Interactions of the orexin/hypocretin neurones and the histaminergic system

Sundvik, Maria; Panula, Pertti

doi:10.1111/apha.12432

Cited by 36 publications

(30 citation statements)

References 132 publications

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“…1 A ). Zebrafish larvae have 10-15 hdc -expressing neurons per brain hemisphere (Sundvik and Panula, 2015), compared with ∼5000 in rodents (Ericson et al, 1987) and ∼60,000 in humans (Airaksinen et al, 1991). To explore the role of histamine in regulating sleep in zebrafish, we generated a hdc mutant using the TALEN method (Sander et al, 2011).…”

Section: Resultsmentioning

confidence: 99%

Genetic Analysis of Histamine Signaling in Larval Zebrafish Sleep

Chen

Singh

Oikonomou

et al. 2017

eNeuro

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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 nonfunctional. 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.

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Section: Resultsmentioning

confidence: 99%

Genetic Analysis of Histamine Signaling in Larval Zebrafish Sleep

Chen

Singh

Oikonomou

et al. 2017

eNeuro

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“…In other animal models, reserpine has been shown to induce anxiety-like behaviour 27–29 , although this effect has not been seen in all studies 30 . The dark-induced short-lasting hyperactivity has been suggested to represent shelter seeking behaviour after nightfall or a reaction to find a way back to light after sudden onset of darkness 18, 31 . In nature, such a situation could be caused by an approaching predator that casts a shade on the fish.…”

Section: Discussionmentioning

confidence: 99%

Storage of neural histamine and histaminergic neurotransmission is VMAT2 dependent in the zebrafish

Puttonen

Semenova

Sundvik

et al. 2017

Sci Rep

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Monoaminergic neurotransmission is greatly dependent on the function of the vesicular monoamine transporter VMAT2, which is responsible for loading monoamines into secretory vesicles. The role of VMAT2 in histaminergic neurotransmission is poorly understood. We studied the structure and function of the histaminergic system in larval zebrafish following inhibition of VMAT2 function by reserpine. We found that reserpine treatment greatly reduced histamine immunoreactivity in neurons and an almost total disappearance of histamine-containing nerve fibers in the dorsal telencephalon and habenula, the most densely innervated targets of the hypothalamic histamine neurons. The reserpine treated larvae had an impaired histamine-dependent dark-induced flash response seen during the first second after onset of darkness, implying that function of the histaminergic network is VMAT2 dependent. Levels of histamine and other monoamines were decreased in reserpine treated animals. This study provides conclusive evidence of the relevance of VMAT2 in histaminergic neurotransmission, further implying that the storage and release mechanism of neural histamine is comparable to that of other monoamines. Our results also reveal potential new insights about the roles of monoaminergic neurotransmitters in the regulation of locomotion increase during adaptation to darkness.The function of most monoamine neurotransmitters is dependent on the vesicular release made possible by the vesicular monoamine transporter 2 (VMAT2). Serotonin and dopamine are loaded into secretory vesicles by VMAT2, and inhibition of VMAT2 leads to rapid depletion of these neurotransmitters through metabolism by the enzyme monoamine oxidase (MAO)1 . Since noradrenaline is synthesized from dopamine inside secretory vesicles 2 , VMAT2 inhibition also lowers noradrenaline levels 1 . VMAT2 inhibition by the indole alkaloid reserpine was previously used as a treatment for psychotic conditions 3 . Depression has often been reported as a side-effect of reserpine treatment, which was a key factor in the development of the monoamine depletion theory of depressive disorders and the reserpine treated animal model for depression, although the monoamine hypothesis has recently been challenged [4][5][6] . Taken together, these findings underline the significance of monoamine dependent neurotransmission in brain physiology.The role of VMAT2 in histaminergic neurotransmission remains unclear. Like the other monoamines, histamine has been described as a substrate for VMAT2 7 . In gastric enterochromaffin-like (ECL) cells, histamine storage is controlled by reserpine 8 , and reserpine induces changes in vesicle morphology and subcellular distribution of histamine 9 . However, histamine is not known to be significantly metabolized by MAO, but is rather metabolized by histamine N-methyltransferase (HNMT) in the brain, followed by subsequent metabolism by MAO 10,11 . In an explant culture from fetal rat hypothalamus, most histamine-immunoreactive neurons display VMAT2-immunoreactivity, w...

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“…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. In transgenic mice that retrogradely transfer green fluorescent protein (GFP) to terminals that project to hypocretin neurons, no evidence was found of synaptic connections from the TMN to hypocretin neurons.…”

Section: Reciprocal Connectionsmentioning

confidence: 99%

Interactions of the histamine and hypocretin systems in CNS disorders

2015

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Histamine and hypocretin neurons are localized to the hypothalamus, a brain area critical to autonomic function and sleep. Narcolepsy type 1, also known as narcolepsy with cataplexy, is a neurological disorder characterized by excessive daytime sleepiness, impaired night-time sleep, cataplexy, sleep paralysis and short latency to rapid eye movement (REM) sleep after sleep onset. In narcolepsy, 90% of hypocretin neurons are lost; in addition, two groups reported in 2014 that the number of histamine neurons is increased by 64% or more in human patients with narcolepsy, suggesting involvement of histamine in the aetiology of this disorder. Here, we review the role of the histamine and hypocretin systems in sleep-wake modulation. Furthermore, we summarize the neuropathological changes to these two systems in narcolepsy and discuss the possibility that narcolepsy-associated histamine abnormalities could mediate or result from the same processes that cause the hypocretin cell loss. We also review the changes in the hypocretin and histamine systems, and the associated sleep disruptions, in Parkinson disease, Alzheimer disease, Huntington disease and Tourette syndrome. Finally, we discuss novel therapeutic approaches for manipulation of the histamine system.

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Interactions of the orexin/hypocretin neurones and the histaminergic system

Cited by 36 publications

References 132 publications

Genetic Analysis of Histamine Signaling in Larval Zebrafish Sleep

Genetic Analysis of Histamine Signaling in Larval Zebrafish Sleep

Storage of neural histamine and histaminergic neurotransmission is VMAT2 dependent in the zebrafish

Interactions of the histamine and hypocretin systems in CNS disorders

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