Pharmacological studies in mammals and zebrafish suggest that histamine plays an important role in promoting arousal. However, genetic studies using rodents with disrupted histamine synthesis or signaling have revealed only subtle or no sleep/wake phenotypes. Studies of histamine function in mammalian arousal are complicated by its production in cells of the immune system and its roles in humoral and cellular immunity, which can have profound effects on sleep/wake states. To avoid this potential confound, we used genetics to explore the role of histamine in regulating sleep in zebrafish, a diurnal vertebrate in which histamine production is restricted to neurons in the brain. Similar to rodent genetic studies, we found that zebrafish that lack histamine due to mutation of histidine decarboxylase (hdc) exhibit largely normal sleep/wake behaviors. Zebrafish containing predicted null mutations in several histamine receptors also lack robust sleep/wake phenotypes, although we are unable to verify that these mutants are completely non-functional. Consistent with some rodent studies, we found that arousal induced by overexpression of the neuropeptide hypocretin (Hcrt) or by stimulation of hcrt-expressing neurons is not blocked in hdc or hrh1 mutants. We also found that the number of hcrt-expressing or histaminergic neurons is unaffected in animals that lack histamine or Hcrt signaling, respectively. Thus, while acute pharmacological manipulation of histamine signaling has been shown to have profound effects on zebrafish and mammalian sleep, our results suggest that chronic loss of histamine signaling due to genetic mutations has only subtle effects on sleep in zebrafish, similar to rodents.
Significance Statement Based on pharmacological studies in several model organisms, histamine is thought to be a key arousal-promoting neuromodulator. However, genetic studies in rodents have reported only subtle phenotypes. Rodent studies are complicated by involvement of histamine in regulating the immune system, which itself affects sleep. In zebrafish, histamine production is restricted to neurons in the brain, thus allowing study of histamine function in arousal without confounding effects of abnormal immune system function. We show that zebrafish lacking histamine synthesis have largely normal sleep/wake behaviors, as do histamine receptor mutants, although we lack tools to verify that the receptor mutants are non-functional. These results suggest that genetic loss of histamine signaling has little effect on sleep/wake behaviors in zebrafish, similar to rodents.
Authors report no conflict of interest.