Hypothalamic Timing Of Sleep And Wakefulness

Circadian rhythms strongly govern the timing of REM sleep, the onset of wakefulness, and behavioral alertness (152). These endogenously generated, daily rhythms are controlled by the suprachiasmatic nucleus (SCN), a small cluster of neurons just above the optic chiasm in the anterior hypothalamus. The SCN acts as a master clock, keeping time with an accuracy of a few minutes each day (153) and adjusting bodily rhythms to seasonal variations in day length. Most likely, each SCN neuron is a competent circadian pacemaker, and the coordinated activity of all SCN neurons results in highly accurate 24-h rhythms. The importance of this nucleus is apparent in people and animals with lesions of the SCN, who may sleep and wake at any time of day.

In addition to its role in timing behavior, the SCN may also promote and consolidate wakefulness. In monkeys, lesions of this nucleus reduce the daily amount of wakefulness and produce very fragmented waking (154). These observations form the foundation of the opponent process model in which the SCN is hypothesized to have an alerting function that opposes rising homeostatic sleep drive across the day (154). In rodents, this wake-promoting role is less apparent, although lesions of SCN outflow regions do produce small reductions in wake-fulness (155).

The SCN drives the rhythms of sleep and wakefulness through projections to nearby hypo-thalamic regions. The SCN sends only minor, direct projections to brain nuclei implicated in state control (145,156), but it heavily innervates several hypothalamic regions, especially an area just dorsal to the SCN known as the subparaventricular zone (SPZ) (157,158). Lesions of the ventral SPZ markedly reduce the circadian rhythms of sleep/wake behavior, but the body temperature rhythm is relatively preserved, demonstrating that the pacemaker itself is intact (159). The SPZ projects to the dorsomedial nucleus of the hypothalamus (DMH), a region implicated in autonomic stress responses, feeding, and the circadian release of corti-costeroids (160). Anatomically precise lesions of the DMH reduce the circadian rhythms of wakefulness, NREM, and REM sleep, with relatively little effect on the daily amounts of these states or the body temperature rhythm (155). The DMH sends excitatory (glutamate and thyrotropin-releasing hormone) projections to wake-promoting regions such as the orexin neurons and LC (155,161). A separate population of GABA-containing DMH neurons innervate the VLPO. Through these excitatory and inhibitory projections, the DMH may integrate rhythmic circadian signals with those mediating feeding and stress to help promote wakeful-ness and suppress sleep at the appropriate times of day.

Neurons in the lateral hypothalamus are essential for diurnal variations in sleep and wake-fulness. Neurochemical lesions of the lateral hypothalamus in rats eliminate the nocturnal rise in wakefulness, resulting in 40-50% waking at all times (162). Because these lesions markedly reduce the number of orexin neurons, one might hypothesize that orexin is essential for the timing of sleep/wake behavior. However, this now appears unlikely because orexin knockout mice housed in constant darkness have normal circadian variations in wake, NREM, and REM sleep (108). Although this demonstrates that orexin peptides are not necessary for these rhythms, the "orexin neurons" are still present in these mice and contain other neurotransmitters including dynorphin and probably glutamate (163,164). Studying the behavior of mice lacking the orexin neurons (165) may help resolve this question. Alternatively, the loss of the wake rhythm with LH lesions may reflect injury to an as-yet-undiscovered class of wake-promoting cells.

Humoral factors secreted from the SCN also influence the timing of sleep. SCN-lesioned animals lack circadian rhythms, but rhythms can be restored with SCN transplants. This restoration of rhythmicity does not require synaptic connections because the daily rhythm of locomotor activity can be partially restored with SCN transplants encased in a polymer that blocks the outgrowth of neurites yet allows passage of small molecules (166). These secreted timing factors include transforming growth factor-a (TGF-a) (167) and proki-neticin 2 (PK2) (168). In nocturnal rodents, TGF-a and PK2 expression is high during the day, and infusion of these peptides suppresses locomotor activity. TGF-a and PK2 receptors are expressed in targets of the SCN, including the SPZ and DMH. Chronic infusions of TGF-a block the circadian variation in sleep/wake behavior in a pattern very similar to that seen with lesions of the SPZ. Thus, release of TGF-a and PK2 from the SCN may act on nearby hypothalamic regions to drive the circadian rhythms of locomotor activity and wakefulness.

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