, 2000 and Thannickal et al., 2000). This finding was quite selective, as the MCH neurons, which are intermingled with the orexin cells, were completely spared, and it probably represented cell loss rather than downregulation of orexin expression as there was concomitant loss of other markers (dynorphin and neuronal activity-related pentraxin) of the orexin cell population (Crocker et al., 2005). The loss of orexins is not due to a simple genetic abnormality, as orexin deficiency is acquired during young adulthood, Selleckchem Screening Library and the vast majority of people with narcolepsy do not have

mutations of the genes encoding the orexin peptides or their OX1 or OX2 receptors (Olafsdóttir et al., 2001 and Peyron et al., 2000). However, because about 90% of people with narcolepsy have human leukocyte antigen DQB1∗0602 (Mignot et al., 2001), researchers have hypothesized that the loss LY2157299 of orexin neurons may be immune-mediated (Lim and Scammell, 2010 and Scammell, 2006). It has recently been proposed that, at least in some individuals, an autoimmune attack on the orexin neurons may be related to antibodies to Tribbles homolog-2, a protein produced by the orexin neurons and other cells in

the brain (Cvetkovic-Lopes et al., 2010 and Kawashima et al., 2010). Several models have been proposed to explain how loss of the orexin neurons results in severe sleepiness. One popular hypothesis is that individuals with narcolepsy may be more sensitive to homeostatic sleep drive as, after a period of sleep deprivation, they fall asleep faster than normal (Tafti et al., 1992a and Tafti et al., 1992b). Mice lacking orexins also tend to fall asleep very quickly after being deprived of sleep, but they recover the lost sleep at a normal rate and to the same extent as wild-type mice (Mochizuki et al., 2004). Thus, orexin deficiency hastens

the transition to sleep, but the accumulation and expression of homeostatic sleep drive appears normal in mice and people with narcolepsy (Khatami et al., 2008 and Mochizuki et al., 2004). Another potential explanation is that circadian waking drive is impaired in narcolepsy. However, this too seems unlikely as mice lacking orexins have normal circadian rhythms of wake and NREM sleep when housed Suplatast tosilate in constant darkness (Kantor et al., 2009 and Mochizuki et al., 2004). A better explanation may be that impaired orexin signaling causes behavioral states to become unstable (Figure 5). In fact, this idea was first raised by Broughton over 20 years ago as narcoleptic people and animals have great difficulty remaining awake, but they also have fragmented sleep and many more transitions between all states (Broughton et al., 1986). This breakdown in the ability to produce cohesive wake and sleep states is consistent with a destabilized switching mechanism.