Physiological reviewThe thermophysiological cascade leading to sleep initiation in relation to phase of entrainment☆
Introduction
The notion that thermoregulation and sleep are interrelated is based on the theory of evolution. There was a convergent evolution for REM sleep and endothermy in mammals and birds, indicating that these parallel developments must have occurred prior to separation of the emerging mammalian and avian lines.1, 2, 3, 4 Based on these observations, some researchers have even deduced causal relationships between induction of sleep (and Slow-Wave-Activity, SWA) and the reduction of core body temperature (CBT).5, 6, 7, 8 The reduction of CBT, which results in energy conservation due to reduced body metabolism, should be the reason why we sleep. However, there is no causality, at least not in humans. We could recently demonstrate that non-REM-sleep and SWA do not influence the thermoregulatory system.9, 10, 11 Nevertheless, this does not mean that the sleep regulatory system and the thermoregulatory system are independent. A further, rather simple, but not meaningless relationship exists, in that all species, independent of whether nocturnal or diurnal in habit, usually sleep or rest during the circadian trough of their CBT rhythm. This observation offers another, inverse explanation, namely, that we rest and sleep when CBT is reduced after heat has been redistributed from the core to the outer layer of the body, the shell. Therefore, heat redistribution from the core to the shell could represent a crucial signal for sleep initiation. Because these thermoregulatory processes are well known to be modulated in a circadian manner, they could additionally serve as an entrainment mechanism for the sleep–wake cycle. Recent findings suggest that the CBT rhythm has internal non-photic zeitgeber properties for the entrainment of multiple peripheral pacemakers distributed all over the body.12(p. 404),13 Based on this, one could consider that increased distal skin temperature in the evening, via enforced skin blood flow, provides a synchronising signal for peripheral circadian oscillators in the extremities. Thermoregulatory heat loss mechanisms could therefore be relevant for ensuring an appropriate phase relationship between the circadian system and the sleep–wake cycle. An important underlying assumption is that phase of entrainment largely determines normal, undisturbed sleep with the criteria of consolidation (sleep continuity) and short sleep onset latency (SOL).14, 15, 16 An abnormal phase of entrainment could thus be a cause of sleep disturbances.14, 15, 16
Sleep is not an isolated phenomenon of the brain alone; sleep is also a behaviour involving the entire body.17, 18 A body that is asleep is in the most relaxed state of normal daily life, and this relaxed state in turn influences the thermoregulatory system, i.e., heat is redistributed from the core to the shell and down-regulates CBT to a lower level.10, 19 Usually this occurs in the evening, when we usually go to sleep, leading to a larger difference between the diurnal maximum and nocturnal minimum values of CBT than without sleep.10, 19, 20, 21, 22, 23, 24 From a functional point of view, it is possible that such an increase of the overt daily amplitude could contribute to entrain a circadian oscillator.25, 26, 27
Organisms are active during the day (diurnal), night (nocturnal) or during twilight (crepuscular). Crepuscular animals, birds and insects can be matinal or vespertine, that is active in the morning or evening, respectively. There are two ways in which this can be manifested. First, by the well-known mechanisms of synchronising the endogenous pacemaker (e.g., light acting on the suprachiasmatic nuclei, SCN), which in turn entrains the rest–activity cycle, and second, by a route that does not directly involve the main pacemaker (so-called masking; e.g., activity, food intake).27, 28 The ‘masking effect’ was first described in experiments with animals.29 Masking complements clock control as a way of helping organisms specialise in a temporal niche.26 Masking in the first place obscures the behaviour of the pacemaker but may eventually influence the phase of the pacemaker via more indirect pathways (feedback mechanisms, e.g., via temperature).13, 27, 28
Section snippets
Regulation of circadian phase and phase of entrainment
The temporal structure of our daily life is under the control of three different clocks: the solar clock, providing light and heat during the day; the social clock, which determines our working and free day schedule16; and the biological (circadian) clock, which is essential for timing of physiological processes across the 24 h, such as activity and sleep, release of hormones and blood constituents, etc.30, 31 The central circadian clock is localised in the SCN of the hypothalamus; recently
Phase of entrainment in relation to sleep disturbances
In the entrained human circadian system under normal daily life situations, CBT exhibits a maximum in the late afternoon, and a minimum towards the end of the sleep episode. This phase relationship between the sleep–wake cycle and the CBT rhythm (phase of entrainment, Ψ) can be changed by means of zeitgebers, e.g., light. In general, Ψ is dependent on how much and in what direction the endogenous τ deviates from the 24-h solar cycle, that is, how much the daily light signal has to advance or
Homeostatic regulation of CBT
In order to understand circadian regulation of the CBT rhythm, it is important to elucidate first how CBT is homeostatically regulated. There is substantial evidence indicating that homeostatic regulation of CBT is controlled by a hierarchically organised set of neuronal mechanisms, with the pre-optic-anterior-hypothalamus (POAH) as the most important control centre.53, 54 In addition to homeostatic regulation, a rostral projection from the circadian pacemaker localised in the SCN to the
Circadian regulation of CBT
All the thermoregulatory mechanisms described above are also involved in the circadian regulation of CBT. The circadian CBT rhythm is a well-described thermophysiological phenomenon in many animals, as well as humans. The first publication of a daily record of CBT in humans already appeared in the middle of the 19th century by Gierse in the form of a thesis.77 He could show that his own oral temperature revealed a maximum temperature in the early evening and a minimum in the early morning hours
Relationship between thermoregulation and sleepiness/sleep regulation
We have shown that SOL is dependent on DPG level ca. 90 min before lights off. We usually choose our sleep times (lights off) when DPG levels are ca. −1 °C or higher (Figure 6). High DPG has been established as a good predictor for short SOL.10, 19, 86
Many appetitive behaviours preceding sleep are known to promote sleep, and they also influence the thermoregulatory system, such as lying down,87, 88, 89 relaxation, searching for a comfortable thermic environment (using bed socks, bedcovers, etc.;
Acknowledgements
I am grateful to Anna Wirz-Justice for her helpful comments to the manuscript and her excellent continuing support. Our work is supported by the Swiss National Science Foundation (#3100A0-102182/1 & #3130-3054991.98/3100-055385.98), the Schwickert-Stiftung, the 6th European Framework Programme EUCLOCK (018741) and the Daimler-Benz-Stiftung project CLOCKWORK.
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Dedicated to Anna Wirz-Justice in recognition of her contributions to the field made during her career at the Psychiatric University Clinics Basel.
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