Cataplexy-Active Neurons in the Hypothalamus Implications for the Role of Histamine in Sleep and Waking Behavior

Noradrenergic, serotonergic, and histaminergic neurons are continuously active during waking, reduce discharge during NREM sleep, and cease discharge during REM sleep. Cataplexy, a symptom associated with narcolepsy, is a waking state in which muscle tone is lost, as it is in REM sleep, while environmental awareness continues, as in alert waking. In prior work, we reported that, during cataplexy, noradrenergic neurons cease discharge, and serotonergic neurons greatly reduce activity. We now report that, in contrast to these other monoaminergic "REM-off" cell groups, histamine neurons are active in cataplexy at a level similar to or greater than that in quiet waking. We hypothesize that the activity of histamine cells is linked to the maintenance of waking, in contrast to activity in noradrenergic and serotonergic neurons, which is more tightly coupled to the maintenance of muscle tone in waking and its loss in REM sleep and cataplexy.

[1]  M. Palkovits,et al.  Immunohistochemical mapping of neuropeptides in the premamillary region of the hypothalamus in rats , 1995, Brain Research Reviews.

[2]  A. Yamatodani,et al.  The effect of orexin-A and -B on the histamine release in the anterior hypothalamus in rats , 2002, Neuroscience Letters.

[3]  R. McCarley,et al.  Extracellular histamine levels in the feline preoptic/anterior hypothalamic area during natural sleep–wakefulness and prolonged wakefulness: An in vivo microdialysis study , 2002, Neuroscience.

[4]  T. Watanabe,et al.  Studies on functional roles of the histaminergic neuron system by using pharmacological agents, knockout mice and positron emission tomography. , 2001, The Tohoku journal of experimental medicine.

[5]  J. Siegel,et al.  Locus coeruleus neurons: cessation of activity during cataplexy , 1999, Neuroscience.

[6]  Emmanuel Mignot,et al.  The Sleep Disorder Canine Narcolepsy Is Caused by a Mutation in the Hypocretin (Orexin) Receptor 2 Gene , 1999, Cell.

[7]  Z. Tran,et al.  Sedation and performance impairment of diphenhydramine and second-generation antihistamines: a meta-analysis. , 2003, The Journal of allergy and clinical immunology.

[8]  R. Salín-Pascual,et al.  Hypothalamic Regulation of Sleep , 2001, Neuropsychopharmacology.

[9]  J. Siegel,et al.  Neuronal activity in narcolepsy: identification of cataplexy-related cells in the medial medulla. , 1991, Science.

[10]  J. Siegel,et al.  Narcolepsy A Key Role for Hypocretins (Orexins) , 1999, Cell.

[11]  J. Siegel,et al.  Treatment with immunosuppressive and anti-inflammatory agents delays onset of canine genetic narcolepsy and reduces symptom severity , 2004, Experimental Neurology.

[12]  G. Vanni-Mercier,et al.  Waking selective neurons in the posterior hypothalamus and their response to histamine H3-receptor ligands: an electrophysiological study in freely moving cats , 2003, Behavioural Brain Research.

[13]  G. Aston-Jones,et al.  Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system , 1999, The Journal of comparative neurology.

[14]  O. Pompeiano,et al.  Noradrenergic and cholinergic mechanisms responsible for the gain regulation of vestibulospinal reflexes. , 1988, Progress in brain research.

[15]  A. Yamanaka,et al.  Orexins activate histaminergic neurons via the orexin 2 receptor. , 2002, Biochemical and biophysical research communications.

[16]  Graeme Henderson,et al.  Locus Coeruleus Neurons , 1984 .

[17]  C. Saper,et al.  Innervation of Histaminergic Tuberomammillary Neurons by GABAergic and Galaninergic Neurons in the Ventrolateral Preoptic Nucleus of the Rat , 1998, The Journal of Neuroscience.

