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. 2020 Jun 23;11:520. doi: 10.3389/fneur.2020.00520

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Copyright © 2020 Re, Batterman, Gerstner, Buono and Ferraro.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Examples of factors that promote changes in sleep/wake state and seizure types associated with each sleep/wake state. Mammals have two main cycles: the 24 h sleep/wake cycle and multiple 90 min slow wave sleep (SWS, i.e., NREM)/REM sleep cycles that typically occur within a 6 to 8 h period of sleep/inactivity. The sleep/wake state of an individual is influenced by various levels of endogenous clock products (that oscillate in a circadian rhythm) as well as external stimuli (zeitgebers) and allostatic factors (relate to the regulation and maintenance of sleep homeostasis) that act on the suprachiasmatic nucleus (SCN). Daylight is an example of a zeitgeber. It acts on melanopsin-containing retinal ganglion cells that transmit signals indicating the levels of environmental light (and thus the likely time of day) through the retinohypothalamic pathway to neurons of the SCN (49). Diminishing daylight reduces the inhibitory signaling of SCN projections to the pineal gland, enabling melatonin secretion. The SCN also regulates sustained sleep/wake states, as lesions of the SCN in rodents disrupt circadian rhythms and lead to random short bursts of sleep and wakefulness (50). Influences on flux in the direction of SWS: Arrow 1: adenosine accumulating from daytime glycogen use, increased release of melatonin in the evening and beyond; Arrow 2: adenosine activating ventrolateral preoptic area (VLPO) “sleep” neurons (foot on SWS gas pedal) (51–53), decreased activity of orexinergic neurons, and allostatic factors (e.g., leptin release after large dinner) promoting VLPO firing. Influences on flux in the direction of REM sleep: Arrow 3: glutamate activating the “REM-ON” neurons of the sublaterodorsal nucleus (SLD, foot on REM gas pedal) (54); Arrow 4: decreased excitatory input to REM-OFF neurons of the ventrolateral periaqueductal gray matter (vlPAG, foot off REM brakes); Arrow 5: orexinergic dysfunction (e.g., narcolepsy). Influences on flux in the direction of wakefulness: Arrow 6: adenosine levels diminishing from glycogen regeneration, decreasing melatonin secretion; Arrow 7: VLPO receiving inhibitory input from “wakefulness neurons” including orexinergic neurons in the lateral hypothalamus, noradrenergic (NE) neurons in the locus coeruleus, serotonergic (5HT) neurons in the raphe nuclei, histaminergic neurons of the tuberomammillary nucleus, and cholinergic neurons of the pons, basal forebrain, and medial septum (foot off wake brake), and a lack of excitatory adenosine (foot off SWS gas pedal); arrow 8: diminished firing of NE and 5HT at vlPAG (foot off wake brake); arrow 9: REM-OFF activated by orexinergic, 5HT, and NE neuronal firing (foot on wake gas).