sectioned at 45 mm using a cryostat and counter-stained with 2% cresyl violet.
Results Neurons were recorded from the VTM which, in infrared videomicroscopy, was easily identi®ed visually at the ventral surface of the posterior hypothalamus as a small and dense structure packed with large, presumably histaminergic, neurons (Ericson et al., 1987). As originally demonstrated in VTM histaminergic neurons (Haas & Reiner, 1988), cells recorded in the present study were all endowed with two important membrane recti®cations. The ®rst one was revealed by a sag during hyperpolarizing pulses (dot in Fig. 1A) and has been shown to depend on the presence of an Ih current (Kamondi & Reiner, 1991). The second one was visible as a delayed return to the baseline (arrow in Fig. 1A) following hyperpolarizing pulses and was shown to depend on two types of transient outward currents (Greene et al., 1990). In addition, and as expected (Haas & Reiner, 1988) from previous studies, these cells also displayed (Fig. 1A, right panel) rather broad action potentials (mean 6 SEM = 2.0 6 0.10 ms, n = 7, measured at mid-height). Altogether these characteristics allow unambiguous identi®cation of histaminergic neurons in the VTM (Stevens et al., 1999). Anatomical control for the sites of the recordings in the slices (Fig. 1B; see Materials and methods), indicate that all (7 out of 7) neurobiotin-injected cells were located within the con®nes of the VTM (Fig. 1C), as con®rmed (n = 2) using a cresyl violet
counter-staining (Fig. 1D, showing an injected cell among a collection of large diameter neurons at the ventral surface of the brain). As described for the histaminergic neurons in the VTM (Ericson et al., 1987), the recorded and injected cells were indeed all large in size (mean large diameter 6 SEM = 24.7 6 1.06 mm; mean small diameter = 15.3 6 0.84 mm, n = 7) and multipolar (3±5 dendrites). All VTM neurons were depolarized and excited (17 out of 17) when tested with either orexin A or B at concentrations ranging from 2 3 10±9 to 10±7 M (Fig. 1E and F). At 10±9 M, neither peptide had any effect (n = 8 cells tested with orexin B, of which 2 also tested with orexin A). The depolarizing effects of the orexins were postsynaptic as they always persisted (n = 5 out of 5) in conditions of synaptic blockade (0.1 mM Ca2+/10 mM Mg2+). When comparing the effects of orexin A and B, both applied at 10±7 M, it was found that orexin B had a stronger effect than did orexin A (mean depolarization 6 SEM for orexin A = 8.3 6 0.71 mV and for orexin B = 10.4 6 0.54 mV; n = 12, paired t-test t = 2.32, P = 0.03). Comparison made at 10±8 M, on a smaller sample, indicated a similar tendency, with orexin B having a stronger effect than orexin A, although not signi®cantly (orexin A = 3.9 6 0.3 mV, orexin B = 5.6 6 1.02 mV; n = 3, paired t-test t = 2.58, P = 0.1).
Discussion The present study shows that the histaminergic neurons of the VTM are depolarized and excited by the orexins and thus suggests that these cells can mediate orexins' action upon wakefulness. Previous studies of orexins' effects in hypothalamic cultures (de Lecea et al., 1998; van den Pol et al., 1998) as well as in other areas (discussed below) indicated that these peptides commonly exert a depolarizing effect. With respect to the receptors involved in the effects of the orexins on VTM neurons, our results indicate that OX2 receptors are implicated, because orexin A and B applied at the same concentration exert a depolarization of a similar amplitude in these cells. Indeed, the original studies that compared the binding of both peptides on the two types of orexin receptors clearly indicated that orexin A and B have a similar af®nity for the OX2 receptor, whereas orexin A has an » 103 higher af®nity than orexin B for the OX1 receptor (Sakurai et al., 1998). It is noteworthy that our results are in agreement with the recent in situ hybridization study comparing OX1 and OX2 receptor distribution in the rat brain and demonstrating that only OX2 receptors are expressed in the VTM neurons (Marcus et al., 2001). Based on the evidence that orexin neurons project to different regions potentially implicated in the control of behavioural states (Peyron et al., 1998), a number of in vivo studies have been performed to test the actions of the orexins by intracerebral administration. Local perfusion of the peptides in the region of the locus coeruleus (Hagan et al., 1999; Bourgin et al., 2000), the laterodorsal tegmentum (Xi et al., 2001) and the basal forebrain/ preoptic area (Methippara et al., 2000) were found to induce a decrease in sleep accompanied by an increase in wakefulness. Given the possible indirect action of orexins on local interneurons or on presynaptic terminals, such studies obviously did not provide information on which cells within a given area or nucleus are directly affected by the peptides. However, at the brainstem level, the effects of orexins were studied in vitro on identi®ed cells including importantly, the noradrenergic neurons of the locus coeruleus (Horvath et al., 1999; Bourgin et al., 2000; Ivanov & Aston-Jones, 2000), the serotonergic neurons of the raphe (Brown et al., 2001) and the dopaminergic neurons of the ventral tegmental area (Nakamura
