Hypnogram wake cycle8/30/2023 ![]() ![]() The monoaminergic arousal centers project to the VLPO and may serve to inhibit its activity ( 6). Despite this evidence, it is almost certain that other molecules also play important signaling roles controlling the initiation and maintenance of sleep. Adenosine receptors are expressed in the VLPO and adenosine activates VLPO neurons in vivo ( 5), making it a reasonable candidate for the “sleep switch.” Caffeine and theophylline are potent adenosine receptor antagonists, which may form the basis for their well-known alerting effects. Adenosine accumulates in basal forebrain during wakefulness and diminishes with ongoing sleep ( 4). The molecular “triggers” that activate the VLPO and initiate sleep onset have not been fully defined, but a substantial body of evidence points to extracellular adenosine as a candidate. This is accomplished by inhibitory neurons of the ventrolateral pre-optic area (VLPO Figure 1B), which remain active throughout sleep ( 3). Initiation and maintenance of sleep require suppression of activity in the ascending arousal systems. ACh, acetylcholine DA, dopamine GABA, gamma amino-butyric acid Gal, galanin HA, histamine LDT, laterodorsal tegmentum NE, norepinephrine ORX, orexin PeF, perifornical region PPT, pedunculopontine tegmentum TMN, tuberomammillary nucleus vPAG, ventral periaqueductal gray matter 5-HT, 5-hydroxytryptamine. Panel B shows pathways arising from the hypothalamus that inactivate the ascending arousal system during sleep. Panel A depicts key elements of the ascending arousal systems, with diffuse excitatory projections to the cortex. For example, it is now clear that narcolepsy results from a selective loss of orexin-releasing neurons in the forebrain, accounting for the excessive daytime sleepiness, fragmented sleep, and cataplexy (sudden muscle weakness without loss of consciousness) associated with this disorder.īrain networks regulating sleep and wakefulness. Despite their apparent redundancy, normal behavioral functioning may require all of these arousing systems. ![]() Major neurochemicals of this “ascending arousal system” include excitatory norepinephrine arising from the locus ceruleus (LC), serotonin from the midline raphe nuclei, histamine from the tuberomammillary nucleus, dopamine from the ventral periacqueductal gray matter, acetylcholine from the pedunculopontine tegmentum, and the laterodorsal tegmentum of the pons and orexin from the perifornical area. Generation and Maintenance of Sleep and WakefulnessĪs depicted in Figure 1A, the cortical activation necessary to maintain wakefulness is supported by an extensive network of subcortical structures and pathways. ![]()
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