The histaminergic system regulates wakefulness and orexin/hypocretin neuron developmentviahistamine receptor H1 in zebrafish

Abstract

The histaminergic and hypocretin/orexin (hcrt) neurotransmitter systems play crucial roles in alertness/wakefulness in rodents. We elucidated the role of histamine in wakefulness and the interaction of the histamine and hcrt systems in larval zebrafish. Translation inhibition of histidine decarboxylase (hdc) with morpholino oligonucleotides (MOs) led to a behaviorally measurable decline in light-associated activity, which was partially rescued by hdc mRNA injections and mimicked by histamine receptor H1 (Hrh1) antagonist pyrilamine treatment. Histamine-immunoreactive fibers targeted the dorsal telencephalon, an area that expresses histamine receptors hrh1 and hrh3 and contains predominantly glutamatergic neurons. Tract tracing with DiI revealed that projections from dorsal telencephalon innervate the hcrt and histaminergic neurons. Translation inhibition of hdc decreased the number of hcrt neurons in a Hrh1-dependent manner. The reduction was rescued by overexpression of hdc mRNA. hdc mRNA injection alone led to an up-regulation of hcrt neuron numbers. These results suggest that histamine is essential for the development of a functional and intact hcrt system and that histamine has a bidirectional effect on the development of the hcrt neurons. In summary, our findings provide evidence that these two systems are linked both functionally and developmentally, which may have important implications in sleep disorders and narcolepsy. development via histamine receptor H1 in zebrafish.

The Neglected Role of Histamine in Alzheimer’s Disease

“…38 The histaminergic and hypocretin/orexin (hcrt) neurotransmitter systems have a major role in alertness and wakefulness in rodents. 39 Furthermore, the histaminergic system has a crucial role in memory and learning. Recently, the deficient histaminergic transmission in the brain in vascular dementia has been reported.…”

Unraveling the Evolutionary Determinants of Sleep

“…Moreover, when these systems have been manipulated pharmacologically or genetically in zebrafish, they have been shown to regulate arousal in much the same way as they do in mammals (Figure 2) [163–167]. Similarly, in flies, activation of aminergic and cholinergic neurons promotes arousal, though some serotonergic neurons may suppress it [28, 168–170].…”

Interactions of the histamine and hypocretin systems in CNS disorders

“…37 The axonal terminals of hypocretin neurons in the TMN contain both hypocretin and glutamate vesicles; 24 both of these transmitters excite histamine neurons. 37,38 The histamine and hypocretin systems have been shown to regulate each other bidirectionally in zebrafish: translational inhibition of HDC reduced the level of hypocretin mRNA and the number of hypocretin neurons, and this reduction was rescued by overexpression of HDC mRNA 39 in an H 1 R-dependent manner. 39 The comprehensive interactions between histamine and hypocretin during development and the functional roles of this interaction have been discussed in recent reviews.…”

“…37,38 The histamine and hypocretin systems have been shown to regulate each other bidirectionally in zebrafish: translational inhibition of HDC reduced the level of hypocretin mRNA and the number of hypocretin neurons, and this reduction was rescued by overexpression of HDC mRNA 39 in an H 1 R-dependent manner. 39 The comprehensive interactions between histamine and hypocretin during development and the functional roles of this interaction have been discussed in recent reviews. 40,41 It remains, however, unclear whether histamine neurons form synaptic connections with hypocretin neurons.…”