, 2001, Sehgal et al., 1994 and Vitaterna et al., 1994) inhibit their own transcription, resulting in oscillatory gene expression ( Allada et al., 1998, Darlington et al., 1998 and Rutila et al., 1998). Transcriptional clocks operating throughout the

body are synchronized by pacemaker neurons in the brain ( Welsh et al., 1995 and Yoo et al., 2004). These neurons and the signals they emit in order to entrain subordinate oscillators have been identified in several species. For examples, the pigment-dispersing factor (PDF)-expressing lateral neurons in Drosophila impose their rhythm through the timed release of the neuropeptide PDF ( Ewer et al., 1992, Renn et al., 1999 and Siwicki et al., 1988); clock neurons in the suprachiasmatic nucleus of mammals ( Lehman et al., 1987 and Ralph et al., 1990) communicate with peripheral oscillators by secreting a variety of peptides,

including buy Palbociclib transforming growth factor α ( Kramer et al., 2001), prokineticin 2 ( Cheng et al., 2002), and cardiotrophin-like cytokine ( Kraves and Weitz, 2006). Many pacemaker neurons display daily variations in electrical activity that are influenced by, and influence, the molecular clock ( Cao and Nitabach, 2008, Nitabach et al., 2002 and Welsh et al., 1995). By comparison, very little is known about the neural mechanisms of sleep homeostasis. Although genetic analyses have begun to identify loci that affect homeostatic sleep control in flies (Bushey et al., 2009, Ishimoto and Afatinib chemical structure Kitamoto, 2010, Koh et al., 2008 and Shaw et al., 2002), mice (Franken et al., 2001 and Kapfhamer et al., 2002), and humans (Viola et al., 2007), these analyses have not yet unearthed a Rosetta Stone until akin to period. Several studies have implicated clock components also in sleep homeostasis ( Naylor et al., 2000, Shaw et al., 2002 and Viola et al., 2007), but it remains unclear whether these genes influence circadian

and homeostatic processes independently or through shared pathways. Some of the genes linked specifically to sleep homeostasis, such as molecular chaperones ( Shaw et al., 2002), components of steroid signaling systems ( Ishimoto and Kitamoto, 2010), or unidentified quantitative trait loci ( Franken et al., 2001), lack unique or well-defined roles in neuronal physiology that could point to particular regulatory mechanisms. Still others, such as modulators of potassium currents ( Koh et al., 2008), Ca2+-regulated synaptic vesicle release ( Kapfhamer et al., 2002), or synaptogenesis ( Bushey et al., 2009), hint that sleep homeostasis—like many other forms of information processing in the nervous system—might involve changes in electrical activity or synaptic communication. However, there has been no indication of the specific nature of these changes, the sites where they occur, or their mechanistic relationship to sleep control.