Designer receptor activated by designer drugs (DREADDs) techniques are widely used to modulate the activities of specific neuronal populations during behavioural tasks. However, DREADDs-induced modulation of histaminergic neurons in the tuberomamillary nucleus (HATMN neurons) has produced inconsistent effects on the sleep–wake cycle, possibly due to the use of Hdc-Cre mice driving Cre recombinase and DREADDs activity outside the targeted region. Moreover, previous DREADDs studies have not examined locomotor activity and aggressive behaviours, which are also regulated by brain histamine levels. In the present study, we investigated the effects of HATMN activation and inhibition on the locomotor activity, aggressive behaviours and sleep–wake cycle of Hdc-Cre mice with minimal non-target expression of Cre-recombinase. Chemoactivation of HATMN moderately enhanced locomotor activity in a novel open field. Activation of HATMN neurons significantly enhanced aggressive behaviour in the resident–intruder test. Wakefulness was increased and non-rapid eye movement (NREM) sleep decreased for an hour by HATMN chemoactivation. Conversely HATMN chemoinhibition decreased wakefulness and increased NREM sleep for 6 h. These changes in wakefulness induced by HATMN modulation were related to the maintenance of vigilance state. These results indicate the influences of HATMN neurons on exploratory activity, territorial aggression, and wake maintenance.

Designer receptor activated by designer drugs (DREADDs) techniques are widely used to modulate the activities of specific neuronal populations during behavioural tasks. However, DREADDs-induced modulation of histaminergic neurons in the tuberomammillary nucleus (HATMN neurons) has produced inconsistent effects on the sleep–wake cycle, possibly due to the use of Hdc-Cre mice driving Cre recombinase and DREADDs activity outside the targeted region. Moreover, previous DREADDs studies have not examined locomotor activity and aggressive behaviours, which are also regulated by brain histamine levels. In the present study, we investigated the effects of HATMN activation and inhibition on the locomotor activity, aggressive behaviours and sleep–wake cycle of Hdc-Cre mice with minimal non-target expression of Cre-recombinase. Chemoactivation of HATMN moderately enhanced locomotor activity in a novel open field. Activation of HATMN neurons significantly enhanced aggressive behaviour in the resident–intruder test. Wakefulness was increased and non-rapid eye movement (NREM) sleep decreased for an hour by HATMN chemoactivation. Conversely HATMN chemoinhibition decreased wakefulness and increased NREM sleep for 6 hours. These changes in wakefulness induced by HATMN modulation were related to vigilance status transition. These results indicate the influences of HATMN neurons on exploratory activity, territorial aggression, and wake maintenance.

Histaminergic neurons are localized in the tuberomammillary nucleus (TMN) of the posterior hypothalamus. These neurons have been postulated to have wake-promoting and arousal-maintaining functions. Previously, we found that the acute and specific activation of histaminergic neurons in the TMN slightly increased wakefulness in mice during the light periods. However, the precise neural mechanism of histaminergic neurons in the regulation of sleep-wake cycles have remained to be elucidated. In this study, we examined the wake-regulatory mechanism of histaminergic neurons by using chemogenetic inhibition methods. We virally expressed hM4Di specifically in the TMNhistaminergic neurons of histidine decarboxylase (Hdc)-Cre mice. Then clozapine-N-oxide (CNO) or saline (SA) were injected at ZT3 (light period) or ZT12 (dark period). We found that CNO injection at ZT12 significantly decreased wakefulness and increased NREM sleep due to prolonged duration of NREM sleep. We also found that the wake to wake transition was significantly decreased and NREM to NREM sleep transition was increased in the CNO group. On the other hand, CNO injection at ZT3 did not alter sleep-wake status. These results indicated that histaminergic neurons in the TMN are important for maintaining the arousal status in mice during the dark periods.