What are the systems and neurotransmitters responsible for wakefulness and for the sleep state?
Our contemporary understanding of the endocrine system includes much more neuroendocrinology. The discussion in this chapter highlights the interactions among the cortex, brain stem, hypothalamus, and pituitary. Central nervous system (CNS) accomplishment of sleep–wake changes can be best modeled as flip switches, where neural networks responsible for either state are mutually inhibitory—that is, when one is active, there is inhibition of the other. If the sleep network is active, then the wakefulness network is inhibited. Importantly, sleep is accomplished through the inhibitory influence of primarily one neurotransmitter on the arousal centers, whereas wakefulness is promoted by an arousal system of several nuclei making several neurotransmitters. Transition to sleep is accomplished through wake-inhibiting neurons primarily localized to ventrolateral preoptic (VLPO) nuclei neurotransmitter gamma-aminobutyric acid (GABA). Thus, the transition from wake to sleep is mediated through the release of GABA from VLPO nuclei, inhibiting the arousal system and its thalamocortical projection. If this arousal system, the so-called reticular activating system (RAS), is inhibited, sleep is promoted. Conceptually, sleep control is subdivided into sleep switches, with NREM switches governing NREM sleep and REM switches governing REM sleep. During NREM sleep, forebrain NREM-on neurons are firing; during REM sleep, REM-on neurons are firing. In turn, when transitioning from sleep to wakefulness, the RAS inhibits the VLPO nuclei. As mentioned, RAS contains a series of activating nuclei making different neurotransmitters: dopamine, acetylcholine, serotonin, histamine, orexin, norepinephrine. A good mnemonic for the wake-promoting neurotransmitters is, ‘DASH ON’. Dorsal and ventral routes of the RAS have been identified. The dorsal route is composed of ascending projections through the thalamus to the cortex; the ventral route projects to the posterior hypothalamus and basal forebrain (BF). This ventral route receives inputs from the melanin-hypocretin (orexin) concentrating neurons in the lateral hypothalamus or cholinergic neurons of the BF. There are also RAS projections down the spinal cord for muscular tone and postural control. Even though these tiny tufts of neurons with their respective neurotransmitters are known as specific nuclei , their visualization evades current clinical imaging techniques.