This review summarizes the brain mechanisms controlling sleep and wakefulness. Wakefulness promoting systems cause low-voltage, fast activity in the electroencephalogram (EEG). Multiple interacting neurotransmitter systems in the brain stem, hypothalamus, and basal forebrain converge onto common effector systems in the thalamus and cortex. Sleep results from the inhibition of wake-promoting systems by homeostatic sleep factors such as adenosine and nitric oxide and GABAergic neurons in the preoptic area of the hypothalamus, resulting in large-amplitude, slow EEG oscillations. Local, activity-dependent factors modulate the amplitude and frequency of cortical slow oscillations. Non-rapid-eye-movement (NREM) sleep results in conservation of brain energy and facilitates memory consolidation through the modulation of synaptic weights. Rapid-eye-movement (REM) sleep results from the interaction of brain stem cholinergic, aminergic, and GABAergic neurons which control the activity of glutamatergic reticular formation neurons leading to REM sleep phenomena such as muscle atonia, REMs, dreaming, and cortical activation. Strong activation of limbic regions during REM sleep suggests a role in regulation of emotion. Genetic studies suggest that brain mechanisms controlling waking and NREM sleep are strongly conserved throughout evolution, underscoring their enormous importance for brain function. Sleep disruption interferes with the normal restorative functions of NREM and REM sleep, resulting in disruptions of breathing and cardiovascular function, changes in emotional reactivity, and cognitive impairments in attention, memory, and decision making.

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Control of Sleep and Wakefulness

Sleep researchers in different disciplines disagree about how fully dreaming can be explained in terms of brain physiology. Debate has focused on whether REM sleep dreaming is qualitatively different from nonREM (NREM) sleep and waking. A review of psychophysiological studies shows clear quantitative differences between REM and NREM mentation and between REM and waking mentation. Recent neuroimaging and neurophysiological studies also differentiate REM, NREM, and waking in features with phenomenological implications. Both evidence and theory suggest that there are isomorphisms between the phenomenology and the physiology of dreams. We present a three-dimensional model with specific examples from normally and abnormally changing conscious states.

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Dreaming and the brain: toward a cognitive neuroscience of conscious states

Publisher Summary This chapter describes the role of adenosine in brain function Adenosine is an endogenous neuromodulator that influences many functions in the central nervous system (CNS) The levels of adenosine increase when there is an imbalance between the rates of energy use and the rates of energy delivery Increased neuronal activity, and hypoxia or ischemia results in elevated levels of adenosine Adenosine receptors (ARs) were based on the ability of methylxanthines, such as theophylline and caffeine to act as antagonists The two receptors, A1 and A2, inhibit and stimulate adenylyl cyclase respectively The functions of ARs include: (1) regulation of nerve activity, (2) regulation of transmitter release, (3) interaction with other transmitter systems, and (4) various other functions Increased extracellular adenosine in response to ischemia and hypoxia acts as a neuro-protectant during cerebral ischemia and other neuronal insults ARs (A 1 Rs and A 2A Rs) are expressed at moderate to high levels in the brain areas enriched with dopaminergic innervation, thus providing an anatomical basis for interaction between these neurotransmitter systems Different features of the phenotypes provide clues to the roles of defects in AR genes in human disease The chapter discusses the roles of adenosine A 2A receptors in neurodegenerative disorders and ARs in psychiatric disorders Caffeine is used to improve wakefulness and the main actions of caffeine are mediated by brain ARs Adenosine might be an endogenous regulator of sleep–wake cycles, as adenosine analogs induced a sleep-like state In addition, ARs may play many roles in pathways that contribute to pain Clearly much additional work is needed to pinpoint the sites and mechanisms of action, as well as the roles in chronic pain states

Adenosine and Brain Function

Adenosine and sleep–wake regulation

Neurobiology of REM and NREM sleep.

Enhancement of rapid eye movement sleep in the rat by cholinergic and adenosinergic agonists infused into the pontine reticular formation

Enhancement of rapid eye movement sleep in the rat by actions at A1 and A2a adenosine receptor subtypes with a differential sensitivity to atropine.

Blockade of GABA, type A, receptors in the rat pontine reticular formation induces rapid eye movement sleep that is dependent upon the cholinergic system

Infusion of adenylyl cyclase inhibitor SQ22,536 into the medial pontine reticular formation of rats enhances rapid eye movement sleep.

pontine reticular formation of the rat is capable of inducing long-lasting increases in REM sleep (Bourgin et al., 1995; Marks and Birabil, 1998). These effects are blocked by a previous injection of the non-selective, muscarinic antagonist atropine supporting mediation by muscarinic receptors (Bourgin et al., 1995; Marks and Birabil, 1998). Five different muscarinic receptor subtypes have been cloned and identified, m1-m5 (reviewed in Hulme et al., 1990). Cells in the pontine reticular formation of the rat contain mRNAcoding for the m2, m3 and m4 subtypes of muscarinic receptors (Buckley et al., 1988; Vilaró et al., 1992; Sugaya et al., 1997). The m2 subtype appears to be the most abundant in the region, but m1-m4 receptor proteins, as revealed by immunohistochemistry, are found in the reticular formation of a variety of species (Levey et al., 1991, 1994; Rye et al., 1995; Ray et al., 1999). The muscarinic receptor subtypes mediating effects on sleep/wake behavior in this region of brain are currently unknown. Several approaches have been applied to the investigation of receptor subtype in the induction of REM sleep in the cat (ValazquezMoctezuma et al., 1989; Baghdoyan et al., 1994, 1998; Shuman et al., 1995; Baghdoyan, 1997; Sakai and Onoe, 1997; Baghdoyan and Lydic, 1999), but a paucity of data exist in the model of this phenomenon in rat (Imeri et al., 1994; Baghdoyan, 1997; Ray et al., 1999). In that the different receptor subtypes couple to different effector mechanisms and have differential anatomical distributions (Caulfield, 1993), a knowledge of receptor subtypes mediating muscarinicinduction of REM sleep will be helpful in the identification of brainstem mechanisms subserving this sleep state. Many muscarinic receptor ligands exhibit a concentrationdependent selectivity with respect to their actions at different receptor subtypes (reviewed in Caulfield, 1993; Hulme et al., 1990). Comparison of efficacy among different ligands can be a useful tool to identify the role of different receptors. We now report on the dose-response relationship for inducing elevations in REM sleep by three muscarinic agonists microinjected into the medial pontine reticular formation of the rat. The results are consistent with mediation by multiple muscarinic receptor subtypes in interaction and appear at variance with results obtained in the cat.

C. G. Birabil

Papers

Enhancement of rapid eye movement sleep in the rat by cholinergic and adenosinergic agonists infused into the pontine reticular formation

Enhancement of rapid eye movement sleep in the rat by actions at A1 and A2a adenosine receptor subtypes with a differential sensitivity to atropine.

Blockade of GABA, type A, receptors in the rat pontine reticular formation induces rapid eye movement sleep that is dependent upon the cholinergic system

Infusion of adenylyl cyclase inhibitor SQ22,536 into the medial pontine reticular formation of rats enhances rapid eye movement sleep.

Comparison of three muscarinic agonists injected into the medial pontine reticular formation of rats to enhance REM sleep