The energy hypothesis of sleep revisited
Introduction
Sleep has been investigated for over a century. Yet, the fundamental question of why we need to sleep remains unanswered. In particular, what physiological functions are fulfilled by sleep? One hypothesis is that sleep is necessary to replenish energy stores in the brain that are depleted during wakefulness. This theory posits that during waking, a relatively active metabolic period in the brain, energy stores become progressively diminished, thereby promoting sleep. During sleep, there is recovery of energy stores and thus restoration of energy balance.
Based on this concept Benington and Heller (1995) proposed that the energy-related substrates glycogen and adenosine are key sleep regulators. They suggested that alterations in astrocytic glycogen and extracellular adenosine in the brain both reflect metabolic alterations that occur during wakefulness and sleep and can influence the amount and quality of subsequent sleep. In particular, this model proposes that glycogen depletion during wakefulness leads to an increase in extracellular adenosine, which facilitates sleepiness and influences delta power during sleep, a measure of sleep homeostasis (Borbely and Achermann, 1999).
This hypothesis led to extensive studies and, over the ensuing years, numerous studies have examined, in relation to sleep and wakefulness, the role of glycogen and adenosine in addition to other aspects of regulation of brain energetics. We review the recent studies on adenosine and glycogen and place them in the context of earlier studies and Benington and Heller’s formulation of the energy hypothesis of sleep. We also discuss changes in other aspects of energy regulation in the brain with wakefulness and sleep. In particular, we discuss new information on the electron transport chain, AMP-activated protein kinase, NPAS2 and clock, uncoupling proteins, reactive oxygen species, and the unfolded protein response. We believe that available evidence does support the notion that wakefulness provides an energetic challenge to the brain, and one of the functions of sleep is to allow for recovery from this energy-challenged state, thereby allowing needed synthetic processes in the brain to occur during sleep. The Benington–Heller hypothesis has been fruitful in terms of stimulating research. The situation is, however, more complex than they proposed.
Section snippets
Adenosine
The production of adenosine has been linked to energy depletion. As the major cellular energy molecule ATP is depleted, the byproduct, AMP, is produced. AMP can be further metabolized to adenosine. Therefore, an increase in adenosine may reflect increased degradation of ATP, and a net decrease in the availability of cellular energy stores (Fig. 1).
One of the proposed functions of sleep is to replenish energy stores in the brain that are depleted during wake. This theory would, therefore,
Conclusion
The Benington–Heller hypothesis stimulated a lot of useful research. While it has turned out to be an oversimplification, this does not detract from its value in providing a focus to investigate the role of energy utilization in determining sleep/wake states. As proposed, there is increasing evidence that adenosine does act to promote sleep. There are, however, questions about whether changes in adenosine with wakefulness reflect altered cellular energy states. The elaboration of the
Acknowledgements
We would like to thank Daniel Barrett and Jennifer Montoya for help in preparation of this manuscript. This research was supported by the National Institute of Aging Grant AG-17628 and National Heart, Lung, and Blood Institute Grants HL-60287 and HL-07953.
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