Short Title Histamin-1 Receptor in Orexin Signaling

Aim: The effect of orexin on wakefulness has been shown to be largely mediated by activation of histaminergic neurons via orexin receptor-2 (OX2R). Consistently, OX2R mRNA is abundantly expressed in histaminergic neurons in the tuberomammillary nucleus (TMN). However, orexin receptors in the other regions of the brain might also play important roles in maintenance of wakefulness. To dissect the role of histaminergic system as downstream mediator of orexin system in regulation of sleep/wake states without compensation by the OX1R-mediated pathway, we analyzed phenotype of H1R;OX1R mice. This mice lack OX1R-mediated regulation of noradrenergic neurons in the locus coeruleus and either H1R system belonging to downstream of OX2R in the TMN. By analyzing H1R;OX1R mice, we aimed to find out the function of OX2R–mediated pathways other than histaminergic system in the TMN in sleep/wake regulation. Methods: We used H1R;OX1R mice, H1R mice, and their littermate wild type mice. REM sleep, NREM sleep, and awake states were determined by polygraphic electroencephalographic/electromyographic (EEG/EMG) recording. Results: We did not observe detectable abnormality in sleep/wake states of H1R mice, consistent with previous studies. H1R;OX1R mice also showed comparable sleep/wake phenotype as wild type mice. This result indicates that regulation of sleep/wake system is