PT  - JOURNAL ARTICLE
AU  - Anna Y. Zecharia
AU  - Xiao Yu
AU  - Thomas Götz
AU  - Zhiwen Ye
AU  - David R. Carr
AU  - Peer Wulff
AU  - Bernhard Bettler
AU  - Alexei L. Vyssotski
AU  - Stephen G. Brickley
AU  - Nicholas P. Franks
AU  - William Wisden
TI  - GABAergic Inhibition of Histaminergic Neurons Regulates Active Waking But Not the Sleep–Wake Switch or Propofol-Induced Loss of Consciousness
AID  - 10.1523/JNEUROSCI.2931-12.2012
DP  - 2012 Sep 19
TA  - The Journal of Neuroscience
PG  - 13062--13075
VI  - 32
IP  - 38
4099  - http://www.jneurosci.org/content/32/38/13062.short
4100  - http://www.jneurosci.org/content/32/38/13062.full
SO  - J. Neurosci.2012 Sep 19; 32
AB  - 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 GABAA or metabotropic GABAB receptors from histidine decarboxylase-expressing neurons. At the cellular level, histaminergic neurons deficient in synaptic GABAA 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 GABAA receptors, for propofol-induced loss of righting reflex. The latter finding makes it unlikely that the histaminergic TMN has a central role in anesthesia. GABAB receptors on histaminergic neurons were dispensable for all behaviors examined. Synaptic inhibition of histaminergic cells by GABAA receptors, however, was essential for habituation to a novel environment.