, 1998). During recovery sleep after 12 hr of sleep deprivation, the slow wave power in the EEG and the firing of VLPO neurons both approximately double. On the other hand, the firing of VLPO neurons does not increase during prolonged wakefulness. Thus, as homeostatic sleep drive accumulates, it may influence other neurons in the brain, such as the median preoptic neurons, which provide input to the VLPO (Chou et al., 2002 and Gvilia et al., 2006), but VLPO neurons do not fire until the state transition itself (Takahashi et al., 2009). This fundamental property of VLPO neurons is consistent with their role in causing rapid and complete state transitions. A second major

influence on sleep state switching is the input from the circadian system ( Achermann and Borbély,

2003 and Borbély Selisistat ic50 and Tobler, 1985). In mammals, daily rhythms are driven by the suprachiasmatic nucleus (SCN) in the hypothalamus, a key pacemaker that influences the timing of a wide range of behaviors and physiological events. SCN neurons are intrinsically rhythmic and drive behavioral responses with a roughly 24 hr period, even in complete darkness. This rhythmicity is generated by a network of transcriptional/translational/posttranslational feedback loops that regulate the expression of clock genes ( Jin et al., 1999 and Reppert and Weaver, 2002). The clock genes are themselves transcription factors that regulate the expression of hundreds if not thousands of other genes. The activity of the SCN is entrained to the daily light-dark http://www.selleck.co.jp/products/MG132.html cycle by inputs from intrinsically photosensitive retinal ganglion cells that express the photopigment melanopsin ( Gooley et al., 2001 and Hattar for et al., 2002). Lesions of the SCN, or disruption of expression of key clock genes, results in loss of most circadian rhythms ( Bunger et al., 2000, Edgar et al., 1993 and Moore and Eichler, 1972). Surprisingly, the SCN has very little direct output to either the wake

or sleep regulatory systems (Watts et al., 1987). Instead, the bulk of its projections run into the subparaventricular zone, a region just dorsal and caudal to the SCN. Cell-body-specific lesions of the ventral subparaventricular zone nearly eliminate the circadian rhythms of sleep and wakefulness, suggesting that neurons in this region are necessary for conveying these output signals (Lu et al., 2001). However, the ventral subparaventricular neurons have few direct outputs to either wake or sleep networks. Instead, they send axons to the dorsomedial nucleus of the hypothalamus (Chou et al., 2003 and Deurveilher and Semba, 2005). The dorsomedial nucleus contains GABAergic neurons that heavily innervate the VLPO and glutamatergic neurons that innervate the lateral hypothalamic area, including the orexin neurons (Chou et al., 2003 and Thompson et al., 1996).