[18]  F. Bloom,et al.  Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle , 1981, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[19]  Y. Urade,et al.  Arousal effect of orexin A depends on activation of the histaminergic system , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[20]  C. Chiu,et al.  Activity of medial mesopontine units during cataplexy and sleep-waking states in the narcoleptic dog , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[21]  O. Pompeiano,et al.  Microinjections of vasopressin in the locus coeruleus complex affect posture and vestibulospinal reflexes in decerebrate cats , 1992, Pflügers Archiv.

[22]  M. Mancia,et al.  The Diencephalon and Sleep , 1990 .

[23]  G. Aston-Jones,et al.  Hypocretin/orexin depolarizes and decreases potassium conductance in locus coeruleus neurons , 2000, Neuroreport.

[24]  R. Szymusiak,et al.  Sleep–waking discharge of neurons in the posterior lateral hypothalamus of the albino rat , 1999, Brain Research.

[25]  Takeshi Sakurai,et al.  Hypocretin/Orexin Excites Hypocretin Neurons via a Local Glutamate Neuron—A Potential Mechanism for Orchestrating the Hypothalamic Arousal System , 2002, Neuron.

[26]  Kojima Structure and function , 2005 .

[27]  J. Tanaka,et al.  Distribution of the histaminergic neuron system in the central nervous system of rats; a fluorescent immunohistochemical analysis with histidine decar☐ylase as a marker , 1984, Brain Research.

[28]  M. Mühlethaler,et al.  Orexins/hypocretins excite basal forebrain cholinergic neurones , 2001, Neuroscience.

[29]  Y. Lai,et al.  Inactivation of the pons blocks medullary-induced muscle tone suppression in the decerebrate cat. , 1998, Sleep.

[30]  M. Kryger,et al.  Principles and Practice of Sleep Medicine , 1989 .

[31]  P. Panula,et al.  Histamine-containing neurons in the rat hypothalamus. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Michael Aldrich,et al.  Reduced Number of Hypocretin Neurons in Human Narcolepsy , 2000, Neuron.

[33]  Sebastiaan Overeem,et al.  A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains , 2000, Nature Medicine.

[34]  J. Siegel,et al.  Behavioral organization of reticular formation: studies in the unrestrained cat. I. Cells related to axial, limb, eye, and other movements. , 1983, Journal of neurophysiology.

[35]  Y. Lai,et al.  Activation of Pontine and Medullary Motor Inhibitory Regions Reduces Discharge in Neurons Located in the Locus Coeruleus and the Anatomical Equivalent of the Midbrain Locomotor Region , 2000, The Journal of Neuroscience.

[36]  M. Jouvet,et al.  Hypothalamo‐preoptic Histaminergic Projections in Sleep‐Wake Control in the Cat , 1994, The European journal of neuroscience.

[37]  W. Baust,et al.  Phasic changes in heart rate and respiration correlated with PGO-spike activity during REM sleep , 2004, Pflügers Archiv.

[38]  R. McCarley,et al.  Activation of Ventrolateral Preoptic Neurons During Sleep , 1996, Science.

[39]  F. Morales,et al.  Chapter 12 – Control of Motoneurons during Sleep , 2005 .

[40]  E. Mignot,et al.  Desmethyl metabolites of serotonergic uptake inhibitors are more potent for suppressing canine cataplexy than their parent compounds. , 1993, Sleep.

[41]  J. Siegel,et al.  Pattern of Hypocretin (Orexin) Soma and Axon Loss, and Gliosis, in Human Narcolepsy , 2003, Brain pathology.

[42]  U. Pirvola,et al.  A histamine-containing neuronal system in human brain , 1990, Neuroscience.

[43]  M. Aldrich Diagnostic aspects of narcolepsy , 1998, Neurology.

[44]  H. Haas,et al.  A persistent sodium current in acutely isolated histaminergic neurons from rat hypothalamus , 1995, Neuroscience.

[45]  B. Jacobs,et al.  Structure and function of the brain serotonin system. , 1992, Physiological reviews.

