Wakefulnesssleep transitions the flipflop switch Figure

As described above, the VLPO is reciprocally connected with a number of the arousal-related nuclei. It was therefore proposed that mutual inhibition would occur between the VLPO and arousal-related nuclei [108]. For example, in vitro investigations showed that VLPO neurons are inhibited by 5-HT and NA [109]. Arousal systems therefore act to inhibit VLPO sleep-promoting activity and, as discussed above, VLPO inhibits wakefulness-promoting systems. Thus, these arousal and sleep-related nuclei are mutually inhibitory. This reciprocal relationship is reminiscent of a "flip flop" switch, as described in electrical engineering [110,111]. As depicted in Figure 2.2, distinct transitions occur between states, and intermediary states do not normally occur in such a system. Since TMN neurons project to VLPO [104], it was assumed that histaminergic input would inhibit VLPO activity. In vitro, histamine had no post-synaptic effect on VLPO activity [112].

Figure 2.2 Graphic depiction of the flip flop switch modelof wakefulness and sleep systems. GABAergic/galaninergic ventrolateral preoptic (VLPO) neurons, active during sleep, are connected to wakefulness promoting brain nuclei, including GABAergic/histaminergic neurons of the tuberomammillary nucleus (TMN), serotonergic neurons of the dorsalraphe nucleus (DR), and noradrenergic neurons of the locus coeruleus (LC). Mutualinhibition between these sleep related and arousal related neurons allows distinct transitions between states (Wake and Sleep). Orexinergic input from the lateralhypothalamus (LH) to the wakefulness related nuclei stabilizes the wakefulness state, and during sleep, VLPO inhibits orexinergic activity, as wellas the other arousalmechanisms.

Figure 2.2 Graphic depiction of the flip flop switch modelof wakefulness and sleep systems. GABAergic/galaninergic ventrolateral preoptic (VLPO) neurons, active during sleep, are connected to wakefulness promoting brain nuclei, including GABAergic/histaminergic neurons of the tuberomammillary nucleus (TMN), serotonergic neurons of the dorsalraphe nucleus (DR), and noradrenergic neurons of the locus coeruleus (LC). Mutualinhibition between these sleep related and arousal related neurons allows distinct transitions between states (Wake and Sleep). Orexinergic input from the lateralhypothalamus (LH) to the wakefulness related nuclei stabilizes the wakefulness state, and during sleep, VLPO inhibits orexinergic activity, as wellas the other arousalmechanisms.

However, other indirect inhibitory TMN mechanisms are possible, including presynaptic effects of histamine on inputs to VLPO. Also, TMN neurons contain GAD65, a synthesizing enzyme for GABA, which may allow inhibition of VLPO neurons during wake. It was hypothesized that orexin plays a crucial role in stabilizing the waking state of the switch, due to its widespread projections to the arousal nuclei [110]. Therefore, abnormalities in orexin systems, such as that seen in narcolepsy, would result in more frequent and abnormal state transitions. Consistent with this model, orexin knock-out mice exhibited increased transitions between wakefulness and sleep states [85]. An incompletely answered question in this model is how the system exits states of wakefulness and sleep; a switch remains flipped or flopped unless a third agent causes a transition. The mechanism of this transition, the agent flipping the switch, is not clearly described, as reflected in the figure.

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