Histamine at the intersection of the sleep-wake cycle and circadian rhythms

Xiao Yu, Great Britain. Dept. For Business Innovation And Skills, Biotechnology And Biological Sciences Research Council (Great Britain), Medical Research Council (Great Britain), Wellcome Trust (London, England), William Wisden
Histamine is central in sleep-wake regulation. First, I mapped the distribution of histamine producing neurons in the adult brain using genetic approaches. Second, to further explore the histaminergic system, I found that a local circadian clock regulates the expression of histidine decarboxylase (HDC), the enzyme producing histamine in hypothalamic neurons. The level of this enzyme varies with time of day and is up-regulated by sleep deprivation. I disrupted this local clock by using HDC-Cre
more » ... by using HDC-Cre recombinase by deleting BMAL1, the transciption factor central to circadian rhythms, selectively in histaminergic neurons, generating HDC-Bmal1 mice. Hdc gene expression in HDC-Bmal1 mice showed a disrupted 24-hour rhythm. This greatly affected natural sleep and reduced recovery sleep after sleep deprivation. Third, the HDC-neurons contain GABA. To understand the role of this GABA, I used different AAVs carrying shRNAs to deliver into the brain to knock down vesicular GABA transporter (vGAT) in histaminergic neurons. Reducing vGAT in HDC-neurons increased general activity and wakefulness in mice; moreover, these GABA in HDC-neurons contributed to recovery sleep after sleep deprivation. To further investigate the mechanism, we conducted an optogenetic method by delivering Channelrhodopsins (ChR2) into the HDC-neurons. We found that photostimulating tuberomamillary nucleus (TMN) fibers in neocortex and striatum triggered GABA release. Thus the decrease of ambient GABA might contribute to the phenotype that we observed in HDC-vGAT knock down mice. In summary, I identified a local "histaminergic clock" that regulates HDC levels, and is necessary for maintaining appropriate sleep-wake cycle architecture as well as sleep homeostasis. I also found GABA produced by HDC-neurons is necessary for regulating the normal behavioral state.
doi:10.25560/26596 fatcat:7yt6jupj4fhidd764kmfw5whky