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  • NVP-TNKS656 A detailed analysis of hypocretinergic neuronal

    2018-11-05

    A detailed analysis of hypocretinergic neuronal activity shows that these neurons are strongly activated when animals are exploring an unknown environment (exploratory motor activity) [50]. In fact, in this study, the number of Hcrt+Fos+neurons was approximately 10 times greater during exploratory motor activity than during repetitive motor activity that occurred during forced locomotion, even though in both paradigms there was a comparable amount of motor activity. Therefore, neither wakefulness nor motor activity per se, were critical with respect to the activation of hypocretinergic neurons. Therefore, we conclude that the hypocretinergic system is engaged when animals are performing goal (reward)-directed behaviors. In agreement with our results, it was found that Hcrt knock-out mice were unable to work for food or water reward during the light phase [51]. Recently, Chase presented the “Unified Survival Theory for the Functioning of the Hypocretinergic System” [52]. The basis of this theory is that the main role of the hypocretinergic system is to initiate, coordinate and maintain survival behaviors and survival-related processes.
    Hypocretinergic neurons and NREM sleep The hypocretinergic neurons, as a component of the activating systems [30], do not participate in NREM sleep. In fact, we demonstrated a lack of Fos NVP-TNKS656 in these neurons during this behavioral state [49]. Subsequently, unit recordings confirmed our early findings [53–55].
    Hypocretinergic neurons and REM sleep There are presentations that argue that hypocretinergic neurons are REM-OFF neurons and that these neurons inhibit REM sleep. The REM-OFF profile concept of the hypocretinergic neurons arose based upon electrophysiological recordings of identified hypocretinergic neurons [53–55]. Lee et al. [54] recorded six hypocretinergic neurons in the hypothalamus of the rat during unanesthesized semi-restricted conditions. They found that the six neurons exhibited the largest firing rate during wakefulness, the rate decreased during NREM sleep, and a nadir was reached during REM sleep. Another study in rats [53], and a study in mice [55], demonstrated similar firing profiles. However, an in-depth analysis of the preceding data reveals that hypocretinergic neurons also discharge during some “phasic” components of REM sleep. Fig. 2 of Lee et al.׳s [54] study illustrates the discharge of one representative neuron; its firing rate increases in relation to muscle twitches during REM sleep as well as during REM sleep that precedes awakening. In addition, their Fig. 2 shows that there is a burst of firing in a short period (just a couple of seconds) of “wakefulness” that is between two REM sleep periods (without a preceding NREM sleep epoch). Amici et al., consider this kind of episodes as a “cluster” type of REM sleep, instead of two independent REM sleep episodes interrupted by an episode of wakefulness [56,57]. Another study in rats also acknowledged that hypocretinergic neurons “occasionally discharge in phasic REM” [53]. In addition, in freely moving mice, hypocretinergic neurons display transient discharges during REM sleep [55]. Hence, at least some hypocretinergic neurons increase their firing rate during the phasic periods of REM sleep. It would be important to examine the pattern of activity of these neurons in an animal that exhibits robust phasic periods of REM sleep, such as the cat [58]. Studies in the cat, strongly suggest that there is hypocretinergic neuronal activity during REM sleep, probably during the phasic events of this state. An increase in the number of Hcrt+Fos+neurons was observed during REM sleep induced by carbachol microinjections into the NPO [48]. In this study, REM sleep was induced by carbachol microinjections in order to generate a state of sufficiently long duration to allow Fos protein to be synthesized in high concentration. Fig. 3A illustrates a representative carbachol-induced period of REM sleep, which has the same characteristics as natural REM sleep. During this state, 34% of the hypocretinergic neurons were activated according to their Fos-expression; representative active “Hcrt+Fos+” neurons are shown in Fig. 3B. The distribution of the active hypocretinergic neurons of a representative experiment is shown in Fig. 4. This result is in agreement with the findings of Kiyashchenko et al. [59]. Utilizing microdialysis in freely moving cats they found an increase in Hcrt-1 release during REM sleep, both in the hypothalamus and basal forebrain. Hence, this study also indicates that hypocretinergic neurons are active during REM sleep, probably in conjunction with phasic events.