ã 2001 Federation of European Neuroscience Societies, European Journal of Neuroscience, 14, 1571±1575
Orexin excites histaminergic neurons 1573
FIG. 1. Effects of orexins on VTM neurons. (A) Electrophysiological identi®cation of VTM neurons. (B) General view of a slice indicating the location of the VTM. An arrowhead points to the location of a neurobiotin-injected cell, which is enlarged in the inset. (C) Localization of all injected neurons (n = 7) in the VTM, including the one identi®ed in panel B. (D) Con®rmation of the localization of the cell illustrated in B among the collection of large-diameter cells characteristic of the VTM (cresyl violet counter-stain). (E and F) Effects of orexin A and B on the cell identi®ed by an arrowhead in panels B±D. Abbreviations: Arc, arcuate nucleus; f, fornix; LH, lateral hypothalamus; MRe, mammillary recess of the 3rd ventricle; PMV, premammillary nucleus ventral part; VTM, ventral tuberomammillary nucleus. Scale bars, 140 mm (B); 20 mm (B inset); 500 mm (C); 30 mm (D).
et al., 2000). In all three of these aminergic systems, the orexins were found to have an excitatory action as evidenced by either a depolarization or an increase in intracellular calcium. The functional signi®cance, with respect to wakefulness, of the studies mentioned above is dif®cult to ascertain at present. Indeed, in the case of the noradrenergic locus coeruleus, it is noteworthy that most orexin receptors in this nucleus are of the OX1 type, at least in rats (Lin et al., 1999; Marcus et al., 2001). Narcolepsy in dogs has been shown to result from a speci®c de®cit of OX2 type receptors (Lin et al., 1999). Although these data apparently cast doubt on the importance of the locus coeruleus in mediating orexins' action on wakefulness, it is still possible that in dogs, in contrast to rats, the OX2 receptors are actually prevalent in the locus coeruleus. If that were the case, the de®cit of OX2 receptors in the locus coeruleus could indeed contribute to canine narcolepsy. Interpreting the actions
of the orexins on the dopaminergic and serotonergic systems (Nakamura et al., 2000; Brown et al., 2001), within the context of wakefulness, is on the other hand also problematic at this stage. Indeed, the role of both amines in behavioural state control is still a matter of debate (Jones, 2000) and will need to be clari®ed ®rst in order to take into account the orexins' effects. Finally, it is noteworthy that neurons of the ventrolateral preoptic nucleus, which have been implicated in promoting sleep (Sherin et al., 1998; Szymusiak et al., 1998; Gallopin et al., 2000) and thus could potentially be targets of the orexins, have been found to be completely insensitive to these peptides (E. Eggermann, unpublished observation). The role of orexins' activation of histaminergic neurons in the tuberomammillary nuclei is easier to interpret given the established implication of histamine in promoting the state of wakefulness
ã 2001 Federation of European Neuroscience Societies, European Journal of Neuroscience, 14, 1571±1575
1574 L. Bayer et al. (discussed in Jones, 2000). Indeed, the major source of histamine in the brain originates from these nuclei (Lin et al., 1986; Inagaki et al., 1988; Panula et al., 1989) and when the receptors for histamine are blocked (Reiner & Kamondi, 1994) or the nuclei inactivated (Sallanon et al., 1989), sedation is induced. Histaminergic neurons, which were shown to be most active during waking (Vanni-Mercier et al., 1984), are thought to facilitate that state by the postsynaptic action that histamine exerts in many brain areas. In particular histamine depolarizes and excites neurons in the thalamus and the cerebral cortex to promote cortical activation of wakefulness (discussed in McCormick & Bal, 1997). In conclusion, our results indicate that the histaminergic neurons of the tuberomammillary nuclei, which are strongly excited by the orexins through an action on OX2 receptors, represent an important link for the orexin system in its role of maintaining the state of wakefulness.
Acknowledgements This study was supported by grants from the Swiss Fonds National, Novartis, OTT, de Reuter and Schmidheiny Foundations to M.M. and M.S., the Canadian MRC to B.E.J. and a Roche fellowship to L.B.
Abbreviations OX, orexin; VTM, ventral tuberomammillary nucleus.
