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.