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 propofolinduced 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.

TASK channels are acid-sensitive and anesthetic-activated members of the family of two-pore-domain potassium channels. We have made the surprising discovery that the genetic ablation of TASK-3 channels eliminates a specific type of theta oscillation in the cortical electroencephalogram (EEG) resembling type II theta (4 -9 Hz), which is thought to be important in processing sensory stimuli before initiating motor activity. In contrast, ablation of TASK-1 channels has no effect on theta oscillations. Despite the absence of type II theta oscillations in the TASK-3 knockout (KO) mice, the related type I theta, which has certain neuronal pathways in common and is involved in exploratory behavior, is unaffected. In addition to the absence of type II theta oscillations, the TASK-3 KO animals show marked alterations in both anesthetic sensitivity and natural sleep behavior. Their sensitivity to halothane, a potent activator of TASK channels, is greatly reduced, whereas their sensitivity to cyclopropane, which does not activate TASK-3 channels, is unchanged. The TASK-3 KO animals exhibit a slower progression from their waking to sleeping states and, during their sleeping period, their sleep episodes as well as their REM theta oscillations are more fragmented. These results imply a previously unexpected role for TASK-3 channels in the cellular mechanisms underlying these behaviors and suggest that endogenous modulators of these channels may regulate theta oscillations.I f a sufficient number of neurons participate in network oscillations, then the local field potentials summate, and measurable voltage oscillations can be recorded in the electroencephalogram (EEG). These oscillations are observed over a wide range of frequencies and reflect the synchronous neuronal activity that occurs during a variety of different behaviors. For example, as animals explore their environments, as they learn and lay down memories, as they process sensory input, and as they sleep, characteristic oscillations occur in the ''theta'' range of frequencies (4-12 Hz) (1). These theta oscillations are often divided into two types (1-5): Type I, which occurs at slightly higher frequencies (6-12 Hz), and type II (also known as arousal theta), which occurs at the lower end of the range (4-9 Hz). Type I theta is associated with exploratory behavior, walking, running, and rearing, whereas type II theta is associated with immobility during the processing of sensory stimuli relevant to initiating, or intending to initiate, motor activity.The neuronal networks that generate these theta oscillations involve ascending pathways from the brainstem that project to the hypothalamus and then to the medial septum/diagonal band of Broca and the hippocampus (6-9). Where the true pacemaker is located is unclear, but the basic requirements for a neuron to oscillate are a depolarizing drive (such as a sodium current) together with a restoring drive, such as a repolarizing potassium current. Most computational models (10-12) include several different ionic currents, som...

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