Interactions Between the Biological Clock and the Sleep Switch

The suprachiasmatic nucleus (SCN) in the anterior hypothalamus is also referred to as the biological clock, since it acts as a major pacemaker in the mammalian brain to drive various circadian rhythms. One important feature of circadian rhythmicity is the sleep-wake cycle, which is greatly influenced by signals originating in the SCN. In spite of the close relation between the circadian timing and sleep-wake regulating systems, their physiological, anatomical, and possibly humoral, interconnections have started only recently to be elucidated (for reviews, see Pace-Schott and Hobson 2002; Saper, Scammell, and Lu 2005).

Transitions between sleep and wakefulness have to be rapid and flawless. Such transitions have been suggested to be controlled by wake-promoting and sleep-promoting nuclei in the hypothalamus and brainstem that are mutually inhibitory, forming a bistable switch that ensures rapid transitions between sleep and wakefulness with no in-between states (Saper et al. 2005).

On one leg of the seesaw switch (Fig. 4.1), are the wake-promoting neural centers, such as histaminergic tuberomammillary nucleus (TMN) in the posterior hypothalamus, and the serotoninergic dorsal raphe nucleus (DRN), and noradrenergic locus coeruleus (LC) in the brainstem. At all these sites, neurons fire during wakefulness, but slow down or stop firing during slow-wave sleep and rapid eye movement (REM) sleep, respectively. On the other leg of the seesaw, these wake-promoting groups of neurons are counteracted by a sleep-promoting cell group, which is located in the ventrolateral preoptic nucleus (VLPO). The GABA- and galanin-containing inhibitory VLPO neurons project to wake-promoting groups of neurons (TMN, DRN, and LC), and are therefore thought to suppress arousal when activated. Thus, they can switch a wake state into a non-REM sleep state. The VLPO in turn is thought to be inhibited during wakefulness by the wake-promoting neurons through their anatomical input. The TMN neurons contain, in addition to the excitatory histamine, also GABA and galanin (Haas and Panula 2003) which could both inhibit the VLPO; an inhibitory function could also be played by serotonin in the DRN and noradrenaline in LC neurons (Pace-Schott et al. 2002).

Figure 4.1. Transmission of circadian signals to components of the sleep switch, depicted as the flip-flop model proposed by Saper et al. (2005). Circadian signals from the SCN to sleep-regulatory nuclei are relayed via the ventral SPZ and the DMH. During wakefulness (A), the DMH is active and a subset of DMH neurons excites the orexinergic neurons in the LH, while a GABAergic subset of DMH neurons instead inhibits the VLPO. Orexinergic cells activate the wake-promoting monoaminergic nuclei (TMN, DRN, LC), which also inhibit the VLPO thereby stabilizing the awake state. During sleep (B), the VLPO inhibits the LH and the monoaminergic nuclei, and this releases the VLPO from the inhibition exerted by monoaminergic nuclei. Excitatory connections are shown as arrows and inhibitory connections as blunt ends. Dashed lines indicate some of the anatomical interconnections, that are yet of unclear functional significance, between the biological clock and sleep switch structures.

Figure 4.1. Transmission of circadian signals to components of the sleep switch, depicted as the flip-flop model proposed by Saper et al. (2005). Circadian signals from the SCN to sleep-regulatory nuclei are relayed via the ventral SPZ and the DMH. During wakefulness (A), the DMH is active and a subset of DMH neurons excites the orexinergic neurons in the LH, while a GABAergic subset of DMH neurons instead inhibits the VLPO. Orexinergic cells activate the wake-promoting monoaminergic nuclei (TMN, DRN, LC), which also inhibit the VLPO thereby stabilizing the awake state. During sleep (B), the VLPO inhibits the LH and the monoaminergic nuclei, and this releases the VLPO from the inhibition exerted by monoaminergic nuclei. Excitatory connections are shown as arrows and inhibitory connections as blunt ends. Dashed lines indicate some of the anatomical interconnections, that are yet of unclear functional significance, between the biological clock and sleep switch structures.

