Norepinephrine is required to promote wakefulness and for hypocretin-induced arousal in zebrafish.
Norepinephrine is required to promote wakefulness and for hypocretin-induced arousal in zebrafish.
复制标题
需要去甲肾上腺素来促进斑马鱼中的清醒和降压素诱导的唤醒。
DOI：
10.7554/elife.07000
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发表时间：
2015-09-16
期刊：
影响因子：
7.7
通讯作者：
Prober DA
中科院分区：
文献类型：
--
作者：
Singh C;Oikonomou G;Prober DA
哺乳动物的药理学研究表明，去甲肾上腺素（NE）在促进唤醒中起着重要作用。然而，内源性NE的作用尚不清楚，关于由于多巴胺β-羟化酶（dbh）突变而缺乏NE的小鼠的睡眠表型的报道相互矛盾。为了研究NE功能的替代脊椎动物模型，我们产生了dbh突变斑马鱼。与小鼠相比，这些动物表现出显着增加的睡眠。令人惊讶的是，尽管睡眠增加，dbh突变的斑马鱼有一个降低的唤醒阈值。在用抑制NE信号传导的小分子处理的斑马鱼中也观察到这些表型，这表明它们是由NE缺乏引起的。利用下丘脑泌素（Hcrt）的基因过表达和表达Hcrt的神经元的光遗传学激活，我们还发现NE对Hcrt诱导的觉醒是重要的。这些结果确立了内源性NE在促进唤醒中的作用，并表明NE是Hcrt神经元的关键下游效应子。http://dx.doi.org/10.7554/eLife.07000.001虽然调节睡眠和觉醒的神经回路还没有完全确定，但至少有两个大脑区域的重要性已经得到了很好的证实。它们是下丘脑，大脑深处的一个结构，控制着一些基本活动，包括饥饿，口渴和睡眠;脑干，连接大脑和脊髓。下丘脑和脑干内的特定神经元通过使用称为神经递质和神经肽的化学物质相互传递信号来调节睡眠-觉醒周期。一整天，一些下丘脑神经元释放一种叫做下丘脑泌素的神经肽，它有助于保持清醒。下丘脑泌素作用于脑干内的神经元，使它们释放其他促进觉醒的神经递质。然而，这些分子的身份尚不清楚。去甲肾上腺素就是一个候选者。增强去甲肾上腺素作用的药物增加清醒，而阻断去甲肾上腺素信号的药物促进睡眠。尽管如此，经过基因改造而缺乏产生去甲肾上腺素的酶的小鼠表现出相对正常的睡眠。这可能是因为在哺乳动物中，去甲肾上腺素在脑外也有重要作用，从而使这种遗传修饰对行为的影响复杂化。或者，虽然缺乏去甲肾上腺素的斑马鱼是健康的，但含有这种修饰的小鼠在发育早期死亡。用特定的药物治疗这些小鼠可以使它们存活，但可能会影响它们的行为。为了阐明去甲肾上腺素的作用及其与下丘脑泌素的相互作用，Singh，Oikonomou和Prober通过遗传修饰斑马鱼创建了一种新的动物模型。与老鼠相反，不能产生去甲肾上腺素的斑马鱼比正常的鱼睡得更多，尽管它们也是较轻的睡眠者，更容易受到惊吓。一种增加下丘脑泌素信号的基因修饰会导致失眠; Singh，Oikonomou和Prober发现这只发生在去甲肾上腺素水平正常的动物中。因此，这些实验表明，下丘脑泌素确实促进觉醒，虽然去甲肾上腺素。Singh，Oikonomou和Prober的工作阐明了去甲肾上腺素在调节睡眠-觉醒周期中的作用。这些发现可能有助于开发针对产生下丘脑泌素的神经元的药物，这可能会改善睡眠障碍的治疗。DOI：http://dx.doi.org/10.7554/eLife.07000.002网站
Pharmacological studies in mammals suggest that norepinephrine (NE) plays an important role in promoting arousal. However, the role of endogenous NE is unclear, with contradicting reports concerning the sleep phenotypes of mice lacking NE due to mutation of dopamine β-hydroxylase (dbh). To investigate NE function in an alternative vertebrate model, we generated dbh mutant zebrafish. In contrast to mice, these animals exhibit dramatically increased sleep. Surprisingly, despite an increase in sleep, dbh mutant zebrafish have a reduced arousal threshold. These phenotypes are also observed in zebrafish treated with small molecules that inhibit NE signaling, suggesting that they are caused by the lack of NE. Using genetic overexpression of hypocretin (Hcrt) and optogenetic activation of hcrt-expressing neurons, we also find that NE is important for Hcrt-induced arousal. These results establish a role for endogenous NE in promoting arousal and indicate that NE is a critical downstream effector of Hcrt neurons. DOI: http://dx.doi.org/10.7554/eLife.07000.001 Although the neural circuits that regulate sleep and wakefulness have yet to be fully identified, the importance of at least two brain regions is well established. These are the hypothalamus, a structure deep within the brain that controls a number of basic activities including hunger, thirst and sleep; and the brainstem, which connects the brain with the spinal cord. Specific neurons within the hypothalamus and brainstem regulate the sleep–wake cycle by signaling to one another using chemicals called neurotransmitters and neuropeptides. Throughout the day, some hypothalamic neurons release a neuropeptide called hypocretin, which helps maintain wakefulness. Hypocretin acts on neurons within the brainstem and causes them to release other neurotransmitters that promote wakefulness. However, the identity of these molecules is unclear. One candidate is norepinephrine. Drugs that enhance the effects of norepinephrine increase wakefulness, whereas those that block norepinephrine signaling promote sleep. Despite this, mice that have been genetically modified to lack the enzyme that produces norepinephrine exhibit relatively normal sleep. This may be because in mammals, norepinephrine also has important roles outside the brain, thus complicating the effects of this genetic modification on behavior. Alternatively, while zebrafish that lack norepinephrine are healthy, mice containing this modification die early in development. Treating these mice with a specific drug allows them to survive, but might affect their behavior. To clarify the role of norepinephrine and its interaction with hypocretin, Singh, Oikonomou and Prober created a new animal model by genetically modifying zebrafish. In contrast to mice, zebrafish that were unable to make norepinephrine slept more than normal fish, although they were also lighter sleepers and were more prone to being startled. A genetic modification that increases hypocretin signaling induces insomnia; Singh, Oikonomou and Prober found that this occurs only in animals with normal levels of norepinephrine. Thus, these experiments indicate that hypocretin does indeed promote wakefulness though norepinephrine. The work of Singh, Oikonomou and Prober has clarified the role of norepinephrine in regulating the sleep–wake cycle. These findings could help in the development of drugs that target the neurons that make hypocretin, which may improve treatments for sleep disorders. DOI: http://dx.doi.org/10.7554/eLife.07000.002