Abstract
Roughly one-third of the human lifetime is spent in sleep, yet the reason for sleep remains unclear. Understanding the physiologic function of sleep is crucial toward establishing optimal health. Several proposed concepts address different aspects of sleep physiology, including humoral and circuit-based theories of sleep-wake regulation, the homeostatic two-process model of sleep regulation, the theory of sleep as a state of adaptive inactivity, and observations that arousal state and sleep homeostasis can be dissociated in pathologic disorders. Currently, there is no model that places the regulation of arousal and sleep homeostasis in a unified conceptual framework. Adenosine is well known as a somnogenic substance that affects normal sleep-wake patterns through several mechanisms in various brain locations via A1 or A2A receptors (A1Rs or A2ARs). Many cells and processes appear to play a role in modulating the extracellular concentration of adenosine at neuronal A1R or A2AR sites. Emerging evidence suggests that A1Rs and A2ARs have different roles in the regulation of sleep. In this review, we propose a model in which A2ARs allow the brain to sleep, i.e., these receptors provide sleep gating, whereas A1Rs modulate the function of sleep, i.e., these receptors are essential for the expression and resolution of sleep need. In this model, sleep is considered a brain state established in the absence of arousing inputs.
Highlights
Sleep is a highly conserved behavior that is vital to survival among all living organisms with a nervous system, from worms to humans
Activation of A1Rs influences slow wave activity (SWA) by both direct and indirect mechanisms; the direct mechanism is based on presynaptic inhibition of cortical and thalamic neurons, which results in relative functional deafferentation along with an A1R-induced increase in whole cell, GIRK channel conductance and decreased hyperpolarization activated currents (Ih), such that adenosine enhances slow oscillations in thalamocortical neurons (Pape, 1992)
An A2AR agonist post-synaptically excites type-2, but not type-1, neurons. These findings suggest that type-2 neurons are involved in initiating sleep, whereas type-1 neurons may contribute to sleep consolidation, because they are only activated in the absence of inhibitory effects from wake-inducing systems (Gallopin et al, 2005)
Summary
Sleep is a highly conserved behavior that is vital to survival among all living organisms with a nervous system, from worms to humans. The adenosine system can affect the gating of SWS-SWA expression by modulating the arousal level, thereby altering the duration of time during which sleep homeostasis and function can occur.
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