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.

A Bidirectional Network for Appetite Control in Larval Zebrafish

“… (b) Quantification of overlap between pERK-positive cells and anti-5HT staining or Tg(TH2:GCaMP5) expression. Other cH cell types, including histaminergic neurons (Chen et al, 2016) are not labeled. Fish 1 corresponds to the fish shown in (a).…”

“…Among areas that showed relatively decreased neural activity upon feeding food-deprived animals, the most significant was the adjacent caudal hypothalamus (cH), which contains monoaminergic neurons -- mainly serotonergic and dopaminergic cells, with a small fraction of histaminergic cells (Chen et al, 2016; Kaslin and Panula, 2001; Lillesaar, 2011). Indeed, in all of nine independent MAP-mapping experiments, activity was reduced in the cH and increased in the LH within 15 min of food presentation (Fig 1c).…”

Knockout of histamine receptor H3 alters adaptation to sudden darkness and monoamine levels in the zebrafish

“…Brains were dissected after fixation and immunohistochemistry was carried out as described previously. 63 As primary antibodies, mouse anti-tyrosine hydroxylase (Immunostar 22941, Hudson, WI, USA) and rabbit anti-serotonin (Sigma S5545, St. Louis, MO, USA) were used at a dilution of 1:1000. As secondary antibodies, Alexa 488-or 568-conjugated goat anti-rabbit and Alexa 568-or 488-conjugated goat anti-mouse (A11034, A11036, A11031 and A11029 Thermo Fisher, Waltham, MA, USA) were used at a dilution of 1:1000.…”

“…The primers used to amplify rpl13a, hdc, th1, th2 and dat have been described previously. 63,69,70 The other primer sequences are included in the supplementary Table S1. The mRNA was quantified using the comparative C(T) method.…”

Cerebral Dopamine Neurotrophic Factor regulates multiple neuronal subtypes and behavior

“…Briefly, the prehybridization and hybridization steps were conducted at 60C for all riboprobes. The specificity of the anti-sense ribosprobe hdc and th2 have been described earlier (28,29) . The cloning primers for the open-22 22 reading frames of cdnf and vGAT cDNA are listed in Table 1.…”