, 2005a). Lesion of the basal forebrain can cause a dramatic increase of EEG delta waves during wakefulness (Berntson et al., 2002; Buzsáki et al., 1988; Fuller et al., 2011), and combined cholinergic and serotonergic blockade completely prevents cortical desynchronization (Vanderwolf and Pappas, 1980). Conversely, stimulation of the basal forebrain induces cortical desynchronization, which can be observed from both the reduced EEG/LFP power

at low frequencies (Metherate et al., 1992) and the decrease in correlated spiking among cortical neurons (Goard and Dan, 2009) (Figure 3). At the cellular level, the desynchronization is known to depend on the muscarinic ACh receptors (mAChRs) in the cortex, and a modeling CAL-101 clinical trial study (Bazhenov et al., 2002) suggests that this may be mediated by both the suppression of excitatory intracortical connections (Gil et al., 1997; Hsieh et al., 2000; Kimura et al., 1999) and the depolarization of cortical pyramidal neurons (McCormick and

Prince, 1985; Nishikawa et al., 1994). Intermingled with the cholinergic neurons are a large number of GABAergic neurons (up to 60% of all neurons in the basal forebrain/preoptic area). These neurons are likely to play diverse roles in brain state regulation, as some of them are active during wakefulness, while others are active during sleep (Manns et al., 2000; Szymusiak and McGinty, 1989). Several studies have identified groups of GABAergic neurons in the ventrolateral old preoptic area (VLPO) and median preoptic nucleus (MnPO) as sleep-promoting cells (Saper et al., buy Fulvestrant 2005; Sherin et al., 1996; Szymusiak and McGinty, 2008). These neurons are more active during sleep than wakefulness, and lesion of the VLPO causes insomnia (Lu et al., 2000). The projections from VLPO and MnPO to the ascending arousal system and lateral hypothalamus allow them to effectively shut down the activity of the wake-promoting

neurons (Sherin et al., 1998; Suntsova et al., 2007), and neuromodulators from the ascending arousal system can in turn inhibit these sleep-active neurons (Gallopin et al., 2000; Manns et al., 2003). This has led to the proposal of an elegant flip-flop circuit for sleep-wake switches based on the mutual inhibition between the VLPO and ascending arousal system (Saper et al., 2010). Outside of the VLPO and MnPO, however, wake- and sleep-active GABAergic neurons seem largely intermingled in the basal forebrain/preoptic area (Manns et al., 2000; Takahashi et al., 2009). Although several studies in the rat showed that basal forebrain lesion causes behavioral unresponsiveness and EEG synchronization (Berntson et al., 2002; Buzsáki et al., 1988; Fuller et al., 2011), in the cat the lesion was found to induce severe insomnia (Szymusiak and McGinty, 1986). These mixed results may be related to the functional diversity of the basal forebrain neurons.