The hypocretin system is a crucial regulator of (REM-)sleep and wakefulness cycle, and seems to be particularly involved in sustained wakefulness since sleep deprivation is associated with an upregulated activity of the system.46 It integrates the activity of nuclei involved in these states including the motor nuclei. Absence of hypocretin leads to attenuated daytime wakefulness and the earlier discussed loss of "state boundary control".47 In this context it is important to realize that the hypocretin system is not required to generate wakefulness or other vigilance states, since these states still occur in almost the normal amounts, when there is no hypocretin transmission. Hypocretin merely stabilizes sleep and wakefulness states. This regulatory role is corroborated by neuro-anatomical findings. The hypocretin system comprises a small group of cells exclusively located in the lateral hypothalamus with efferent connections to virtually all parts of the brain.48
Afferent input is mainly from centers/nuclei that are not primarily involved in the generation of sleep and wakefulness.49 This represents a pattern that may be expected from a "high order" regulatory system. Functionally, the activity of the system is entrained by the biological clock as shown in animal studies.46,50
Most likely, the promotion of wakefulness occurs through the excitatory effects of hypocretin on aminergic brain regions implicated in arousal such as the noradrenergic neurons of the locus coeruleus, the serotonergic neurons of the dorsal raphe, and the histaminergic neurons of the tuberomammillary nucleus.51-55 Of these, the histaminergic neurons may play a prominent role because histamine concentrations are low in hypocretin receptor-2 mutated narcoleptic dogs, and mice lacking the H1 histamine receptor appear to have no waking response to hypocretin.56,57 Hypocretin may also promote wakefulness by exciting cholinergic neurons.58 Hypocretin neurons are active during wakefulness as indicated by the expression of Fos, and the extracellular concentration of hypocretin is high during wakefulness.59-61,61 By increasing the activity of aminergic and pontine cholinergic brain regions, hypocretin may help an individual to maintain long episodes of wakefulness.
How to view the role of hypocretin in the current concept of the control of wakefulness and sleep stages? Briefly summarized, the most recent concept proposes that the sleep-promoting function of the ventrolateral preoptic area, and the wake-promoting function of several monoaminergic nuclei, including the tuberomamillary nucleus, form a reciprocal relationship with the properties of a flip-flop circuit (figure 1).62 This essentially means that systems that promote wakening and sleep interact as an inherently unstable system with the tendency to avoid intermediate states, so that an organism is clearly waking or clearly sleeping with only brief times spent in transitions. The hypocretin system in this model forms a stabilizing "finger on the switch" or, in other words, acts as state boundary controller (figure 1).47,62
6. ENDOCRINE RHYTHMS, AUTONOMIC TONE AND OBESITY
Narcoleptic patients have a tendency to grow obese. This had already been observed more than 70 years ago.63 Recent studies point to a specific role of hypocretin in the genesis of this obesity. A first hint came from the observation that narcoleptic patients with measurable hypocretin levels (a small minority of the total patient population) tended to be less obese than patients with undetectably low levels.16 A subsequent study in a large group of typical narcoleptic patients, known to have undetectable hypocretin-1 in more than 90% of cases, and comparably sleepy patients with idiopathic hypersomnia (who have normal hypocretin levels), confirmed this impression and suggests that hypocretin deficiency per se promotes body weight gain.29 Hypocretin-deficient narcoleptics were significantly heavier than age- and sex- matched controls, and the percentage of obese patients (BMI > 30kg/m2) was significantly higher in the narcoleptic group. In addition, waist circumference and the percentage body fat were significantly increased as well in the narcoleptics (figure 2). The increased body weight is not explained by a higher caloric intake, as narcoleptics actually eat less during the day.30
These metabolic findings and the evidence of involvement of hypocretin in endocrine regulation in animal studies incited additional neuroendocrine studies in human narcolepsy. A study of diurnal rhythms of leptin, hypothalamo-pituitary-adrenal, somatotropic-, gonadal-, and thyroid hormones in hypocretin deficient male narcoleptic patients showed abnormalities in all secretion patterns, the most robust in leptin.
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