ABSTRACT
The orexin (hypocretin) system has multiple upstream activators/inhibitors and downstream targets. This chapter discusses the input and output systems of orexin-producing neurons, and their physiological roles as a link between sleep/wakefulness states and energy homeostasis
II. Efferents of Orexin Neurons
The finding of orexin (hypocretin) deficiency in narcoleptic patients suggests that orexin has an important role in the normal regulation of sleep/wakefulness (1,2). Orexin neurons might be especially important for stabilization of behavioral states, because the major symptom in narcolepsy is inability to maintain behavioral states, which results in sleep/wakefulness fragmentation. When orexin-A was injected intracerebroventricularly into rats during the light period, it caused increased wakefulness time and decreased REM and non-REM sleep time (3). This also caused prolonged wakefulness. In rats, Fos expression of orexin neurons is increased during the dark active period (4), and orexin level in cerebrospinal fluid also peaks during the dark active period and decreases during the light rest period (5). These observations suggest that orexin neurons are active during the active period and support wakefulness, and are inactive during the sleep period. The activities of monoaminergic neurons in the brain stem and hypothalmus are reportedly synchronized and strongly associated with behavioral states: they fire tonically during wakefulness, less during non-REM sleep, and not at all during REM sleep (6). This regulation might be at least in part by orexin neurons, which are also wake-active, because orexin neurons project to and excite histaminergic neurons in the tuberomammillary nucleus (TMN), noradrenergic neurons in the locus coeruleus (LC) and serotonergic neurons in the dorsal raphe (DR) (7-9), and the presence of OX1R in the LC and OX2R in the TMN and both receptors in the DR has been confirmed (10). Consistent with this hypothesis, isolated cells
from these nuclei are all activated by orexins in vitro (3,11,12). Among these systems, the effect of orexin on wakefulness is showed to be largely mediated by activation of the histaminergic system through activation of OX2R in rodents. In rats, i.c.v. injection of orexin during the light period potently increases the wake period, and this effect is markedly attenuated by the H1 antagonist, pyrilamine (12). Furthermore, the effect of orexin-A on wakefulness in mice is almost completely absent in H1-receptor deficient mice (13). OX2R knockout mice exhibit a narcoleptic phenotype, while OX1R knockout mice show only mild fragmentation of behavioral states (14). Because OX2R is abundantly expressed in the TMN, while OX1R is heavily expressed in the LC, the TMN seems to be an important effecter site of orexin for sleep/wakefulness regulation. Orexin neurons also contain an additional neurotransmitter, dynorphin (15). Dynorphin in orexin neurons might inhibit GABAergic input to TMN neurons, and thus act in concert with orexin to increase the excitability of these neurons (16).