The sleep switch is influenced by the SCN through indirect polysynaptic pathways, and also to some extent through direct, though relatively sparse, connections

(Fig. 4.1). The main bulk of SCN efferents terminate within the hypothalamus, targeting especially the subparaventricular zone (SPZ) and the dorsomedial nucleus of the hypothalamus (DMH). These areas integrate SCN-derived signals with noncircadian signals, and convey information to downstream target nuclei, which are involved in the circadian regulation of feeding, body temperature, sleep, and corticosteroid release. The DMH plays a key role in sleep regulation, and lesions of the DMH cause altered circadian rhythms in sleep-wakefulness behavior (Chou, Scammell, Gooley, Gaus, Saper, and Lu 2003). The DMH projects to all components of the sleep switch, as well as to the lateral hypothalamus (LH), which is the exclusive site of neurons containing the peptide orexin. In addition, the SCN has some sparse direct projections to the TMN and the VLPO (Abrahamson and Moore 2001; Chou, Bjorkum, Gaus, Lu, Scammell, and Saper 2002).

Orexin-containing neurons could play a strategic role in the cross talk between the circadian system and the sleep switch. Orexin exists in two forms (orexin-A and orexin-B, also known as hypocretin-1 and hypocretin-2), which are derived from the same precursor (prepro-orexin) and are colocalized in the same neurons. Orexin release in the cerebrospinal fluid has a daily oscillation which is under SCN control (Zhang et al. 2004). Besides other physiological functions, orexin has been especially implicated in arousal (review in Sutcliffe and de Lecea (2002)). In particular, orexin is suggested to stabilize the sleep-switch by activating the TMN and the other wake-promoting nuclei, thereby preventing untimely transitions from wakefulness to sleep. The orexin-containing neurons receive sparse direct innervation from the SCN, and are targets of polysynaptic pathways relayed via intrahypothalamic targets of SCN efferents, which, as mentioned above, are represented by the SPZ and DMH, and also include the median preoptic area (Abrahamson, Leak, and Moore 2001; Aston-Jones, Chen, Zhu, and Oshinsky 2001; Chou et al. 2003). Through indirect projections via hypothalamic relays, the SCN, therefore, reaches both sleep-promoting preoptic nuclei and wake-regulatory cell groups.

Recent physiological evidence indicates that sleep states can alter the activity of the SCN, indicative of a feedback mechanism (Deboer, Vansteensel, Detari, and Meijer 2003). The anatomical pathways involved in this circuit remain, however, to be determined. The homeostatic sleep process can also feed back on the orexin-containing cells in the LH, indicating that sleep homeostatic and circadian signals converge on these cells (Deboer et al. 2004).

In addition to the switch which regulates sleep-wakefulness described above, a putative switch for the regulation of REM/non-REM sleep has been recently identified in defined brainstem structures (the sublaterodorsal nucleus, the precoeruleus nucleus, lateral pontine tegmentum, and the periaqueductal grey matter) (Lu, Sherman, Devor, and Saper 2006).

Furthermore, the potential role of diffusible factors on sleep switch structures is of special interest in the context of inflammatory signaling. Besides classical synaptic transmission, there is now substantial evidence that the SCN can regulate state-dependent behavior also via diffusible molecules reviewed in Mistlberger (2005). The two candidate molecules discovered so far are transforming growth factor (TGF)-a and prokineticin-2, which are expressed in the SCN. A remarkable finding is that astrocytes are the source of TGF-a in the SCN (Li, Sankrithi, and Davis 2002), thus implicating glial cells in diffusible outputs of the biological clock. In view of the main role played by activation of glia (both astrocytes and microglia) in inflammatory signaling, diffusible factors released by SCN glia could potentially play an important role in inflammatory conditions. This is an unexplored issue that remains open for future investigations.

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