In narcolepsy cataplexy there is an

In narcolepsy–cataplexy, there is an increase in the incidence of REM sleep behavioral disorder (RBD) [77]. In RBD the mechanisms that produce atonia are significantly reduced, which supports the hypothesis that the dysfunction of the hypocretinergic system produces instability of motor regulatory systems during REM sleep.
Working hypothesis 1: hypocretinergic neurons are active during “phasic” REM sleep EEG activation, theta activity in the hippocampus and muscle atonia are the classic biomarkers for the identification of REM sleep. Accompanying these “tonic” signs are rapid eye movements, muscle twitches, PGO waves, breathing irregularities as well as heart rate and blood pressure increases that constitute the phasic events of REM sleep. Other signs such as acceleration of the theta rhythm also correlate with these phasic events [78]. Experimental evidences suggest that while hypocretinergic neurons turn off during “tonic” REM sleep, at least a subset of these neurons discharge in burst during phasic REM sleep [53–55]. Furthermore, during REM sleep induced by carbachol, there is an activation of 34% of hypocretinergic neurons [48]. In addition, Hcrt-1 synaptic release increases during REM sleep [59]. These data suggest that hypocretinergic neurons are active during the “phasic” component of REM sleep (Fig. 5).
Working hypothesis 2: hypocretinergic neurons are involved in the generation of the “phasic” phenomena of REM sleep If hypocretinergic neurons are active during “phasic” REM sleep, they are likely to promote the phasic events of REM sleep. Hypocretins directly activate motor nuclei, breathing neuronal networks and sympathetic output that control the fda approved [40,79–81], as well as the medial septum where the pacemaker for the hypocamppal theta rhythm is located [82]. By these means, hypocretinergic neurons promote the “phasic” components of REM sleep (Fig. 5). Yamuy et al. [40] demonstrated in lumbar motoneurons that the juxtacellular administration of hypocretin-1 and electrical activation of hypocretinergic neurons activate motoneurons. Therefore, it is likely that the “phasic” discharge of hypocretinergic neurons during REM facilitates motoneuron activity and muscle twitches. The intracerebroventricular injection of either hypocretin 1 and 2 increases heart rate, mean arterial pressure and renal sympathetic activity in conscious rats [79]. Hypocretins stimulate breathing and knocking-out the preprohypocretin gene in mice reduces CO2-induced increases in breathing by 50% and increases the frequency of spontaneous sleep apneas [81]. Lesions of medial septum neurons by hypocretin-2 conjugated with the neurotoxin saporin abolishes theta rhythm of the hippocampus during both active wakefulness and REM sleep, suggesting that hypocretin facilitates theta rhythm generation [82]. All these effects induced by hypocretin involve ergotropic or energy-expending behaviors [52]. Although disturbances in the phasic components of REM sleep occurs in narcolepsy–cataplexy and in hypocretin-deficient mice [83–85], new experimental approaches are needed in order to confirm the relationship between hypocretins and “phasic” REM sleep.
Working hypothesis 3: there are complementary but opposite functions of hypocretin and MCH in the control of REM sleep Due to the importance of the MCHergic system in sleep physiology [86,87], it is relevant to examine the interactions between the MCHergic and the hypocretinergic systems. A strong anatomical relationship exists between hypocretinergic and MCHergic neurons in the hypothalamus. As it is shown in Fig. 1, MCHergic neurons are intermingled with Hcrt-containing neurons in the postero-lateral hypothalamus, mainly at the tuberal and tuberomammillar levels [9]. MCHergic fibers are in close relationship with hypocretinergic neurons and vice versa, which suggest the existence of reciprocal synaptic contacts between both types of cells [9,88]. This fact as well as the presence of hypocretinergic receptors on MCHergic neurons indicates the existence of an important functional interaction between both systems [89]. In this regard, Hcrt increases MCH mRNA expression in hypothalamic neurons, directly excites MCHergic neurons and increases glutamate release onto them [90,91]. On the other hand, MCH modulates Hcrt-mediated effects on behavioral state and synaptic transmission in the lateral hypothalamus [92]. In addition, the efficacy of glutamatergic synapses on hypocretinergic neurons is enhanced in MCHR1 knockout mice, and Hcrt-1-induced firing is facilitated. On the contrary, in wild-type mice, MCH significantly attenuates Hcrt-1 induced enhancement of spike frequency in hypocretinergic neurons, but not its basal activity. Furthermore, in these neurons, MCH attenuates Hcrt-1-induced enhancement of the frequency of miniature excitatory postsynaptic currents. These effects imply that MCH exerts a unique inhibitory influence on hypocretinergic signaling as a way to fine-tune the output of these neurons.