Alternatively, while zebrafish that lack norepinephrine are healthy, mice containing this modification die early in development. This may be because in mammals, norepinephrine also has important roles outside the brain, thus complicating the effects of this genetic modification on behavior. Despite this, mice that have been genetically modified to lack the enzyme that produces norepinephrine exhibit relatively normal sleep. Drugs that enhance the effects of norepinephrine increase wakefulness, whereas those that block norepinephrine signaling promote sleep. However, the identity of these molecules is unclear. Hypocretin acts on neurons within the brainstem and causes them to release other neurotransmitters that promote wakefulness. Throughout the day, some hypothalamic neurons release a neuropeptide called hypocretin, which helps maintain wakefulness. Specific neurons within the hypothalamus and brainstem regulate the sleep–wake cycle by signaling to one another using chemicals called neurotransmitters and neuropeptides. 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. eLife digestĪlthough 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 results establish a role for endogenous NE in promoting arousal and indicate that NE is a critical downstream effector of Hcrt neurons. 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 phenotypes are also observed in zebrafish treated with small molecules that inhibit NE signaling, suggesting that they are caused by the lack of NE. Surprisingly, despite an increase in sleep, dbh mutant zebrafish have a reduced arousal threshold. In contrast to mice, these animals exhibit dramatically increased sleep. To investigate NE function in an alternative vertebrate model, we generated dbh mutant zebrafish. 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). Pharmacological studies in mammals suggest that norepinephrine (NE) plays an important role in promoting arousal.