Somatic theories of sleep function

Sleep has historically been thought of as a time when our body reverses the wear and tear of wakefulness; but is sleep fundamentally concerned with somatic functions? As reviewed by Akerstedt and Nilsson, mortality rates in short and long sleepers do indicate a link between sleep and physical well-being [46]. Individuals who sleep much more or much less than average have higher mortality rates and greater incidences of myocardial infarction and type 2 diabetes [46]. Sleep also appears to be vital for animals because prolonged sleep deprivation is fatal in rats and fruit flies [47-50]. Although the precise cause of death is not linked to a specific organ or neural pathology in these studies, it does not appear to be due to the stress of the sleep deprivation procedure [48,49,50, 51,52,53,54]. How then, does sleep influence the body and what evidence is there that this is a core function of sleep?

Endocrine systems, metabolism, and sleep

One possible explanation for the link between sleep and physical health is that sleep regulates metabolic/ endocrine systems that control energy balance in the body [44,55,56,57,58]. NREM sleep is associated with increases in growth hormone (GH) release, and substances which increase GH concentrations in the brain (in some studies) increase NREM sleep [46,55,56]. NREM sleep is also associated with a suppression of the hypothalamic-pituitary-adrenal (HPA) axis, and it is believed that an interplay between growth hormone-releasing hormone (GHRH) and corticotropin-releasing hormone (CRH) influences the quality of sleep [46,55,56]. More recently, it has been shown that prolonged total sleep deprivation in rodents reduces thyroid hormone levels and the pulsatile release of GH and prolactin that normally occurs during NREM sleep [52]. A very intriguing series of studies also shows that simply curtailing sleep in humans increases the risk for diabetes, and negatively impacts blood glucose metabolism [8]. In addition, anatomical and transgenic studies in rodents have revealed interactions between peptides important in feeding and satiety (ghrelin and leptin, respectively), and areas of the brain that control sleep/wake expression [58]. For example, studies in mice and rats indicate that leptin and ghrelin interact with hypocretin- and melanin-concentrating hormone (MCH)-containing neurons in the lateral hypothalamus, which in turn regulate arousal and sleep (reviewed in [58]).

Despite these findings, it is still unclear if a core function of sleep is to regulate metabolic/endocrine biology. Shorter periods of sleep deprivation (24-72 hours) only modestly affect organ function, athletic performance, and recovery from exercise [59-61]. With respect to interactions between sleep and the endocrine system, the close correlation between GH release and NREM sleep is not universally found in other vertebrates. For example, only faint associations between GH release and sleep are observed in rodents [62]. Non-human primates display strong circadian rhythms in corticosterone release, but no association between GH release and NREM sleep [63,64]. Even in humans the reduction in pulsatile GH release by sleep deprivation can be compensated for by large pulses that occur during wakefulness [65]. The effects of exogenous GH, somatostatin, or blockade of GHRH receptors on mammalian sleep expression are also quite variable, with some studies showing no effects [66-69].

Some of the other changes in human metabolism observed after sleep deprivation appear to be strongly influenced by circadian mechanisms or may reflect side-effects of sleep deprivation rather than sleep per se. For example, cortisol release is under circadian control [9], is known to increase after sleep deprivation [70], and has been linked to some of the metabolic disturbances reported after sleep deprivation [71]. Sleep deprivation is also known to reduce cortical metabolism [72], which may contribute to elevated blood glucose following restricted sleep [8]. If indeed the fundamental purpose of sleep is to regulate blood glucose, using the brain as a glucose "sponge" seems a rather inelegant way to do it.

The evidence that sleep is principally concerned with food intake is likewise less than straightforward. As is true for changes in hormones, it is not clear if the cycling of leptin and ghrelin in humans reflects the influence of sleep, or independent circadian rhythms in the release of these peptides [8]. Studies in rodents have produced mixed results. The putative associations between leptin and ghrelin release and sleep observed in humans do not occur in rats [73]. Constitutive knock-out of leptin (ob/ob) [74] or leptin (db/db) receptors [75] in mice results in abnormal sleep patterns (increases in NREM sleep, sleep fragmentation), but it is not clear if these changes are secondary to other abnormalities, developmental or otherwise, in these mouse lines. For example, ob/ob mice do not thermoregulate normally [74], and ob/ob and db/db mice both display abnormal levels of motor activity [74,75]; either abnormality would be expected to impact sleep expression, if only indirectly. Ghrelin knock-out mice display even fainter sleep phenotypes, displaying modest increases in NREM sleep time versus wild-type mice both in the baseline and following recovery from sleep deprivation [76]. The effects of knocking out melanin-concentrating hormone (MCH) or the MCH type 1 receptor (MCH R1) are also inconclusive. MCH knock-out mice are hyperactive (with a corresponding reduction in sleep time), but show normal compensatory changes in sleep following sleep deprivation [77]. MCH R1 knock-outs, however, show no hyperactivity, an increase in REM sleep amounts, and a small increase in the homeostatic response to sleep deprivation [78]. As is true for other constitutive knock-out mice, it is unknown how many of these changes are due to developmental compensation or other indirect effects of the absent gene.

Immune function

There appear to be stronger and more direct links between sleep and the immune system [45,56,57]. Bacterial and viral infection in animals and humans are known to increase NREM sleep time via the release of several immune factors (primarily cytokines). Importantly, some of these effects appear to reflect direct modulation of sleep/wake areas of the brain rather than indirect effects of fever [45,56,57]. Exogenous administration of cytokines like tumor necrosis factor (TNF) and interleukin 1B (IL-1B) also increase NREM sleep amounts, while antagonists of these cytokines or their receptors reduce sleep time. In addition, the endogenous release of TNF and IL-1B levels is highest during the normal rest phase in rodents [56,57], and in contrast to molecular deletion of feeding/satiety peptides, knockout of several immune factors leads to pronounced alterations in sleep/wake expression and sleep homeostasis [79,80].

As is true for endocrine/metabolic and sleep interactions, a number of issues must be resolved before one can conclude that sleep's primary function concerns immune biology. First, it has not been definitively shown that sleep is necessary for a healthy immune system. Some studies indicate that short periods of sleep deprivation or sleep restriction decrease immune function as measured by changes in cytokines, lymphocytes, immune cell activity, and control of microorganisms [81-85]. In other studies, however, sleep deprivation has negligible effects on immunity, and with continued sleep deprivation, markers of normal immune function return to baseline and, in some cases, are heightened [56,86-89]. In addition, during prolonged sleep deprivation rats given antibiotics still die even though their tissues are free from infection; thus the cause of death cannot be ascribed to compromised host defense [51]. The knock-out mouse studies are intriguing, but once again, these are constitutive gene deletions, and the resulting phenotypes reflect a mixture of compensatory effects as well as absence of the targeted gene. In this regard, it is important to point out that some mice lacking immune peptides are underweight and show disturbances in locomotor activity and abnormalities in temperature regulation [79,80].

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