Hypocretinergic activation during REM sleep
Hypocretinergic activation during REM sleep is likely related to the activation that occur during certain patterns of somatomotor activity . Although motor output is inhibited at the motoneuron level during REM sleep, supraspinal motor systems are very active during this state [60–62]. In fact, in conjunction with PGO waves, a phasic event that occurs during REM sleep, there is a potentiation of the REM sleep-related hyperpolarization of motoneurons . Microinjections studies also suggest that Hcrt may contribute with some aspects of REM sleep. Hcrt-1 applied into the gigantocellular nucleus and dorsal paragigantocellular nucleus of the medullary reticular formation, which are sites that have been previously identified that generate atonia by electrical stimulation, produced bilateral hindlimb muscle atonia, similar to which occurs during REM sleep atonia and cataplexy . We demonstrated previously the presence of hypocretinergic projections to the NPO, the REM sleep executive area in the pons . Microinjections of Hcrt-1 or Hcrt-2 into the NPO of the cat increase the time spent in REM sleep and result in a decrease in the latency to the generation of this state . Furthermore, the juxtacellular application of Hcrt-1 results in an increase in the excitability of NPO neurons, which is associated with the induction of REM sleep . In addition, Hcrt-1 increases glucose assay release in the NPO of the rat [66,67]. In this regard, it is known that acetylcholine levels within this region increase during REM sleep . However, a decrease in REM sleep when Hcrt-1 is microinjected into the NPO of the cat was also described . Furthermore, the iontophoretic application of Hcrt-1 into the NPO of the rat produces an inhibition of NPO neurons, which can be blocked by previous iontophoretic application of bicuculline, a GABAA receptors antagonist . In fact, it has been shown that Hcrt increases GABA levels in the NPO of the rat, and hypocretin and GABA interact within this nucleus to promote wakefulness [71,72]. The presence of Hcrt-2 receptors on GABAergic neurons within the NPO may be the cellular basis for this effect . The paradoxical or contradictory findings involving the REM sleep and wakefulness promoting actions of Hcrt within the NPO were reconciled by Xi and Chase . They demonstrated that the microinjections of Hcrt-1 within the NPO generate REM sleep when applied during NREM sleep, but promote wakefulness when applied during this behavioral state. Thus, the behavioral state of the animal at the time of the application of Hcrt determines whether REM sleep or wakefulness occurs. It is attractive to note that hypocretinergic cells in the hypothalamus may be involved in the control of both active wakefulness and REM sleep, and that within both patterns of behavioral state control changes in motor activity play a predominant role. This pattern of duality of behavioral state control with opposite motor responses is reminiscent of the phenomenon of Reticular Response-Reversal in the NPO [75,76]. This phenomenon involves mechanisms that result in the facilitation of wakefulness and somatomotor activation during wakefulness, as well as the generation of REM sleep and its accompanying pattern of motor inhibition during this sleep state [75,76]. Reticular Response-Reversal determines, for example, that auditory stimulation promotes somatomotor activation during wakefulness, and also increases the hyperpolarization of motoneurons and produces atonia during REM sleep . It is well known that in the “twitches” that occur during REM sleep, there is an increase in the frequency of motoneuron postsynaptic inhibitory potentials (IPSPs) that generate atonia compared with the tonic periods of REM sleep. Paradoxically, there is also an important increase in excitatory drives (excitatory postsynaptic potentials, EPSPs) that also impinge on motoneurons during “phasic” REM sleep. Hence, there is a competition between these opposing forces during phasic REM sleep; the winner determines whether motoneurons discharge or remain silent . Hypocretins are likely related to this phenomenon; these peptides may facilitate motor activity during wakefulness and the phasic components of REM sleep by direct actions onto motoneurons (see below). Furthermore, throughout REM sleep, hypocretinergic activation of the NPO generates motor inhibition due to processes involving Reticular Response-Reversal process [3,52].