Roles of orexin-producing neurons in awakening from anesthesia : Analyses using various genetically-modified mice

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We analyze the in vivo and in vitro phenotype of mice lacking the GABA_<B1> gene specifically in orexin neurons (GABA_<B1>^<flox/flox> ; orexin-Cre mice), and demonstrate that GABA_B receptors on orexin neurons are essential in stabilizing and consolidating sleep/wake states. In GABA_<B1>^<flox/flox> ; orexin-Cre brain slices, we show that the absence of GABA_B receptors decreases the sensitivity of orexin neurons to both excitatory and inhibitory inputs, due to an augmented GABA_A-mediated inhibition that increases the membrane conductance and shunts postsynaptic currents in these neurons. This increase in GABA_A-mediated inhibitory tone is apparently due to an OX1 orexin receptor-mediated activation of local GABAergic interneurons that project back onto orexin neurons. GABA_<B1>^<flox/flox> ; orexin-Cre mice exhibit severe fragmentation of sleep/wake states during both the light and dark periods, without showing an abnormality in total sleep time or signs of cataplexy. Thus, GABA_B receptors on orexin neurons are crucial in the appropriate control of the orexinergic tone through sleep/wake states, thereby stabilizing the state switching mechanisms. We also made mice lacking the 5HT1a gene specifically in orexin neurons, and are anlyzing their phenotypes.