The LC consists of a very small number of noradrenergic neurons (∼1,500 in rat), but it projects widely to almost the entire central nervous system (Berridge, 2008; Sara, 2009). Optogenetic stimulation of the noradrenergic neurons can cause an immediate transition from sleep to wakefulness (Carter et al., 2010). Although Gemcitabine earlier studies suggested that the effect of LC stimulation on cortical activation is indirect (Dringenberg and Vanderwolf, 1998), probably through its projection to the basal forebrain cholinergic circuit, a recent study showed that pharmacological blockage of noradrenergic signaling within the cortex prevents the desynchronization

when the animal is awake (Constantinople and Bruno, 2011), indicating that the intracortical release of noradrenaline is important for the desynchronization. The

histaminergic neurons located click here in the TMN in the posterior hypothalamus show similar projection patterns (Thakkar, 2011). Antihistamine drugs promote sleep, and lesion of the histamine neurons or blockade of histamine synthesis induces hypersomnia (Monti, 1993). The serotonergic neurons in the DRN also project widely to the cortex and subcortical areas. Application of agonists to a variety of 5-HT receptors enhances wakefulness, whereas antagonist application increases sleep (Dugovic et al., 1989; Monti and Jantos, 2008). Genetic knockout of the 5-HT1B receptors also changes the ratio between REM and NREM sleep (Boutrel et al., 1999). Interestingly, all of these monoaminergic neurons fire at high rates during wakefulness, low rates during many NREM sleep, and they virtually stop firing during REM sleep (Aston-Jones and Bloom, 1981; Jacobs and Fornal, 1991;

Kocsis et al., 2006; Steininger et al., 1999; Takahashi et al., 2006, 2010). Thus, these neurons appear to serve similar functions in promoting cortical desynchronization and behavioral arousal (Jones, 2003). The cholinergic neurons in the brainstem are clustered in the pedunculopontine tegmental (PPT) and lateral dorsal tegmental (LDT) nuclei, and they project extensively to the thalamus, hypothalamus, and basal forebrain (Hallanger et al., 1987; Jones and Cuello, 1989; Steriade et al., 1988). These neurons fire at high rates during wakefulness. However, unlike the monoaminergic neurons, which cease firing during REM sleep, the cholinergic neurons are also highly active during REM sleep (Maloney et al., 1999; McCarley and Hobson, 1975; Steriade et al., 1990). Since both wakefulness and REM sleep are associated with desynchronized EEG, activity of these cholinergic neurons appears to be linked to cortical activation but not necessarily behavioral arousal.