Galaninは、ガランイン受容体1を介してヒスタミン作動性ニューロンを阻害する

Galanin-expressing neurons in the ventrolateral preoptic area (VLPO^galanin) are active during sleep and play an important role regulating non-rapid eye movement (NREM) sleep. It is generally believed that VLPO^galanin neurons promote sleep via inhibitory actions in arousal promoting regions of the brain. Histaminergic neurons are a population of wake-active neurons that receive strong projections from the sleep-active VLPO^galanin neurons. However, the ability of galanin to influence the activity of histaminergic neurons has received limited attention. Here, using whole-cell patch clamp electrophysiological recordings from genetically identified histaminergic neurons in male mice, we explore the mechanisms by which galanin influences histaminergic neuron electrical excitability. Our results reveal that galanin is a powerful inhibitor of histaminergic neuron activity and demonstrate that the inhibitory effects of galanin are mediated by galanin receptor 1 (GALR1) and the subsequent opening of G protein-coupled inwardly rectifying (GIRK) and large conductance calcium-activated potassium (BK) channels. Furthermore, we identify that histaminergic neurons highly express Galr1 mRNA and show that the GALR1-mediated hyperpolarization of histaminergic neurons is largely independent of action potential-dependent synaptic transmission, or fast excitatory or inhibitory neurotransmitters. Together, these results suggest that direct post-synaptic activation of GALR1 expressed on histaminergic neurons mediates the inhibitory effects of galanin on these neurons. This data also supports the notion that the sleep-promoting effects of VLPO^galanin neuron activation may occur via the ability of galanin to inhibit the arousal-promoting histaminergic neurons.Significance Statement The "flip-flop switch" model of sleep and wakefulness proposes that sleep-active galanin-expressing neurons in the ventrolateral preoptic area (VLPO) promote sleep via inhibitory actions on arousal promoting neurons, such as the histaminergic neurons. However, the molecular mechanisms surrounding this theory are lacking. Here, we report that histaminergic neurons are strongly inhibited by galanin, an effect that occurs via galanin receptor 1 (GALR1) mediated opening of potassium channels. The GALR1-induced inhibition persisted in blockers of synaptic transmission and Galr1 mRNA was expressed in histaminergic neurons. Together, these results suggest galanin inhibits histaminergic neurons via GALR1 expressed on histaminergic neurons and supports the notion that galanin-expressing VLPO neurons could silence the wake-active histaminergic neurons to promote sleep.