Neuroscience Center and Institute of Biomedicine, Anatomy, Faculty of Medicine, P.O.B. 63, 00014 University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland.
FASEB J. 2011 Dec;25(12):4338-47. doi: 10.1096/fj.11-188268. Epub 2011 Sep 1.
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.
组胺能和下丘脑分泌素/食欲素（hcrt）神经递质系统在啮齿动物的觉醒/清醒中起着至关重要的作用。我们阐明了组胺在觉醒中的作用以及组胺和 hcrt 系统在幼鱼斑马鱼中的相互作用。用吗啉代寡核苷酸（MO）抑制组氨酸脱羧酶（hdc）的翻译导致与光相关的活动在行为上可测量的下降，hdc mRNA 注射部分挽救了这种下降，而组胺受体 H1（Hrh1）拮抗剂苯海拉明处理则模拟了这种下降。组胺免疫反应纤维靶向背侧端脑，该区域表达组胺受体 hrh1 和 hrh3，并含有主要的谷氨酸能神经元。DiI 示踪显示，来自背侧端脑的投射支配 hcrt 和组胺能神经元。hdc 的翻译抑制以 Hrh1 依赖性方式减少 hcrt 神经元的数量。hdc mRNA 的过表达挽救了这种减少。hdc mRNA 注射本身导致 hcrt 神经元数量的上调。这些结果表明，组胺对于功能性和完整的 hcrt 系统的发育是必不可少的，并且组胺对 hcrt 神经元的发育具有双向作用。总之，我们的研究结果提供了证据表明这两个系统在功能和发育上是相互联系的，这可能对睡眠障碍和发作性睡病有重要意义。
