Reassessing the role of histaminergic tuberomammillary neurons in arousal control

The histaminergic neurons of the tuberomammillary nucleus (TMN^HDC) of the posterior hypothalamus have long been implicated in promoting arousal. More recently, a rolefor GABAergic signaling bythe TMN^HDCneurons in arousal control has been proposed. Here, we investigated the effects of selective chronic disruption of GABA synthesis (via genetic deletion of the GABA synthesis enzyme, glutamic acid decarboxylase 67) or GABAergic transmission (via genetic deletion of the vesicular GABA transporter (VGAT)) in the TMN^HDCneurons on sleep-wake in male mice. We also examined the effects of acute chemogenetic activation and optogenetic inhibition of TMN^HDCneurons upon arousal in male mice. Unexpectedly, we found that neither disruption of GABA synthesis nor GABAergic transmission altered hourly sleep-wake quantities, perhaps because very few TMN^HDCneurons coexpressed VGAT. Acute chemogenetic activation of TMN^HDCneurons did not increase arousal levels above baseline but did enhance vigilance when the mice were exposed to a behavioralcage change challenge.Similarly, acuteoptogeneticinhibitionhadlittle effectuponbaselinelevelsof arousal. In conclusion,we could not identify a role for GABA release by TMN^HDCneurons in arousal control. Further, if TMN^HDCneurons do release GABA, the mechanism by whichthey do so remains unclear. Ourfindings supportthe viewthat TMN^HDCneurons may be importantfor enhancing arousal under certain conditions, such as exposure to a novel environment, but play only a minor role in behavioral and EEG arousal under baseline conditions.