title: GABAergic inhibition of histaminergic neurons regulates active waking but not the sleep-wake switch or propofol-induced loss of consciousness.
abstract: The activity of histaminergic neurons in the tuberomammillary nucleus (TMN) of the hypothalamus correlates with an animal's behavioral state and maintains arousal. We examined how GABAergic inputs onto histaminergic neurons regulate this behavior. A prominent hypothesis, the "flip-flop" model, predicts that increased and sustained GABAergic drive onto these cells promotes sleep. Similarly, because of the histaminergic neurons' key hub-like place in the arousal circuitry, it has also been suggested that anesthetics such as propofol induce loss of consciousness by acting primarily at histaminergic neurons. We tested both these hypotheses in mice by genetically removing ionotropic GABA(A) or metabotropic GABA(B) receptors from histidine decarboxylase-expressing neurons. At the cellular level, histaminergic neurons deficient in synaptic GABA(A) receptors were significantly more excitable and were insensitive to the anesthetic propofol. At the behavioral level, EEG profiles were recorded in nontethered mice over 24 h. Surprisingly, GABAergic transmission onto histaminergic neurons had no effect in regulating the natural sleep-wake cycle and, in the case of GABA(A) receptors, for propofol-induced loss of righting reflex. The latter finding makes it unlikely that the histaminergic TMN has a central role in anesthesia. GABA(B) receptors on histaminergic neurons were dispensable for all behaviors examined. Synaptic inhibition of histaminergic cells by GABA(A) receptors, however, was essential for habituation to a novel environment.
authors.affiliation: Biophysics Section, Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Anna Y
authors.initials: AY
authors.lastname: Zecharia
authors.forename: Xiao
authors.initials: X
authors.lastname: Yu
authors.forename: Thomas
authors.initials: T
authors.lastname: Götz
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Ye
authors.forename: David R
authors.initials: DR
authors.lastname: Carr
authors.forename: Peer
authors.initials: P
authors.lastname: Wulff
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bettler
authors.forename: Alexei L
authors.initials: AL
authors.lastname: Vyssotski
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Brickley
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Franks
authors.forename: William
authors.initials: W
authors.lastname: Wisden
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D001921:Brain / Q000378:metabolism; D004558:Electric Stimulation; D004569:Electroencephalography; D004576:Electromyography; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D059330:GABAergic Neurons / Q000187:drug effects / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006185:Habituation, Psychophysiologic / Q000235:genetics; D006632:Histamine / Q000378:metabolism*; D006640:Histidine Decarboxylase / Q000235:genetics / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000009:adverse effects; D007026:Hypothalamic Area, Lateral / Q000166:cytology; D066298:In Vitro Techniques; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009433:Neural Inhibition / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018408:Patch-Clamp Techniques; D015742:Propofol / Q000009:adverse effects; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D022661:RNA, Untranslated; D011963:Receptors, GABA-A / Q000172:deficiency; D012018:Reflex / Q000187:drug effects / Q000235:genetics; D012890:Sleep / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014474:Unconsciousness / Q000139:chemically induced / Q000503:physiopathology*; D014851:Wakefulness / Q000235:genetics / Q000502:physiology*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D006993:Hypnotics and Sedatives; D011506:Proteins; D012333:RNA, Messenger; D022661:RNA, Untranslated; D011963:Receptors, GABA-A; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D006632:Histamine; D001616:beta-Galactosidase; D006640:Histidine Decarboxylase; C013411:biocytin; D008239:Lysine; D015742:Propofol