Abstract
Histamine and its two receptors, histamine-gated chloride channel subunit 1 (HisCl1) and ora transientless (Ort), are known to control photoreception and temperature sensing in Drosophila. However, histamine signaling in the context of neural circuitry for sleep-wake behaviors has not yet been examined in detail. Here, we obtained mutant flies with compromised or enhanced histamine signaling and tested their baseline sleep. Hypomorphic mutations in histidine decarboxylase (HDC), an enzyme catalyzing the conversion from histidine to histamine, caused an increase in sleep duration. Interestingly, hisCl1 mutants but not ort mutants showed long-sleep phenotypes similar to those in hdc mutants. Increased sleep duration in hisCl1 mutants was rescued by overexpressing hisCl1 in circadian pacemaker neurons expressing a neuropeptide pigment dispersing factor (PDF). Consistently, RNA interference (RNAi)-mediated depletion of hisCl1 in PDF neurons was sufficient to mimic hisCl1 mutant phenotypes, suggesting that PDF neurons are crucial for sleep regulation by the histamine-HisCl1 signaling. Finally, either hisCl1 mutation or genetic ablation of PDF neurons dampened wake-promoting effects of elevated histamine signaling via direct histamine administration. Taken together, these data clearly demonstrate that the histamine-HisCl1 receptor axis can activate and maintain the wake state in Drosophila and that wake-activating signals may travel via the PDF neurons.
Highlights
Sleep is known to be crucial for the physiology and life of an animal [1], the precise regulatory mechanisms that govern sleep are not yet fully understood
Our results revealed that administration of 250 mM histamine to pigment dispersing factor (PDF) neuron-ablated flies could not reduce their daytime and nighttime sleep duration, confirming that PDF neurons are important for wake-activation by histamine (Figure 6C–E)
Using genetic and pharmacological methods to manipulate histamine signaling, we show that the histamine-gated chloride channel subunit 1 (HisCl1) receptor and its downstream signaling cascade regulate wake-evoking behavior in Drosophila, while ora transientless (Ort) receptor does not show any sleep/wake regulatory function
Summary
Sleep is known to be crucial for the physiology and life of an animal [1], the precise regulatory mechanisms that govern sleep are not yet fully understood. Histamine, a monoamine synthesized from histidine by histidine decarboxylase (HDC), is a major neurotransmitter that regulates learning, immune reactions [8], and sleep-wake behavior [9,10]. The H2 receptor, which activates cAMP signaling by activating adenylate cyclase, has memory modulating effects, but has little impact on sleep/wake regulation [13,15]. The H3 receptor acts as an auto-receptor in presynaptic histaminergic neurons and controls histamine turnover through feedback inhibition of histamine synthesis and release. The H3 receptor is located on presynaptic terminals and can affect the sleep/wake cycle as well as learning and memory by controlling histamine synthesis and release [16,17,18]. The H4 receptor is highly expressed in bone marrow and white blood cells and mediates several immune responses [19]
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