[46]  E. Mignot,et al.  Decreased brain histamine content in hypocretin/orexin receptor-2 mutated narcoleptic dogs , 2001, Neuroscience Letters.

[47]  J. Siegel,et al.  Cataplexy-related neurons in the amygdala of the narcoleptic dog , 2002, Neuroscience.

[48]  Peter B. Reiner,et al.  Electrophysiological properties of cortically projecting histamine neurons of the rat hypothalamus , 1987, Neuroscience Letters.

[49]  Y. Lai,et al.  Changes in Inhibitory Amino Acid Release Linked to Pontine-Induced Atonia: An In Vivo Microdialysis Study , 2003, The Journal of Neuroscience.

[50]  M. I. Smith,et al.  Orexin A activates locus coeruleus cell firing and increases arousal in the rat. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[51]  T. Sejnowski,et al.  Thalamocortical oscillations in the sleeping and aroused brain. , 1993, Science.

[52]  M. Serafin,et al.  Orexins (hypocretins) directly excite tuberomammillary neurons , 2001, The European journal of neuroscience.

[53]  H. Kowarzyk Structure and Function. , 1910, Nature.

[54]  J. Siegel,et al.  Pontomedullary glutamate receptors mediating locomotion and muscle tone suppression , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[55]  Hippocampal interneuron activity in unanesthetized rats: Relationship to the sleep-wake cycle , 1993, Neuroscience Letters.

[56]  Jon T. Willie,et al.  Distinct Narcolepsy Syndromes in Orexin Receptor-2 and Orexin Null Mice Molecular Genetic Dissection of Non-REM and REM Sleep Regulatory Processes , 2003, Neuron.

[57]  G. Aghajanian,et al.  Hypocretin (orexin) enhances neuron activity and cell synchrony in developing mouse GFP‐expressing locus coeruleus , 2002, The Journal of physiology.

[58]  J. Siegel,et al.  Activity of dorsal raphe cells across the sleep–waking cycle and during cataplexy in narcoleptic dogs , 2004, The Journal of physiology.

[59]  Y. Lai,et al.  Changes in Monoamine Release in the Ventral Horn and Hypoglossal Nucleus Linked to Pontine Inhibition of Muscle Tone: An In Vivo Microdialysis Study , 2001, The Journal of Neuroscience.

[60]  J. Siegel,et al.  Rostral brainstem contributes to medullary inhibition of muscle tone , 1983, Brain Research.

[61]  M. Jouvet,et al.  Evidence for histaminergic arousal mechanisms in the hypothalamus of cat , 1988, Neuropharmacology.

[62]  Jun Lu,et al.  Afferents to the Ventrolateral Preoptic Nucleus , 2002, The Journal of Neuroscience.

[63]  H. Haas,et al.  Orexin/Hypocretin Excites the Histaminergic Neurons of the Tuberomammillary Nucleus , 2001, The Journal of Neuroscience.

[64]  R. K. Lim,et al.  A Stereotaxic atlas of the dog`s brain , 1960 .

[65]  J. Siegel,et al.  Systemic administration of hypocretin-1 reduces cataplexy and normalizes sleep and waking durations in narcoleptic dogs. , 2000, Sleep research online : SRO.

[66]  Yan Zhu,et al.  A neural circuit for circadian regulation of arousal , 2001, Nature Neuroscience.

[67]  Luis de Lecea,et al.  Hypocretin-1 Modulates Rapid Eye Movement Sleep through Activation of Locus Coeruleus Neurons , 2000, The Journal of Neuroscience.

[68]  C. Kushida,et al.  Electroencephalographic correlates of cataplectic attacks in narcoleptic canines. , 1985, Electroencephalography and clinical neurophysiology.

[69]  J. Siegel,et al.  Intravenously administered hypocretin‐1 alters brain amino acid release: an in vivo microdialysis study in rats , 2003, The Journal of physiology.