I

Stage 3: Deep sleep

Stage 4: Deep sleep V (more intense)

Slow-wave/delta sleep

Stage 5: REM

Figure 1 Normal nocturnal sleep cycle. NREM, non-rapid eye movement; REM, rapid eye movement.

stages with a combined duration of 20-40 min that is referred to as slow wave sleep (SWS) or delta sleep. The early stages of NREM repeat prior to the onset of REM. As sleep progresses, each successive cycle differs from the preceding one in terms of duration and NREM-REM organization. The last cycle is usually the longest with SWS tending to diminish significantly in the last cycle. Stage 5, the final stage, is the REM phase (dream, paradoxical, or desynchronized sleep). Sleep architecture refers to the amount and distribution of the individual sleep stages, e.g., minutes of REM and NREM sleep.

6.06.1.5 Overview of Sleep Physiology and Pharmacology

Sleep and wake states are evaluated using three physiological variables: EEG, EOG, and EMG. Functional neuroimaging can also be used to probe sleep-wake physiology and metabolic processes, particularly those in deep brain structures. EEG expression of sleep-wake activity results from the synchronization/desynchronization of the thalamocortical circuitry.

Sleep is normally tightly regulated, playing a critical role in mammalian homeostasis.9 Over the last two decades, considerable information has accumulated regarding the neuroanatomical structures and neurotransmitter systems involved in sleep-wake physiology.10'11 Sleep is controlled via the ventrolateral preoptic nucleus (VLPO) with wake being controlled via the hypothalamus (Figure 2).12 While the brainstem (ascending reticular activating system) and thalamocortical system have been historically viewed as being dominant in sleep physiology, the hypothalamus is now recognized as the key anatomical center for sleep regulation. Hypothalamic sleep regulating systems interact with the endogenous circadian pacemaker, the superchiasmatic nuclei (SCN) lying just above the optic chiasm (Figure 2). The SCN is sensitive to photic stimuli relayed from the retina via the retinohypothalamic tract that is distinct from the visual transduction pathway.

The SCN modulates sleep-wake cycles with a 24 h circadian rhythm synchronized by a variety of stimuli including light and melatonin and regulated by specific clock genes.13,14 The SCN also generates signals that: (1) oppose or (2) initiate sleep drive, the latter a function of the time an individual remains awake, and thus, the greater that the circadian signal exceeds sleep drive, the greater will be the wake propensity.15

6.06.1.5.1 Wake promotion

The wake/sleep systems broadly represent counterelements of the 'sleep switch,' a hypothalamic circuit sustaining either a state of wake or sleep, with either system inhibiting the other when active. Wake is sustained through excitatory activity in wake promoting structures in the hypothalamus and brainstem. These include the locus ceruleus, dorsal raphe, tuberomammillary nucleus (TMN) and the laterodorsal tegmental and pedunculopontine tegmental nuclei (PPT/LDT) in the pons.

6.06.1.5.2 Sleep promotion

Multiple inhibitory neuronal projections from the VLPO innervate wake-promoting systems to directly suppress wake-promoting nuclei via g-amino-butyric acid (GABA) and galanin systems. The sleep switch functions as an on/off switch with negligible intermediate physiological states between sleep and wake. Sleep-wake control represents a reciprocal interaction between brainstem monoaminergic and cholinergic systems, with the paracrine neurotransmitter adenosine mediating sleep homeostasis/need, with levels in the basal forebrain increasing during the wake period, as compared to sleep-inhibiting cholinergic neurons activated during wake thus promoting the sleep state.12,16

6.06.1.6 Neurotransmitter Systems

Many neurotransmitter candidates are involved in regulating sleep and wake/arousal, the primary of which include: norepinephrine (NE), serotonin (5HT), histamine (HIS), and dopamine (DA).10,11 During wake, neurons sensitive to these neurotransmitters are activated inhibiting the sleep-promoting neurons of the VLPO. Additional neurotrans-mitter systems involved in sleep-wake include: orexin/hypocretin (Ox/Hcrt), acetylcholine (ACh), adenosine (Ado), melatonin (MT), glutamate (Glu), and GABA.10 During wake and arousal, ACh, NE, HIS, and orexin neurons are active decreasing during the SWS phase, being quiescent during REM sleep except for ACh neurons which discharge at a high rate during the REM stage. GABAergic neurons act in an opposite manner to those involved in arousal. Interactions between these various neurotransmitters are complex and perhaps redundant, reflecting the importance of sleep homeostasis for survival. It is only in the past decade that research tools and systems have been available to begin to dissect the pharmacology and pathophysiology of sleep. The only unambiguous data is for adenosine as the endogenous sleep-inducing agent.12

Thalamus Cortical activation Sleep spindle EEG synchronization

Hypothalamus Sleep/wake switch

Brainstem Ascending cortical activation REM/SWS switch

Hypothalamus Sleep/wake switch

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