Document Detail

GABAergic inhibition of histaminergic neurons regulates active waking but not the sleep-wake switch or propofol-induced loss of consciousness.
MedLine Citation:
PMID:  22993424     Owner:  NLM     Status:  MEDLINE    
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.
Anna Y Zecharia; Xiao Yu; Thomas Götz; Zhiwen Ye; David R Carr; Peer Wulff; Bernhard Bettler; Alexei L Vyssotski; Stephen G Brickley; Nicholas P Franks; William Wisden
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  32     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-09-20     Completed Date:  2012-12-03     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  13062-75     Citation Subset:  IM    
Biophysics Section, Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom.
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MeSH Terms
Action Potentials / drug effects,  physiology
Animals, Newborn
Brain / metabolism
Electric Stimulation
Exploratory Behavior / drug effects,  physiology
GABAergic Neurons / drug effects,  physiology*
Green Fluorescent Proteins / genetics
Habituation, Psychophysiologic / genetics
Histamine / metabolism*
Histidine Decarboxylase / genetics,  metabolism
Hypnotics and Sedatives / adverse effects
Hypothalamic Area, Lateral / cytology
Lysine / analogs & derivatives,  metabolism
Mice, Inbred C57BL
Mice, Transgenic
Mutation / genetics
Neural Inhibition / drug effects,  genetics,  physiology*
Patch-Clamp Techniques
Propofol / adverse effects
Proteins / genetics,  metabolism
RNA, Messenger / metabolism
Receptors, GABA-A / deficiency
Reflex / drug effects,  genetics
Sleep / drug effects,  genetics,  physiology*
Unconsciousness / chemically induced,  physiopathology*
Wakefulness / genetics,  physiology*
beta-Galactosidase / metabolism
Grant Support
094211//Wellcome Trust; BB/G021619/1//Biotechnology and Biological Sciences Research Council; G021691//Biotechnology and Biological Sciences Research Council; G0800399//Medical Research Council; G0800399//Medical Research Council; G0901892//Medical Research Council; G0901892//Medical Research Council; G0901892(93854)//Medical Research Council; //Wellcome Trust
Reg. No./Substance:
0/Gt(ROSA)26Sor protein, mouse; 0/Hypnotics and Sedatives; 0/Proteins; 0/RNA, Messenger; 0/Receptors, GABA-A; 0/enhanced green fluorescent protein; 147336-22-9/Green Fluorescent Proteins; 2078-54-8/Propofol; 51-45-6/Histamine; 56-87-1/Lysine; EC; EC Decarboxylase; G6D6147J22/biocytin
Comment In:
J Neurosci. 2013 Jan 23;33(4):1295-6   [PMID:  23345205 ]

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