References Bourgin, P., Huitron-Resendiz, S., Spier, A.D., Fabre, V., Morte, B., Criado, J.R., Sutcliffe, J.G., de Henriksen, S.J. & Lecea, L. (2000) Hypocretin-1 modulates rapid eye movement sleep through activation of locus coeruleus neurons. J. Neurosci., 20, 7760±7765. Broberger, C., de Lecea, L., Sutcliffe, J.G. & Hokfelt, T. (1998) Hypocretin/ orexin- and melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: relationship to the neuropeptide Y and agouti gene-related protein systems. J. Comp. Neurol., 402, 460±474. Brown, R.E., Sergeeva, O., Eriksson, K.S. & Haas, H.L. (2001) Orexin A excites serotonergic neurons in the dorsal raphe nucleus of the rat. Neuropharmacology, 40, 457±459. Chemelli, R.M., Willie, J.T., Sinton, C.M., Elmquist, J.K., Scammell, T., Lee, C., Richardson, J.A., Williams, S.C., Xiong, Y., Kisanuki, Y., Fitch, T.E., Nakazato, M., Hammer, R.E., Saper, C.B. & Yanagisawa, M. (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell, 98, 437±451. Chicurel, M. (2000) Neuroscience. The sandman's secrets. Nature, 407, 554± 556. Cutler, D.J., Morris, R., Sheridhar, V., Wattam, T.A., Holmes, S., Patel, S., Arch., J.R., Wilson, S., Buckingham, R.E., Evans, M.L., Leslie, R.A. & Williams, G. (1999) Differential distribution of orexin-A and orexin-B immunoreactivity in the rat brain and spinal cord. Peptides, 20, 1455±1470. Date, Y., Mondal, M.S., Matsukura, S. & Nakazato, M. (2000) Distribution of orexin-A and orexin-B (hypocretins) in the rat spinal cord. Neurosci. Lett., 288, 87±90. Date, Y., Ueta, Y., Yamashita, H., Yamaguchi, H., Matsukura, S., Kangawa, K., Sakurai, T., Yanagisawa, M. & Nakazato, M. (1999) Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc. Natl Acad. Sci. USA, 96, 748±753. Dodt, H.U. & Zieglgansberger, W. (1994) Infrared videomicroscopy: a new look at neuronal structure and function. Trends Neurosci., 17, 453±458. Ericson, H., Watanabe, T. & Kohler, C. (1987) Morphological analysis of the tuberomammillary nucleus in the rat brain: delineation of subgroups with antibody against L-histidine decarboxylase as a marker. J. Comp. Neurol., 263, 1±24. Gallopin, T., Fort, P., Eggermann, E., Cauli, B., Luppi, P.H., Rossier, J., Audinat, E., MuÈhlethaler, M. & Sera®n, M. (2000) Identi®cation of sleeppromoting neurons in vitro. Nature, 404, 992±995.
Gencik, M., Dahmen, N., Wieczorek, S., Kasten, M., Bierbrauer, J., Anghelescu, I., Szegedi, A., Menezes Saecker, A.M. & Epplen, J.T. (2001) A prepro-orexin gene polymorphism is associated with narcolepsy. Neurology, 56, 115±117. Greene, R.W., Haas, H.L. & Reiner, P.B. (1990) Two transient outward currents in histamine neurones of the rat hypothalamus in vitro. J. Physiol. (Lond.), 420, 149±163. Haas, H.L. & Reiner, P.B. (1988) Membrane properties of histaminergic tuberomammillary neurones of the rat hypothalamus in vitro. J. Physiol. (Lond.), 399, 633±646. Hagan, J.J., Leslie, R.A., Patel, S., Evans, M.L., Wattam, T.A., Holmes, S., Benham, C.D., Taylor, S.G., Routledge, C., Hemmati, P., Munton, R.P., Ashmeade, T.E., Shah, A.S., Hatcher, J.P., Hatcher, P.D., Jones, D.N., Smith, M.I., Piper, D.C., Hunter, A.J., Porter, R.A. & Upton, N. (1999) Orexin A activates locus coeruleus cell ®ring and increases arousal in the rat. Proc. Natl Acad. Sci. USA, 96, 