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  • gamma secretase inhibitor The pleasure or reward zone of the


    The “pleasure” or “reward” zone of the hypothalamus [13,23–25] is congruent with the site of the greatest concentration of hypocretinergic neurons [26,27]. It is important to consider that, in addition to the hypocretinergic neurons, other groups of neurons such as the melanin concentrating-hormone (MCH) containing neurons are present within this area [9]. The anatomical interrelation between these groups of neurons is shown in Fig. 1.
    Afferents to hypocretinergic neurons Hypocretinergic neurons receive inputs from several regions such as the allocortex, many hypothalamic nuclei, periaqueductal gray matter, the dorsal raphe nucleus (DRN), and parabrachial regions, which suggest that these neurons integrate a variety of interoceptive, exteroceptive and homeostatic signals [28]. Several neurotransmitters act on hypocretinergic neurons [29]. Glutamate depolarizes these neurons acting through AMPA and NMDA receptors, and GABA inhibits these neurons through GABAA and GABAB receptors. Neurotransmitters used by neurons that form part of the activating systems [30], such as serotonin, noradrenaline, gamma secretase inhibitor and dopamine, modulate the activity of hypocretinergic neurons. An in vitro study in mice has shown that serotonin and noradrenaline hyperpolarize hypocretinergic neurons through 5HT1A and α2 receptors, respectively [29]. A weak depolarization mediated by α1 receptor was also observed in the presence of a α2-receptor antagonist. In rats, both noradrenaline and acetylcholine have a predominant excitatory effect [31]. Carbachol (a mixed cholinergic agonist) depolarizes 27% and hyperpolarizes 6% of the population of hypocretinergic neurons in mice [29]; these effects are mediated by different muscarinic receptors. Interestingly, histamine has almost no effect on hypocretinergic neurons. D1 and D2 dopamine receptors have opposing effects on excitatory presynaptic terminals that impinge on hypocretinergic neurons [32].
    Projections of the hypocretinergic neurons Hypocretinergic neurons project throughout the central nervous system [26]; furthermore, the activity of the peripheral organs is also influenced by the Hcrts [33]. Hypocretinergic neurons also have the potential to mediate complex functions since they exhibit the morphology of prototypical “command” neurons, which are small groups of highly specialized cells that coordinate and integrate, in a complementary fashion, the activities of a vast number of neural and hormonal systems [34–36]. Sensory and motor nuclei are directly innervated by hypocretinergic neurons [37–40]. These neurons also project to the thalamus and cortex [26], wherein they directly influence thalamo-cortical activities that support cognitive functions. Dense concentrations of hypocretin-containing axon terminals are located in the tuberomammillary nucleus of the hypothalamus, a waking-promoting area [41], as well as in brainstem areas such as the laterodorsal and pedunculopontine tegmental nucleus (LDT–PPT), locus coeruleus (LC) and DRN [26,42–44], that are known to participate in the control of sleep and wakefulness [30]. We demonstrated that hypocretinergic neurons project to the nucleus pontis oralis (NPO), which is considered to exert executive control over the initiation and maintenance of REM sleep [45]. A single injection of a cholinergic agonist, such as carbachol, within the NPO of the cat, results in the generation of a state that consists of all the behavioral and electrographic signs of REM sleep with a very short latency (30s to a few minutes); this state lasts up to two hours (see below).
    Hypocretinergic neurons and wakefulness Early studies revealed that the intraventricular injection of Hcrt promotes wakefulness [46,47]. These data, as well as the fact that the lack of hypocretinergic neurons in narcoleptic patients induces hypersomnia [1], strongly suggested that this system promotes wakefulness. However, by means of Fos technology (the Fos protein is a marker of neuronal activity), we demonstrated in the cat, that hypocretinergic neurons are not active during wakefulness per se [48]. On the contrary, hypocretinergic system becomes active during aroused wakefulness when the animal is moving. In the absence of motor activity during alert wakefulness, quiet wakefulness or quiet sleep, the hypocretinergic system is not activated to any significant extent [49]. In this regard, several reports confirmed that the hypocretinergic neurons are involved in the promotion of somatomotor activity. The data in Fig. 2 demonstrates that while Hcrt-containing neurons do not express Fos during quiet wakefulness, they are active during active wakefulness.