A refinement of these views has elaborated the complex interaction of specially functioning nuclei in the hypothalamus, pons, and basal forebrain. Reciprocal connections among these areas, modulated by input from regions of the brain that sense environmental conditions, allow the organism to adapt sleep cycles to its needs and to external circumstances. The suprachiasmatic nucleus (SCN) of the hypothalamus has no direct influence on the sleep cycle but does integrate ambient light cues, and thereby affects various circadian rhythms, including sleep, as discussed in Chap. 26. Experiments in animals and analyses of cases of von Economo encephalitis (that caused a pathologic sleep syndrome) have indicated that the ventrolateral preoptic nucleus of the hypothalamus (VLPO) sends fibers to all the other major cell groups of the hypothalamus and brainstem that are engaged in arousal. Damage to the VLPO results in pathologic wakefulness and the virtual absence of sleep. The SCN has only minimal projections to the VLPO and to orexin-containing neurons (see further on), but it does strongly innervate the subparaventricular zone (SPZ) and the dorsomedial hypothalamic nuclei. The last of these areas integrates feeding, temperature, light, and other cues from SPZ and SCN. The brain contains a three-stage pathway for the control of the sleep rhythm.
The above-described interconnections and the action of the integrated system that causes the sleep state have been summarized by Saper and colleagues and schematically in Fig. 18-4, taken from their publication. The current conceptualization is one of an unstable “flip-flop” switch that depends on mutual inhibition of the monoaminergic system and the VLPO. (In engineering terms, a flip-flop switch favors one position or the other, avoiding intermediate states.) The state of the switch is indirectly stabilized by the orexin neurons. In this model, the awake state is maintained by monoaminergic activity (locus ceruleus, tuberomammillary nucleus [TMN], and the raphe nuclei) that inhibits the VLPO. Sleep occurs when the VLPO is activated, which reciprocally removes the tonic inhibitory action of the monoaminergic system. The orexin neurons act through the monoaminergic system as a stabilizing influence to prevent rapid transitions from one state to the other.
Apart from the overall diurnal sleep cycle, evidence from animal studies suggests that the physiologic mechanisms and transitions between NREM and REM sleep are governed by the pontine reticular formation and are influenced by acetylcholine. Cholinergic neurons are found in two major loci in the parabrachial region of the dorsolateral pontine tegmentum—in the pedunculopontine group of nuclei and the lateral dorsal tegmental group. The cholinergic cell groups project rostrally, but the precise anatomy of this projection system has not been defined. Cells from these groups make up parts of the ascending reticular activating system.
Despite the heuristic value of Hobson’s reciprocal interaction hypothesis, some of its features remain controversial. Although it is generally agreed that cholinergic mechanisms selectively promote REM sleep, and its components—rapid eye movements, absence of activity in the antigravity muscles (i.e., atonia), and desynchronized EEG—the role of amines has been more difficult to establish. Thus, lesions of the locus ceruleus and raphe nuclei, which contain neurons rich in norepinephrine, do not greatly alter REM sleep. Nevertheless, a considerable body of pharmacologic data suggests that a decrease in monoamines causes an increase in REM activity and vice versa. Insofar as the bulk of cholinergic and aminergic neurons are found in the pedunculopontine group of nuclei, Shiromani and colleagues have suggested that interaction between these neurons occurs in the region of the pedunculopontine nuclei rather than in the medial pontine reticular formation, as suggested by Hobson and associates.