10911±10916. Hara, J., Beuckmann, C.T., Nambu, T., Willie, J.T., Chemelli, R.M., Sinton, C.M., Sugiyama, F., Yagami, K., Goto, K., Yanagisawa, M. & Sakurai, T. (2001) Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron, 30, 345±354. Horvath, T.L., Peyron, C., Diano, S., Ivanov, A., Aston-Jones, G., Kilduff, T.S. & van den Pol, A.N. (1999) Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system. J. Comp. Neurol., 415, 145±159. Hungs, M. & Mignot, E. (2001) Hypocretin/orexin, sleep and narcolepsy. Bioessays, 23, 397±408. Inagaki, N., Yamatodani, A., Ando-Yamamoto, M., Tohyama, M., Watanabe, T. & Wada, H. (1988) Organization of histaminergic ®bers in the rat brain. J. Comp. Neurol., 273, 283±300. Ivanov, A. & Aston-Jones, G. (2000) Hypocretin/orexin depolarizes and decreases potassium conductance in locus coeruleus neurons. Neuroreport, 11, 1755±1758. Jones, B.E. (2000) Basic mechanisms of sleep-wake state. In Kryger, M.H., Roth, T. & Dement, W.C. (eds), Principles and Practice of Sleep Medicine. Saunders, Philadelphia, pp. 134±154. Kamondi, A. & Reiner, P.B. (1991) Hyperpolarization-activated inward current in histaminergic tuberomammillary neurons of the rat hypothalamus. J. Neurophysiol., 66, 1902±1911. Kilduff, T.S. & Peyron, C. (2000) The hypocretin/orexin ligand-receptor system: implications for sleep and sleep disorders. Trends Neurosci., 23, 359±365. de Lecea, L., Kilduff, T.S., Peyron, C., Gao, X., Foye, P.E., Danielson, P.E., Fukuhara, C., Battenberg, E.L., Gautvik, V.T., Bartlett, F.S., Frankel, W.N., van den Pol, A.N., Bloom, F.E., Gautvik, K.M. & Sutcliffe, J.G. (1998) The hypocretins: hypothalamus-speci®c peptides with neuroexcitatory activity. Proc. Natl Acad. Sci. USA, 95, 322±327. Lin, L., Faraco, J., Li, R., Kadotani, H., Rogers, W., Lin, X., Qiu, X., de Jong, P.J., Nishino, S. & Mignot, E. (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell, 98, 365±376. Lin, J.S., Luppi, P.H., Salvert, D., Sakai, K. & Jouvet, M. (1986) Histamineimmunoreactive neurons in the hypothalamus of cats. C R Acad. Sci. III, 303, 371±376. Lu, X.Y., Bagnol, D., Burke, S., Akil, H. & Watson, S.J. (2000) Differential distribution and regulation of OX1 and OX2 orexin/hypocretin receptor messenger RNA in the brain upon fasting. Horm. Behav., 37, 335±344. Marcus, J.N., Aschkenasi, C.J., Lee, C.E., Chemelli, R.M., Saper, C.B., Yanagisawa, M. & Elmquist, J.K. (2001) Differential expression of orexin receptors 1 and 2 in the rat brain. J. Comp. Neurol., 435, 6±25. McCormick, D.A. & Bal, T. (1997) Sleep and arousal: thalamocortical mechanisms. Annu. Rev. Neurosci., 20, 185±215. Methippara, M.M., Alam, M.N., Szymusiak, R. & McGinty, D. (2000) Effects of lateral preoptic area application of orexin-A on sleep-wakefulness. Neuroreport, 11, 3423±3426. Mignot, E., Lin, L., Rogers, W., Honda, Y., Qiu, X., Lin, X., Okun, M., Hohjoh, H., Miki, T., Hsu, S.H., Leffell, M.S., Grumet, F.C., FernandezVina, M., Honda, M. & Risch, N. (2001) Complex HLA-DR and ±DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am. J. Hum. Genet., 68, 686±699. Nakamura, T., Uramura, K., Nambu, T., Yada, T., Goto, K., Yanagisawa, M. & Sakurai, T. (2000) Orexin-induced hyperlocomotion and stereotypy are mediated by the dopaminergic system. Brain Res., 873, 181±187. Nambu, T., Sakurai, T., Mizukami, K., Hosoya, Y., Yanagisawa, M. & Goto, K. (1999) Distribution of orexin neurons in the adult rat brain. Brain Res., 827, 243±260.
