title: A Novel Developmental Role for Dopaminergic Signaling to Specify Hypothalamic Neurotransmitter Identity.
abstract: Hypothalamic neurons expressing histamine and orexin/hypocretin (hcrt) are necessary for normal regulation of wakefulness. In Parkinson's disease, the loss of dopaminergic neurons is associated with elevated histamine levels and disrupted sleep/wake cycles, but the mechanism is not understood. To characterize the role of dopamine in the development of histamine neurons, we inhibited the translation of the two non-allelic forms of tyrosine hydroxylase (th1 and th2) in zebrafish larvae. We found that dopamine levels were reduced in both th1 and th2 knockdown, but the serotonin level and number of serotonin neurons remained unchanged. Further, we demonstrated that th2 knockdown increased histamine neuron number and histamine levels, whereas increased dopaminergic signaling using the dopamine precursor l-DOPA (l-3,4-dihydroxyphenylalanine) or dopamine receptor agonists reduced the number of histaminergic neurons. Increases in the number of histaminergic neurons were paralleled by matching increases in the numbers of hcrt neurons, supporting observations that histamine regulates hcrt neuron development. Finally, we show that histaminergic neurons surround th2-expressing neurons in the hypothalamus, and we suggest that dopamine regulates the terminal differentiation of histamine neurons via paracrine actions or direct synaptic neurotransmission. These results reveal a role for dopaminergic signaling in the regulation of neurotransmitter identity and a potential mechanism contributing to sleep disturbances in Parkinson's disease.
authors.affiliation: From the Neuroscience Center and Department of Anatomy, University of Helsinki, 00290 Helsinki, Finland and.
authors.forename: Yu-Chia
authors.initials: YC
authors.lastname: Chen
authors.affiliation: From the Neuroscience Center and Department of Anatomy, University of Helsinki, 00290 Helsinki, Finland and.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Semenova
authors.affiliation: From the Neuroscience Center and Department of Anatomy, University of Helsinki, 00290 Helsinki, Finland and.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Rozov
authors.affiliation: From the Neuroscience Center and Department of Anatomy, University of Helsinki, 00290 Helsinki, Finland and.
authors.forename: Maria
authors.initials: M
authors.lastname: Sundvik
authors.affiliation: the Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah 84113.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Bonkowsky
authors.affiliation: From the Neuroscience Center and Department of Anatomy, University of Helsinki, 00290 Helsinki, Finland and pertti.panula@helsinki.fi.
authors.forename: Pertti
authors.initials: P
authors.lastname: Panula
mesh_terms: D000818:Animals; D059290:Dopaminergic Neurons / Q000378:metabolism*; D006632:Histamine / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism*; D007980:Levodopa / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000235:genetics / Q000378:metabolism*; D000068797:Orexins / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D059326:Serotonergic Neurons / Q000378:metabolism; D012893:Sleep Wake Disorders / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018377:Neurotransmitter Agents; D000068797:Orexins; D029961:Zebrafish Proteins; D007980:Levodopa; D006632:Histamine; D014446:Tyrosine 3-Monooxygenase; C546091:th2 tyrosine hydroxylase 2, Danio rerio
keywords: dopamine; dopamine receptor; histamine; hypothalamus; morpholino; orexin; zebrafish