REVIEW ARTICLE What are the mechanisms activating the sleep-active neurons located in the preoptic area? Pierre-Hervé LUPPI and Patrice FORT UMR5167 CNRS, Institut Fédératif des Neurosciences de Lyon (IFR 19), Université de Lyon, Lyon, France Abstract The purpose of this review is to outline the mechanisms responsible for the induction and mainte- nance of slow-wave sleep (SWS, also named non–rapid eye movement or non-REM sleep). The latest hypothesis on the mechanisms by which cortical activity switches from an activated state during waking to a synchronised state during SWS is presented. It is proposed that the activated cortical state during waking is induced by the activity of multiple waking systems, including the seroton- ergic, noradrenergic, cholinergic and hypocretin systems located at different subcortical levels. In contrast, the neurons inducing SWS are mainly localized in the ventrolateral preoptic (VLPO) and median preoptic nuclei. These neurons use the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). The notion that the switch from waking to SWS is due to the inhibition of the waking systems by the VLPO sleep-active neurons is introduced. At the onset of sleep, the sleep neurons are activated by the circadian clock localized in the suprachiasmatic nucleus and a powerful hypnogenic factor, adenosine, which progressively accumulates in the brain during waking. Key words: benzodiazepine, caffeine, hypnotics, hypothalamus, insomnia, non-REM sleep. NEURONAL NETWORKS RESPONSIBLE FOR SLEEP ONSET AND MAINTENANCE The localization of the sleep center in the preoptic area The neuropathologist von Economo was the first to report that damage to the preoptic area (POA) induced insomnia in humans and to propose that this region produces sleep. 1 Then, Ranson 2 in monkeys, Nauta 3 in rats and McGinty in cats 4,5 showed that POA lesions induced a profound and persistent insomnia. Further, electrical stimulation of the POA induces EEG slow- wave activity and the onset of slow-wave sleep (SWS). 6 Finally, neurons displaying an elevated discharge rate during SWS compared to waking (W) were recorded over a large forebrain area covering the horizontal limb of the diagonal bands of Broca, the substantia innomi- nata and POA. 7–9 More recently, using c-Fos as a marker of neuronal activation in rats having slept for a long period before sacrifice, it has been reported that sleep-active (c-Fos+) neurons are more densely packed within a small neu- ronal core named the ventrolateral preoptic nucleus (VLPO) than in these forebrain areas. 10 Additional c-Fos+ neurons were later observed after sleep recovery within the median preoptic nucleus (MnPn), adjacent to VLPO. 11 It was further shown that the density of c-Fos+ neurons in the VLPO and MnPn was positively corre- lated with sleep quantity and sleep consolidation during the last hour preceding sacrifice. In addition, numerous Correspondence: Dr Pierre-Hervé Luppi, UMR5167 CNRS, Faculté de Médecine RTH Laennec, 7, Rue Guillaume Paradin, 69372 LYON cedex 08, France. Email: krueger@vetmed.wsu.edu Accepted 11 July 2010. Sleep and Biological Rhythms 2011; 9 (Suppl. 1): 59–64 doi:10.1111/j.1479-8425.2010.00464.x 59 © 2011 The Authors Sleep and Biological Rhythms © 2011 Japanese Society of Sleep Research