ã 2001 Federation of European Neuroscience Societies, European Journal of Neuroscience, 14, 1571±1575
Orexin excites histaminergic neurons 1575 Nishino, S., Ripley, B., Overeem, S., Lammers, G.J. & Mignot, E. (2000) Hypocretin (orexin) de®ciency in human narcolepsy. Lancet, 355, 39±40. Panula, P., Pirvola, U., Auvinen, S. & Airaksinen, M.S. (1989) Histamineimmunoreactive nerve ®bers in the rat brain. Neuroscience, 28, 585±610. Paxinos, G. & Watson, C. (1997). The Rat Brain in Stereotaxic Coordinates. Academic Press, San Diego. Peyron, C., Faraco, J., Rogers, W., Ripley, B., Overeem, S., Charnay, Y., Nevsimalova, S., Aldrich, M., Reynolds, D., Albin, R., Li, R., Hungs, M., Pedrazzoli, M., Padigaru, M., Kucherlapati, M., Fan, J., Maki, R., Lammers, G.J., Bouras, C., Kucherlapati, R., Nishino, S. & Mignot, E. (2000) A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nature Med., 6, 991±997. Peyron, C., Tighe, D.K., van den Pol, A.N., Lecea, L., Heller, H.C., Sutcliffe, J.G. & Kilduff, T.S. (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J. Neurosci., 18, 9996±10015. van den Pol, A.N. (1999) Hypothalamic hypocretin (orexin): robust innervation of the spinal cord. J. Neurosci., 19, 3171±3182. van den Pol, A.N. (2000) Narcolepsy: a neurodegenerative disease of the hypocretin system? Neuron., 27, 415±418. van den Pol, A.N., Gao, X.B., Obrietan, K., Kilduff, T.S. & Belousov, A.B. (1998) Presynaptic and postsynaptic actions and modulation of neuroendocrine neurons by a new hypothalamic peptide, hypocretin/ orexin. J. Neurosci., 18, 7962±7971. Reiner, P.B. & Kamondi, A. (1994) Mechanisms of antihistamine-induced sedation in the human brain: H1 receptor activation reduces a background leakage potassium current. Neuroscience, 59, 579±588. Sakurai, T., Amemiya, A., Ishii, M., Matsuzaki, I., Chemelli, R.M., Tanaka, H., Williams, S.C., Richardson, J.A., Kozlowski, G.P., Wilson, S., Arch., J.R., Buckingham, R.E., Haynes, A.C., Carr, S.A., Annan, R.S., McNulty, D.E., Liu, W.S., Terrett, J.A., Elshourbagy, N.A., Bergsma, D.J. & Yanagisawa, M. (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell, 92, 573±585. Sallanon, M., Denoyer, M., Kitahama, K., Aubert, C., Gay, N. & Jouvet, M.
(1989) Long-lasting insomnia induced by preoptic neuron lesions and its transient reversal by muscimol injection into the posterior hypothalamus in the cat. Neuroscience, 32, 669±683. Sherin, J.E., Elmquist, J.K., Torrealba, F. & Saper, C.B. (1998) Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat. J. Neurosci., 18, 4705±4721. Siegel, J.M. (1999) Narcolepsy: a key role for hypocretins (orexins). Cell, 98, 409±412. Stevens, D.R., Kuramasu, A. & Haas, H.L. (1999) GABAB-receptor-mediated control of GABAergic inhibition in rat histaminergic neurons in vitro. Eur. J. Neurosci., 11, 1148±1154. Sutcliffe, J.G. & de Lecea, L. (2000) The hypocretins: excitatory neuromodulatory peptides for multiple homeostatic systems, including sleep and feeding. J. Neurosci. Res., 62, 161±168. Szymusiak, R., Alam, N., Steininger, T.L. & McGinty, D. (1998) Sleepwaking discharge patterns of ventrolateral preoptic/anterior hypothalamic neurons in rats. Brain Res., 803, 178±188. Thannickal, T.C., Moore, R.Y., Nienhuis, R., Ramanathan, L., Gulyani, S., Aldrich, M., Cornford, M. & Siegel, J.M. (2000) Reduced number of hypocretin neurons in human narcolepsy. Neuron, 27, 469±474. Trivedi, P., Yu, H., MacNeil, D.J., Van der Ploeg, L.H. & Guan, X.M. (1998) Distribution of orexin receptor mRNA in the rat brain. FEBS Lett., 438, 71± 75. Vanni-Mercier, G., Sakai, K. & Jouvet, M. (1984) Speci®c neurons for wakefulness in the posterior hypothalamus in the cat. C R Acad. Sci. III, 298, 195±200. Willie, J.T., Chemelli, R.M., Sinton, C.M. & Yanagisawa, M. (2001) To eat or to sleep? orexin in the regulation of feeding and wakefulness. Annu. Rev. Neurosci., 24, 429±458. Xi, M., Morales, F.R. & Chase, M.H. (2001) Effects on sleep and wakefulness of the injection of hypocretin-1 (orexin-A) into the laterodorsal tegmental nucleus of the cat. Brain Res., 901, 259±264.
ã 2001 Federation of European Neuroscience Societies, European Journal of Neuroscience, 14, 1571±1575
